C9.Endocrine system

Endocrine control of physiological functions represents broadly targeted, slow acting but funda-

mental means of homeostatic control, as opposed to the rapidly reacting nervous system. In

endocrine disease there is usually either an excess or a lack of a systemic hormonal mediator,

but the cause may be at one of a number of stages in the endocrine pathway. Thyroid disease

and diabetes mellitus represent contrasting extremes of endocrine disease and its management.

Diabetes is one of the most serious and probably the most common of multisystem diseases.

Optimal control of diabetes requires day-to-day monitoring, and small variations in medication

dose or patient activity can destabilize the condition. Therapy requires regular review and

possible modification. Furthermore, long-term complications of diabetes cause considerable

morbidity and mortality.

Thyroid disease is a disorder of thyroid hormone production that has, compared to diabetes, equally profound overall effects on metabolic and physiological function. However, it causes few acute problems and has far fewer chronic complications. Moreover, management is much easier, requiring less intensive monitoring and few dose changes. Furthermore, control is rarely disturbed by short-term variations in patient behaviour.

Diabetes mellitus

Diabetes

mellitus

is

primarily

a

disorder

of

carbohydrate

metabolism

yet

the

metabolic

problems

in

properly

treated

diabetes

are

not

usually troublesome and are relatively easy to

control.

It

is

the

long-term

complications

of

diabetes that are the main causes of morbidity

and

mortality.

People

with

diabetes

suffer

far

more

from

cardiovascular

and

renal

disease

than other people, and diabetes is the principal

cause of acquired blindness in the West. Most

people with diabetes do not die from metabolic

crises such as ketoacidosis but from stroke, MI

or chronic renal failure.

Diabetes is associated with obesity and lack of

exercise, and the steady increase in prevalence

in the West is being reproduced in large parts of

the developing world as they adopt that life-

style. Diabetes is in danger of becoming almost

pandemic. Particularly worrying is the rise in the

incidence

of

diabetes

of

both

types

in

ever

younger patients. This threatens to put an intol-

erable strain on health services, particularly in

developing countries.

Physiological principles of glucose and insulin metabolism

Insulin action

Insulin

is

the

body’s

principal

anabolic

hormone. It expands energy stores during times

of

adequate

nutrition

against

times

of

food

shortage. Opposing this action are several cata-

bolic ‘counter-regulatory’ or ‘stress’ hormones

that mobilize glucose for use when increased

energy

expenditure

is

necessary.

The

most

important of these are adrenaline (epinephrine),

corticosteroids, glucagon, growth hormone and

growth

factors.

These

two

opposing

systems

work in harmony to maintain glucose home-

ostasis. Insulin also enhances amino acid utiliza-

tion

and

protein

synthesis,

the

latter

action

being shared with growth hormone.

Insulin action has three main components

(Figure 9.1):

•

Rapid: in certain tissues (e.g. muscle), insulin

facilitates the active transport of glucose and

amino

acids

across

cell

membranes, enhancing uptake from the blood.

•

Intermediate:

within

all

cells,

insulin

promotes the action of enzymes that convert

glucose,

fatty

acids

and

amino

acids

into more complex, more stable storage forms.

•

Long-term:

because

of

increased

protein

synthesis, growth is promoted.

One

important

consequence

is

the

prompt

(though not complete) clearance of glucose from the blood after meals. Glucose would otherwise be lost in the urine because of the kidney’s

limited capacity for reabsorbing glucose filtered at the glomerulus.

Glucose transport

Glucose

uptake

into

cells

across

the

cell

membrane is dependent on the concentration

gradient between the extracellular medium (e.g.

blood

plasma,

gastrointestinal

contents)

and

the cell interior. However, because glucose is

such

an

important

metabolite,

there

exist

a

number of membrane transport pumps or facili-

tators in certain tissues. There are special insulin- independent

sodium-dependent

transporters

(SGLT) for uptake from the GIT into intestinal

cells and a variety of insulin-dependent and

insulin-independent glucose transporters (GLUT)

for most other tissues or organs (Table 9.1).

In muscle and adipose tissue the transporter

depends on an insulin-requiring active pump for

glucose uptake, so insulin deficiency deprives

them of glucose. Other cells, particularly in the

liver, brain, kidney and GIT, do not absolutely

require insulin for glucose uptake, but diffusion

is

nevertheless

facilitated

by

it.

In

the

liver,

enhanced

phosphorylation

of

glucose

drives

intracellular concentrations down, encouraging

uptake. Insulin lack does not deprive tissues such

as these of glucose; on the contrary, the hyper-

glycaemia associated with diabetes can produce

intracellular glucose overload, and this may be

responsible for some diabetic complications (p.

593). This is particularly relevant to tissues such

as nerves, which are freely permeable to glucose.

Insulin also facilitates the uptake of amino acids into liver and muscle, and of potassium into most cells. This latter effect is exploited therapeutically

for

the

rapid

reduction

of hyperkalaemia (see Chapter 14).

Metabolic effects

By facilitating certain enzymes and inhibiting

others, insulin has wide-ranging effects on inter-

mediary metabolism in most tissues (Table 9.2;

Figure 9.1). The synthesis of the energy stores

(glycogen in liver and skeletal muscle, fat in liver

and adipose tissue) is facilitated, and their break-

of glucose and insulin metabolism

583

down is inhibited. Tissue growth and cell divi-

sion are also promoted by enhanced nucleic acid (DNA, RNA) synthesis, amino acid assimilation and protein synthesis.

Overall effect

Only a general appreciation of how insulin and the catabolic hormones control everyday meta-

bolic variations is given here (see also References and further reading).

Anabolic actions of insulin

Following a meal, glucose is absorbed from the GIT into the blood and rapidly transported into the cells, to be converted into forms suitable for storage and later use.

In the liver some glucose is converted into

glycogen and stored but most is converted into

lipid (free fatty acid, FFA [or non-esterified fatty

acid, NEFA], and triglyceride). Lipid is released

into the blood as very-low-density lipoprotein

(VLDL), to be taken up and stored in adipose

tissue. However, the release of glucose into the

blood is inhibited. Hepatic regulation of glucose

output is an important mechanism for limit-

ing the uptake of glucose into tissues where

transport is independent of insulin.

In adipose tissue, fat breakdown is inhibited

and

glucose

uptake

promoted.

The

glucose

provides glycerol for esterification with FFAs,

and the resulting fat is stored. Adipose tissue also

takes

up

the

fat-containing

chylomicrons

obtained by digestion (see Chapter 3). In muscle,

fat

metabolism

is

inhibited

and

glycogen

is

synthesized, which increases glucose availability

for immediate energy needs. Amino acid uptake

is promoted so that growth can be continued.

Catabolic actions of counter-regulatory hormones

During stresses such as ‘fight or flight’, infection

or any major trauma, catabolic hormones reverse

these processes. Blood glucose is rapidly raised to

supply energy for the muscles and if this is insuf-

ficient fats can also be mobilized. Peripheral

oxidation of FFAs produces large amounts of

energy, but in the liver excess acetyl-CoA is

produced. This is condensed to produce high-

energy ketoacids such as acetoacetate, which

many tissues can utilize in small amounts. In

insulin insufficiency these ‘ketone bodies’ may

accumulate in the plasma, causing ketoacidosis.

Insulin deficiency

The consequences of insulin deficiency, and thus

many of the clinical features of diabetes, can be

deduced from these considerations (Figure 9.2).

It will be explained below that obese type 2

patients may not at first have an absolute defi-

ciency of insulin; rather, there is a degree of

insulin resistance. This may be described as a relative lack because the result is the same; more-

over, eventually their insulin levels do fall. There are important differences between the physio-

logical effects of partial (or relative) deficiency and total insulin deficiency.

Partial deficiency (type 2)

Even

small

amounts

of

insulin

will

prevent

severe metabolic disruption, especially acceler-

ated fat metabolism, i.e. ketosis. Thus, although

fasting blood glucose levels may be raised, the

main problems only arise after meals; these arise

from

impaired

glucose

transport

and

cellular

uptake resulting in impaired clearance from the

blood. Adipose and muscle tissue cannot take up

glucose efficiently, causing it to remain in the

blood, and glucose deficiency in muscle may

cause

weakness.

Becuse

other

tissues

cannot

compensate

sufficiently

to

assimilate

the

entire

postprandial

glucose

load,

the

blood

glucose

level

rises

causing

hyperglycaemia (÷11 mmol/L).

When the blood glucose level increases so that

the

concentration

in

the

glomerular

filtrate

exceeds the renal threshold (see Chapter 14,

p. 876), glucose is lost in the urine (glycosuria).

Urinary

glucose

acts

as

an

osmotic

diuretic

carrying with it large volumes of water (polyuria

and urinary frequency), resulting in excessive

thirst and fluid intake (polydipsia). Because of

reduced fat uptake by adipose tissue, plasma

lipid levels rise, especially triglycerides (dyslipi-

daemia). LDL is relatively unaffected but HDL is

reduced, increasing atherogenic risk (Chapter 4).

Protein synthesis may be reduced but patients

are often still relatively obese. However, they

usually do lose weight in the weeks before first

diagnosis, in part due to dehydration.

Total deficiency (type 1)

With no insulin at all there is severe hypergly-

caemia at most times. This may raise the blood

osmotic pressure sufficiently to cause neurolog-

ical

complications

including

coma;

this

is

discussed on pp. 594-596. Cellular metabolism is

profoundly disturbed. No glucose is available for

energy

metabolism,

and

the

first

result

is

a

depletion of liver and muscle glycogen stores.

Subsequently fat is mobilized, mainly from

adipose tissue, so that plasma triglyceride and

FFA levels rise, as does lipoprotein. These supply

energy

needs

for

a

little

longer

while

the

patient loses yet more weight. The brain cells

switch to metabolizing the hepatically produced

keto-acids. Fat stores are not replenished, and

eventually may be exhausted. Finally, protein

must be broken down into amino acids, which

can be converted to glucose in the liver (gluco- neogenesis), at the expense of lean muscle mass. Other than in uncontrolled diabetes, this process normally occurs only in times of prolonged star-

vation; it is a desperate remedy that is akin to

burning the house down to keep warm. Further, without insulin, any glucose so produced cannot be utilized effectively anyway. This situation is inevitably fatal within months.

Thus many of the clinical problems in type

2

diabetes

are

a

direct

consequence

of

hyperglycaemia, while in type 1 diabetes there is

also

disrupted

intracellular

metabolism.

In

addition, chronic complications occur in both

types,

related

to

both

hyperglycaemia

and

dyslipidaemia. These are discussed below.

Insulin physiology

Insulin

(molecular

weight

about

5800 Da)

is

composed of 51 amino acids in two chains of

21 (A

chain)

and 30 (B

chain)

amino

acids

connected by two disulphide bridges. It is syn-

thesized in the pancreatic islet beta-cells. Other

cells in the islets are the alpha-cells (producing

glucagon) and the delta-cells (producing somato-

statin). Islet cells altogether comprise less than

3% of the pancreatic mass. Insulin is stored in

granules

in

combination

with

C-peptide

as

proinsulin (molecular weight 9000 Da), which is

split before release into the portal vein. Insulin

has

a

plasma

half-life

of

only

about 5 min.

Approximately 50% of insulin is extracted by the

liver, which is its main site of action, and after

utilization it is subsequently degraded. Eventu-

ally,

kidney

peptidase

also

metabolizes

some

insulin. C-peptide is less rapidly cleared and is

thus a useful index of beta-cell function. The

main control of insulin level is plasma glucose: a

rise stimulates both the release and the synthesis

of insulin. Amino acids and possibly fats also promote insulin release (Figure 9.3).

A wide variety of other neuronal, endocrine,

pharmacological and local influences on insulin

release have been identified (Figure 9.3), but

their physiological or pathological significance

is

not

established.

Adrenergic

beta-receptors

mediate release, so beta-blockers can theoreti-

cally

inhibit

this,

though

stimulation

of

inhibitory adrenergic alpha-receptors, magnified

during

the

hyperglycaemic

stress

response,

usually predominates.

Interestingly,

glucose

is

a

more

powerful stimulant orally than parenterally, and various gut

hormones

have

been

implicated

in

this. Glucagon also promotes insulin release, possibly to facilitate cellular uptake of the glucose that it causes to be released into the plasma.

Pattern of secretion

It

is

important

to

note

also

that

there

is

a

continuous

basal

level

of

insulin

secretion

throughout

the 24 h,

independent

of

food

intake, which contributes to the regulation of

metabolism and promotes glucose uptake into

cells. This amounts to about 1 unit/h. Following

a meal

there

is

an

additional

bolus

secreted,

which

is

biphasic.

Within 1 min

of

blood

glucose

levels

rising,

preformed

insulin

is

released from granules

in

beta-cells

into

the

blood.

This

release

is

stimulated

by

certain

antidiabetic agents (insulin secretagogues) and

is the first component to be compromised in

early

diabetes.

Should

hyperglycaemia

persist,

further insulin synthesis is stimulated and there is

a

delayed

second

phase

of

secretion

after about 45 min.

Appoximately 5-10 units

are secreted with each meal.

Thus the plasma insulin concentration curve

normally closely parallels the plasma glucose

concentration curve throughout the day, reflect-

ing every small change in nutrient supply or

demand (Figure 9.4). Considering these subtle

and

sometimes

rapid

adaptations,

it

can

be

appreciated how far current therapeutic methods

fall short of mimicking the physiological ideal.

In non-diabetics, the total daily secretion of insulin is probably rather less than the average daily requirement in type 1 diabetes of 50 units of exogenous insulin, mainly because of losses at the injection site.

Amylin

The 37-amino acid peptide amylin is co-secreted

with

insulin

from

beta-cells.

It

appears

to

contribute

to

glucose

regulation

by

a

local

(paracrine) action on islet cells, which moderates

intestinal glucose uptake, thereby reducing the

load presented to the pancreas, or by suppressing

glucagon

secretion.

In

diabetes,

amylin

defi-

ciency parallels that of insulin and it is believed

that

patients

whose

postprandial

hypergly-

caemia is not adequately controlled by conven-

tional

therapy

may

benefit

from

amylin

agonists, although none is yet in clinical use.

Insulin receptors

These are present on the cell surfaces of all

insulin-sensitive tissues and are normally down- regulated by insulin, especially if it is present at

continuously high levels, e.g. the hyperinsuli-

naemia of over-eating, obesity or obesity-related

type 2

diabetes.

This

may

account

for

the

reduced insulin sensitivity (insulin resistance)

found in some patients and the beneficial effect

of weight reduction, especially of abdominal fat,

on glucose tolerance: there is a vicious cycle

whereby hyperglycaemia and reduced insulin

action reinforce one another. Long-term insulin

treatment

also

often

gradually

reduces

the

insulin requirement, perhaps owing to reduced

glucose levels. However, there is still much to be

learned about the interactions between insulin,

insulin receptors and carbohydrate metabolism.

Epidemiology and classification

The

hallmark

of

diabetes

is

hyperglycaemia,

owing to abnormalities of insulin secretion or

action. There are two primary forms of diabetes

and a variety of minor secondary ones. In type 1

diabetes there is usually gross destruction of the

insulin-secreting pancreatic beta-cells. In type

2

diabetes

insulin

is

secreted

but

is

either inadequate or insufficiently effective to meet

metabolic needs.

The current WHO definition of diabetes is

based on standardized measurements of plasma

glucose concentrations. It defines three classes,

diabetes,

impaired

glucose

tolerance

and

impaired

fasting

blood

glucose (Table 9.3).

Patients in the second category are borderline

and about half will progress to frank diabetes

eventually (up to 5% per year). However, they

need not be treated immediately, depending on

age and the presence of other risk factors: older

patients or those with no cardiovascular risk

factors may just be monitored. More recently the

category of impaired fasting glucose has been

introduced in an attempt to identify at an even

earlier stage those with latent or ‘pre-diabetes’

who should be monitored. It is a less reliable

predictor but has the advantge that it does not

require a glucose tolerance test (see below).

Often,

a

single

random

plasma

glucose

of

÷11.1 mmol/L (blood

glucose 10 mmol/L)

is

sufficient for diagnosis in a patient with classic

symptoms, although this should be confirmed

with

a

fasting

plasma

glucose ÷7 mmol/L.

Laboratories may report plasma glucose levels, as

specified by the American Diabetic Association

diagnostic

criteria,

whereas

finger

prick

tests

measure

blood

levels;

nevertheless,

it

is

customary always to refer to blood glucose in

discussing diabetes. In borderline cases the oral

glucose

tolerance

test

(OGTT)

can

be

performed:

the

patient’s

blood

glucose

is

measured before and at 2 h after a standardized

75-g

glucose

load,

given

orally

following

an

overnight fast.

Epidemiology

Diabetes is known to affect more than 2% of the UK population, and probably as many again are likely to have impaired glucose tolerance or even frank diabetes if screened. The prevalence varies considerably between populations. For example, Europeans are prone to type 1, especially in

northern Europe, whereas the incidence in Japan is less than 10% of that in Finland.

Type 2 seems to be related partly to the afflu-

ence

of

a

population,

possibly

through

the

prevalence of obesity, inactivity or both, which

are major risk factors. However, genetic factors

are also important. In some ethnic groups the

prevalence is very high, e.g. in some Pacific

Islanders and the North American Pima Indians

it reaches 50%. Among South Asian immigrants

to the UK it is five times that in the host popu-

lation, suggesting a possible genetic suscepti-

bility to changed environmental factors, e.g. a

diet richer in fats and sugar.

Classification

Primary diabetes - type 1 and type 2

In

the

vast

majority

of

cases

there

is

direct

damage to the pancreatic islet cells. Different

attempts to classify diabetes comprehensively

have been confounded by the use of criteria that

are not mutually exclusive (e.g. age at onset,

patient build or need for insulin). For example,

some older (‘maturity onset’ or type 2) patients

eventually require insulin, some older patients

need

it

from

the

start (‘latent

autoimmune

diabetes in the adult’, LADA) and a few younger

patients may not (‘maturity onset diabetes of the

young’,

MODY).

Whether

the

patient

needs

insulin may be the most practical distinction,

but does not correspond consistently with other

important parameters.

A classification based on the pathogenesis of

the pancreatic damage is now accepted as the

most meaningful. This distinguishes two broad

types (Table 9.4), which correspond roughly with

insulin dependency. The key criterion is the mode

of pancreatic damage, but many other distinc-

tions follow from this classification, including

natural history, family history and patient type.

These will be discussed in the following sections.

Secondary diabetes

A minority of cases with identifiable primary

causes (e.g. severe pancreatitis, steroid-induced diabetes) do not fit readily into either of the

conventional categories. They may or may not require insulin for treatment (p. 591).

Aetiology and pathogenesis

Primary diabetes

Despite

having

similar

clinical

pictures

and complications, types 1 and 2 primary diabetes have very different causes (Table 9.5).

Type 1 diabetes

In type 1 diabetes the islet beta-cells are almost

completely

destroyed

by

an

autoimmune

process. Antibodies against all islet cells, and

beta-cells

specifically,

are

found

in 80%

of

patients. However, interestingly, it is not these

anti-islet antibodies that mediate cell destruction

but T-cells; the islets are invaded by inflamma-

tory

cells

causing

insulitis.

Insulin

autoanti-

bodies may also be found but their significance

is

uncertain.

As

is

usual

with

autoimmune

disease, there is rarely a strong family history:

siblings

or

children

of

people

with

type 1

diabetes have about a 5% chance of developing

the disease. However, there is a correlation with

the patient’s HLA tissue type (see Chapter 2)

and in a minority of patients an association with

other

autoimmune

diseases,

especially

of

endocrine

tissues (e.g.

thyroiditis,

pernicious

anaemia).

Overt

diabetes

may

follow

many

years

of

subclinical

pancreatic

damage,

and

when

it

occurs there is usually less than 10% of func-

tional islet cell mass remaining. Clinical onset is

usually abrupt, over a few weeks, and often asso-

ciated with, or precipitated by, a metabolic stress

such as an infection, which acutely increases

insulin demand beyond capacity. This might

account for the winter seasonal peak in inci-

dence and also the brief temporary remission

that frequently follows, as the infection remits

and the marginal insulin levels once again just

compensate.

Subsequently,

full-blown

disease

irreversibly takes hold. As with other autoim-

mune diseases, viral infection may be causing

the expression of a normally suppressed HLA

receptor, which subsequently activates lympho-

cytes (see Chapter 2). Other environmental trig-

gers such as toxins or certain foods (including

milk protein) may also be involved.

Autoantibodies

may

be

found

in

some

patients up to 15 years before the onset of acute

disease. This could eventually provide a means

of

early

identification

of

prediabetes,

so

that

they may be treated prophylactically, possibly

by immunotherapy. However, such markers are

also often found in close relatives who never

develop

the

disease,

and

the

chance

of

the

identical twin of a diabetic patient subsequently

developing

diabetes

is

less

than 50%.

The

introduction

of

the

category

of ‘impaired

fasting

glucose’

was

another

attempt

at

early

identification of potential sufferers.

Thus it seems that in type 1 diabetes there is a

genetically determined HLA-dependent suscepti-

bility that requires an environmental trigger for

full

expression.

Following

contact

with

this

trigger, which may never be encountered, swift

deterioration and complete insulin dependence

are inevitable. There is still considerable ignor-

ance of the relative contributions of genes and

environment

and

of

specific

environmental

factors.

Type 2 diabetes

These patients have one or more of the following fundamental abnormalities, and in established disease all three commonly coexist:

m

•

Absolute

insulin

deficiency,

i.e.

reduced

insulin secretion.

•

Relative

insulin

deficiency:

not

enough

insulin

is

secreted

for

metabolic

increased

needs (e.g. in obesity).

•

Insulin resistance and hyperinsulinaemia: a

peripheral insulin utilization defect.

In most cases type 2 diabetes is associated with

obesity (particularly

abdominal

obesity)

on

first presentation, and in a quarter of all people

with diabetes simple weight reduction reverses

the hyperglycaemia. This is commonly associ-

ated with peripheral insulin resistance owing

to

receptor-binding

or

post-receptor

defects.

Obesity

and

reduced

exercise

also

contribute

to

insulin

resistance

and

are

modifiable

risk

factors for type 2 diabetes. The resultant hyper-

glycaemia

induces

insulin

hypersecretion,

hyperinsulinaemia and insulin receptor down-

regulation, i.e. further insulin resistance. Hyper-

glycaemia itself is known to damage beta-cells

owing to the direct toxic effect of excessive intra-

cellular glucose metabolism, which produces an

excess of oxidative by-products; these cannot be

destroyed by natural scavengers such as catalase

and

superoxide

dismutase.

The

vicious

cycle

eventually depletes (‘exhausts’) the beta-cells,

intrinsic insulin levels fall and some patients

may

eventually

come

to

require

exogenous

insulin therapy. Thus, type 2 diabetes is usually a

progressive

disease,

although

the

late

onset

usually means that some patients die before

requiring insulin.

There is still debate as to the primary defect of

type 2 diabetes. It has also been proposed that

the amyloid deposits (insoluble protein) long

known to be found in the pancreas of type 2

patients are related to abnormalities in amylin

secretion

(p.

586)

and

contribute

to

the

pancreatic defect.

There is an association between abdominal

obesity,

hyperinsulinaemia,

insulin

resistance, hyperlipidaemia, type 2 diabetes and hyperten-

sion, and this combination of risk factors is

termed metabolic syndrome. However, despite much research, as yet it is not known which of these factors (if any) is the prime cause, or if

there is another underlying reason.

Genetics

The genetic component in type 2 diabetes is

much greater than in type 1. A family history is

very common, often involving several relatives.

Identical twins almost always both develop the

disease, and offspring with both parents having

diabetes have a 50% chance of developing the

disease. The ‘thrifty gene’ hypothesis proposes

that the ability to store fat efficiently - and

hence develop obesity - conferred a survival

advantage

in

more

primitive

societies

where

famine was a regular phenomenon, hence its

persistence in the genome. This may explain

why

some

pre-industrial

groups (e.g.

Pacific

Islanders)

readily

develop

diabetes

when

exposed to the industrialized lifestyle.

Secondary diabetes

Most diabetes results from primary defects of the

pancreatic

islet

cells.

However,

there

are occasionally

other

causes

of

ineffective insulin action, impaired glucose tolerance and hyperglycaemia (Table 9.6).

Natural history

591

Natural history

Onset

About 80-90% of diabetic patients have type 2

diabetes, which tends to occur late in life, hence

the obsolete description ‘maturity onset’. Onset

is usually insidious and gradual, patients toler-

ating mild polyuric symptoms perhaps for many

years.

The other 10-20% have type 1 diabetes and require insulin at the outset. Almost invariably they become ill at an early age: the peak onset of

type 1

is

around

puberty,

starting

most commonly in the winter months. Although the disease may be present subclinically for some considerable time (months, or possibly years), clinical onset is invariably abrupt.

Presentation

Type

2

diabetes

is

usually

first

diagnosed

following one of three common presentations

(Table 9.7):

•

About

half

of

patients

first

complain

of

increasing polyuria and/or polydipsia.

•

In about a third it is a chance finding of glyco-

suria or hyperglycaemia at a routine medical examination.

•

In

less

than

20%

of

cases

the

patient

complains of symptoms subsequently found

to result from a complication secondary to

diabetes.

Type 2 patients may be asymptomatic or may

have been only mildly symptomatic for several

years. Commonly, they ignore these symptoms

or attribute them to ageing, and only present

when classical symptoms such as polyuria, thirst,

tiredness or recent weight loss (even though the

patient may still be relatively obese) become

unacceptable. In many other cases their diabetes

is only detected when they undergo a medical

examination, e.g. for insurance purposes or a

new job. Alternatively, the complaint may be of

an infective complication not obviously linked

to diabetes, at least not in the patient’s mind,

such as recurrent candida infections or boils, a

non-healing foot lesion or a persistent urinary-

tract

infection.

Rarely,

as

the

complications

proceed

insidiously

even

during

this

early

period, the primary reason for consultation may

result

from

vascular

disease,

nephropathy,

neuropathy, retinopathy or impotence. In some

cases IHD, even MI, is the first presentation.

A common manifestation of the complications

is the ‘diabetic foot’. The patient presents with

a

possibly

gangrenous

foot

lesion,

probably

following

a

recent

injury

and

subsequent

infection.

Only very rarely will a type 2 patient first

present

with

metabolically

decompensated

disease (ketoacidosis). These patients will prob-

ably have had impaired glucose tolerance for some time and then have undergone some major

stress such as MI or serious infection. Another

possible trigger factor could be starting a drug

that impairs glucose tolerance, e.g. a thiazide

diuretic

or

an

atypical

antipsychotic.

Such

stresses may also uncover latent disease in a less

dramatic manner.

Unfortunately, a severe acute presentation is

far more common at the onset of type 1 disease.

This is usually associated with some metabolic

stress (e.g. infection), and presents with rapid

weight

loss,

weakness,

extreme

thirst,

severe

polyuria,

urinary

frequency

and

multiple

nocturia. Some may even go on to acute meta-

bolic decompensation (ketoacidosis) and even

coma, being practically moribund on hospital

admission.

Following

recovery

with

insulin

therapy

there

may

follow

some

months

of

apparent remission with a reduced or absent

insulin requirement, the so-called ‘honeymoon

period’,

but

these

patients

then

deteriorate

rapidly. Before the isolation and therapeutic use

of insulin in the 1920s they inevitably died

shortly thereafter.

Progression

Insulin

secretion

in

type

2

diabetes

declines

relatively slowly, but up to one-third of patients

may eventually need exogenous insulin, i.e. they

are ‘insulin-requiring’

as

opposed

to

insulin-

dependent.

In most type 1 diabetes, pancreatic beta-cell

destruction is already almost complete at diag-

nosis, and routine insulin requirements do not

generally increase. However, in both types the

multisystem complications progress throughout

life

at

rates

that

vary

considerably

between

patients and will very likely be the eventual

cause of death. People with diabetes have a

reduced life expectancy, although the prognosis

has greatly improved with advances in treat-

ment. Younger patients have mortality rates of

up to five times that of the general population,

while for older ones it is about twice normal. The

precise

prognosis

for

any

given

patient

will

depend on many factors, but particularly the

overall consistency of control of blood glucose.

Clinical features

Symptoms

The symptoms of diabetes as summarized in

Table 9.8 are best understood in relation to their pathogenesis.

Symptoms due to hyperglycaemia

The

classic

symptoms,

which

give

diabetes

mellitus its name (‘sweet fountain’), are easily

explained by the osmotic effect of the elevated

blood glucose levels that occur when glucose is

denied entry to cells. They are more pronounced

when the blood glucose level rises rapidly, e.g.

in decompensation or acute onset. The osmotic

effect of chronic hyperglycaemia will to some

extent

be

compensated

by

compensatory

hyponatraemia and an increased intracellular

osmolarity (see Chapter 14).

When the blood glucose level exceeds the

renal

threshold (about 10 mmol/L),

glucose

appears in the urine in large quantities. The

traditional

method

of

distinguishing

diabetes

mellitus from diabetes insipidus - almost the

only two idiopathic causes of chronic polyuria -

was simply to taste the urine: in the former case

it is sweet, and in the latter literally insipid

(tasteless).

Glycosuria

predisposes

to

urinary-

tract infection, partly because of the favourable

growth medium presented to perineal organisms

and partly because diabetic patients are generally

more

susceptible

to

infection (see

below).

Complications

593

Diabetic urine dries to leave a white glucose

deposit, a clue that sometimes leads to diagnosis:

there may be underwear stains or white specks

on the shoes of elderly males (from careless

micturition).

Severe

plasma

hyperosmolarity

may

reduce

the

intraocular

pressure,

causing

eyeball

and

lens

deformity,

and

glucose

may alter lens refraction: both lead to blurred

vision. This is sometimes a prodromal sign of

hyperglycaemic crisis in type 1 diabetes.

Impaired metabolism and complications

The metabolic consequences of insulin lack were

discussed in detail above. The pathophysiology

of

hyperglycaemia

and

ketoacidosis

is

now

considered.

Complications

Most complications of diabetes are due to either

acute metabolic disturbances or chronic tissue

damage.

Acute complications

The

most

common

acute

complications

are

disturbances

in

glycaemic

control.

Optimal

management

of

diabetes

aims

for

a

delicate

balance, preventing excessive glucose levels but

not forcing glucose levels too low. A variety of

circumstances can drive the glucose level outside

these narrow limits, and if treatment is not

adjusted accordingly, the result is either excess or insufficient glucose in the blood (Table 9.9).

Hyperglycaemia/ketoacidosis

Causes, pathogenesis and symptoms

Hyperglycaemia

in

treated

diabetes

usually

arises because normal medication is somehow

omitted

or

becomes

insufficient

to

meet

an

increased insulin requirement. Drugs that raise

blood

glucose

levels

can

also

interfere

with

control. When diabetic control is lost, blood

glucose rises and the symptoms develop gradu-

ally over a number of hours. Above a blood

m

glucose level of approximately 15-20 mmol/L, both

hyperosmolar

and

metabolic

problems develop (Figure 9.5; Table 9.10).

Blood glucose levels can exceed 50 mmol/L

and this high osmotic load (which is also in the

extracellular fluid) cannot be matched within

those cells from which glucose is excluded owing

to the absence of insulin. Thus, water is drawn

from

the

intracellular

compartment

and

this

causes

tissue

dehydration.

This

particularly

affects the brain where the resultant reduced

intracranial pressure leads to CNS depression.

The skin is also dehydrated, and loses its elas-

ticity; this reduced skin turgor can be detected by

pinching a fold of skin and noting its delay in

springing back, but this is less conclusive in the

elderly,

in

whom

skin

elasticity

is

already

reduced.

In the kidney the high load of glucose in the

glomerular filtrate, not all of which can be reab-

sorbed, produces an osmotic diuresis. This results

in

a

reduction

in

circulating

fluid

volume,

leading to hypotension and reflex tachycardia.

The high urine volumes also cause a loss of elec-

trolytes,

especially

sodium

and

potassium.

However, the plasma potassium level may be

paradoxically high because acidosis inhibits the

Na/K pump throughout the body, preventing

intracellular potassium uptake (see below and

Chapter 14, p. 891). Osmoreceptors and baro-

receptors detect the electrolyte and fluid losses,

causing thirst, but as CNS depression and confu-

sion develop the patient often cannot respond

by drinking.

In the absence of glucose, many cells start to

metabolize fat instead. Adipose tissue releases fatty acids, and the liver converts some of these to acid ketones that can be readily utilized as an

alternative energy source by many tissues. The

resulting

metabolic

acidosis (diabetic

ketoaci-

dosis) is misinterpreted by the respiratory centre

as

carbon

dioxide

retention,

resulting

in

an

increased respiratory drive and hyperventilation.

Acidosis impairs oxygen dissociation from Hb,

exacerbating

the

gasping (overbreathing, ‘air

hunger’), and also causes peripheral vasodilata-

tion, exacerbating the hypotension. Both respi-

ratory rate and blood oxygen level fall as coma

supervenes.

Ketoacidosis

is

more

likely

to

develop in type 1 patients, although fortunately

it is uncommon.

People with type 2 diabetes usually secrete

sufficient insulin to prevent them developing

ketoacidosis (except during severe stress), but

they may still suffer hyperosmolar non-ketotic

hyperglycaemic states. This may result in coma

and is associated with a higher mortality than

ketoacidosis.

Management

Diabetic ketoacidosis is a medical emergency with about a 15% mortality rate. Close moni-

toring and very careful attention to the patient’s fluid

and

electrolyte

balance

and

blood

biochemistry are essential (Table 9.11). Imme-

diate attention is life-saving, but the patient may take several days to stabilize.

IV

soluble

insulin

is

essential.

An

initial

bolus

of

about

6 units

is

followed

by

contin-

uous

infusion (6 units/h).

Fluid

replacement

needs are estimated from measurements of the

CVP and plasma sodium level. Hyponatraemia

(‘appropriate

hyponatraemia’,

glucose

having

osmotically

displaced

sodium

in

the

plasma)

and/or

sodium

depletion

require 0.9%

saline

administration. However, if the dehydration has

caused hypernatraemia, especially in the non-

ketotic

patient,

hypotonic

saline (e.g. 0.45%)

may be indicated. Severe hypotension or shock

require

plasma

replacement (see

Chapter 14

p. 903).

Potassium

replacement

is

difficult

to

manage

because

the

initial

hyperkalaemia

masks a total body potassium deficit. However,

once

insulin

is

started

and

potassium

moves

intracellularly, closely monitored IV potassium

replacement

is

required.

Acidosis

will

often

resolve spontaneously with conservative therapy

as ketone production falls and existing ketones

are metabolized. Many clinicians would not use

bicarbonate unless blood pH was below 7.00 for

fear of overcompensating.

Hypoglycaemia

Causes

In all forms of diabetes, hypoglycaemia (blood

glucose

3 mmol/L)

is

much

more

common

than

symptomatic

hyperglycaemia,

and

it

develops

very

rapidly,

sometimes

within

minutes.

Usually,

either

an

excessive

insulin

dose is accidentally injected (many patients have

eyesight problems) or else the normal dose of

insulin or antidiabetic agent is not matched by

an adequate dietary intake (Table 9.9). Insulin-

induced

hypoglycaemia

is

usually

associated

with

injections

of

short-acting

insulin.

Deliberate overdosing is not unknown.

Hypoglycaemia

induced

by

sulphonylurea

antidiabetic drugs is rarer but more prolonged,

more severe and more difficult to treat than

insulin-induced hypoglycaemia. The elderly are

especially prone, partly because the drugs are

cleared

more

slowly

and

partly

because

of

impaired

homeostasis.

Drug

interactions

that

might

potentiate

oral

antidiabetic

drugs

are

considered on p. 615. Alcohol not only causes

hypoglycaemia by inhibiting hepatic gluconeo-

genesis but also impairs the patients’ perception

of it, reducing their ability to respond.

m

Pathogenesis and symptoms

Hypoglycaemic symptoms fall into two main

groups (Table 9.12).

At

glucose

levels

below

about 4 mmol/L

insulin

release

is

inhibited

and the counter-regulatory hormones such as

glucagon and adrenaline are released in an effort

to raise blood glucose. At a glucose level below

3.5 mmol/L

the

body

responds

by

activating the sympathetic nervous system and adrenal

medulla (the ‘fight

or

flight’

response).

The consequent

sympathetic/adrenal

symptoms (Table 9.12) should provide the patient with a preliminary warning (but see below).

As

the

glucose

level

falls

below

about

2.5 mmol/L, neurological signs develop owing to

the deficiency of glucose in the brain. These

neuroglycopenic features may be noticed more

by others than by patients themselves, although

many patients do report an awareness of subjec-

tive prodromes. Sometimes the signs are subtle

changes in mood or visual disturbances, but

eventually there is almost always erratic behav-

iour resembling drunkenness. This has some-

times led to police arrest and delayed treatment,

occasionally with fatal results. Frequent hypo-

glycaemic attacks may have a cumulative delete-

rious effect on higher brain function (cognition),

especially in the elderly. All people with diabetes

should carry, in addition to a readily available

sugar source such as dextrose tablets, a card or bracelet

stating

that

they

have

diabetes

and

should be given sugar if found acting strangely.

A patient’s ability to recognize ‘hypos’ (their

hypoglycaemic awareness) should be checked

regularly because it tends to diminish. Long-

term diabetes patients become less sensitive to

the warning signs and thus more vulnerable.

This

may

result

partly

from

autonomic

neuropathy and partly from reduced counter-

regulatory hormone response. It is also possible

that frequent attacks may reduce the patient’s

ability

to

recognize

them.

Awareness

is

pro-

gressively

reduced

by

frequent

hypogly-

caemic episodes but may be at least partially

restored by minimizing or eliminating episodes

through relaxing control slightly, more careful

monitoring and patient education.

Most of the adrenergic symptoms are medi-

ated by beta-receptors, and so may be antago-

nized

by

concurrent

beta-blocker

therapy.

Although this rarely presents a serious problem,

such drugs should be avoided in people with

diabetes

if

they

already

experience

hypogly-

caemic

unawareness.

Otherwise,

there

is

no

contra-indication

but

a

cardioselective

beta-

blocker is preferred. Theoretically, beta-blockers

might help by preventing beta-mediated insulin

release (Figure 9.3), but this is swamped by the

symptom-masking effect.

Management

Although

both

hypoglycaemia

and

hypergly-

caemia can result in coma, there is rarely any

problem distinguishing them, especially as rapid

blood

glucose

test

stick

methods

are

readily

available. A test dose of glucose would clinch

matters

because

hypoglycaemia

will

be

very

rapidly reversed, whereas glucose would have no

significant effect, either helpful or harmful, in

hyperglycaemia.

In

contrast,

insulin

given

blindly

would

severely

exacerbate

hypogly-

caemia and should never be given where there is

doubt.

The

conscious

patient

must

take

glucose

tablets, or sugar, chocolate, sweet tea, etc. Semi-

conscious

or

comatose

patients

require

IV

glucose 20%

or

IM

glucagon (1 mg).

The

Complications

597

response is usually satisfyingly prompt, occur-

ring

within

minutes.

Glucagon

injection

can

usually be managed easily by patients’ relatives,

who

should

be

fully

informed

on

how

to

recognize

and

deal

with

hypoglycaemic

episodes. Unless patients or their relatives are

taught to recognize the early signs, the patient

may

become

comatose

before

being

able

to

correct it.

Persistent

hypoglycaemic

attacks

require

reassessment of therapy. Dietary modification

may be required (e.g. increased carbohydrate),

although this might compromise weight reduc-

tion efforts. Modern intensive insulin therapy

regimens aimed at producing ‘tight’ glycaemic

control

have

increased

the

likelihood

of

hypoglycaemia, and a judgement of risk and

benefit has to be made when such regimens are

considered (p. 626).

Unstable diabetes

A

small

proportion

of

people

with

type

1

diabetes prove exceptionally difficult to control,

experiencing

frequent

episodes

of

hypogly-

caemia, hyperglycaemia or both. They are vari-

ously termed brittle, unstable or labile. It is

unlikely that this condition is inherent to their

disease, and specific causes are always sought.

Poor compliance through error, ignorance or

disability, e.g. visual problems measuring insulin

doses,

unrecognized

intercurrent

illness

and

drug interaction must first be eliminated. In

older patients with recurrent hypoglycaemia the

possibility of reduced hypoglycaemic awareness

must be investigated.

Recurrent

hyperglycaemia/ketoacidosis

is more

common

in

young

patients

and

may

sometimes be associated with psychological or psychopathological factors such as teenage rebel-

lion or illness denial, self-destructive impulses or

other

emotional

instability.

A

particular subgroup has been identified of slightly obese females aged 15-25 years who may be covertly manipulating their therapy adversely. Supervised IV therapy in some of these patients seems to resolve the problem temporarily.

Chronic complications

In many patients, even before diagnosis, wide-

spread damage occurs in the kidney, nerves, eyes or vascular tree (Figure 9.6). These long-term complications are to different degrees common to both types of diabetes, and their prevention or treatment are the real challenges for diabetes

management and research.

Pathogenesis

It is important to determine whether or not

these chronic problems are a direct consequence

of hyperglycaemia. If so, then optimal control to

achieve normoglycaemia would be expected to

minimize them. Evidence has accumulated that

this is broadly true for the so-called microvas-

cular complications (mainly kidney, eye, nerves).

The fact that similar complications arise in most

types of diabetes, despite their different aetiolo- gies, supports the hyperglycaemia hypothesis. The extensive Diabetes Control and Complica-

tions Trial (DCCT; 1992) confirmed that better control is associated with less severe complica-

tions in type 1 diabetes. The UK Prospective

Diabetes Study (UKPDS; 1998) supported the same hypothesis in type 2 patients.

Other

hypotheses

have

been

proposed.

It

could

be

that

an

as

yet

unidentified

primary

lesion in diabetes is responsible independently

for both the hyperglycaemia and the complica-

tions.

If

so,

correcting

one

would

not

neces-

sarily

improve

the

other.

Some

complications

could be secondary to the abnormal pattern or

amount

of

insulin

secretion,

which

is

not

completely rectified by conventional treatment.

For

example,

the

hyperinsulinaemia

seen

in

many type 2 patients may contribute to blood

vessel disease (macrovascular complications) or

hypertension.

Alternatively,

the

abnormally

high

levels

of

counter-regulatory

hormones usually found in diabetes may be deleterious.

The

involvement

of

growth

hormone

and

insulin-like

growth

factor

in

angiopathy

has

also

been

investigated

but

no

clear

pattern

detected.

Finally,

there

seems

to

be

a

genetic

variation

in

the

susceptibility

to

different

complications,

regardless

of

the

degree

of

glycaemic control.

Thus there is unlikely to be a simple answer,

but the general strategy of normalizing blood

glucose

is

well

established

as

the

best

we

currently have for minimizing complications.

Three general mechanisms are proposed for the

pathological basis of the complications: protein

glycation

(glycosylation),

abnormal

polyol

metabolism

and

accelerated

atheromatous

arterial changes.

Glycation

Normally, almost all body protein is to some

extent glycated, i.e. glucose molecules from body

fluids are covalently bound to free amine groups

on protein side chains. The degree of glycation is

directly

proportional

to

the

average

blood

glucose level. An accessible marker for this is

Hb glycation, particularly the HbA1c fraction.

Other proteins, and also lipids and nucleopro-

tein, throughout the body are similarly affected.

In

excess,

one

result

is

the

formation

of

abnormal crosslinks between different regions of

protein

chains.

Protein

configuration

is

thus

changed,

disrupting

secondary

and

tertiary

structure

and

hence

function.

Basement

membrane proteins seem particularly susceptible

to glycation, the result being thickening and

increased

permeability (i.e.

reduced

selective

barrier function). As basement membranes are

present in most tissues, and especially in blood

vessels, this could account for the widespread,

multisystem distribution of diabetic complica-

tions. Chronic hyperglycaemia also results in

oxidative

stress

through

increases

in

mito-

chondrial

superoxide

formation,

producing

advanced glycation end-products (AGPs) that

can cause a variety of damaging effects.

Basement

membrane

damage

in

capillaries

and

smaller

arterioles

can

cause

microan-

giopathy and subsequent ischaemia in almost

any organ. Retinopathy is undoubtedly caused

in part by this mechanism. Neuropathy may

Complications

599

result from a combination of this and direct

glycation of the sheaths of small nerve axons,

e.g. sensory nerves. Similarly, glycation of the

glomerular basement membrane probably causes

the characteristic glomerular sclerosis of diabetic

nephropathy,

although

renal

arterial

disease

probably also contributes. Glycation of tendon

sheaths and joint capsules may be responsible

for the joint problems, particularly the stiffness

in hands and feet, that some patients suffer;

glycation of collagen in skin sometimes gives it a

thickened, waxy appearance. The myocardium

may also be affected, as may immune cells such

as macrophages and leucocytes.

Polyol metabolism

Some tissues do not require insulin for glucose

transport

into

their

cells (Table 9.1),

relying

instead simply on diffusion down a concentra-

tion

gradient.

Thus,

while

other

tissues

are

glucose-depleted in diabetes, these will accumu-

late excess glucose in the presence of hypergly-

caemia. Being surplus to energy needs, some of

the excess glucose is reduced to polyols such as

sorbitol by the enzyme aldose reductase via an

otherwise little used pathway (Figure 9.7).

The

resulting

polyols

are

not

readily

elimi-

nated from the cells, possibly because they are

more polar than glucose and of greater molec-

ular

weight.

Furthermore,

low

dehydrogenase

activity, particularly in the eye lens and nerve

sheaths, means that they are not metabolized

efficiently.

The

resultant

accumulation

of

osmotically active molecules draws water into

the

cells,

causing

them

to

expand,

severely

disrupting

their

function

and

possibly

killing

them. Retinal blood vessels, the eye lens and

the

glomeruli

may

be

damaged

in

this

way,

contributing

to

retinopathy,

cataract

and

nephropathy,

respectively.

It

has

long

been

known that an analogous intracellular accumu-

lation of galactitol in the lens is linked to the

high

prevalence

of

cataracts

in

the

inherited

metabolic disorder galactosaemia.

A further abnormality may also contribute.

Myoinositol,

an

important

intermediate

in

energy handling, may (although also a polyol)

instead of accumulating become deficient. By a

poorly understood series of steps this deficiency

may impair nerve conduction (Figure 9.7).

Macroangiopathy

Almost

all

people

with

diabetes

suffer

from

increased obstructive vascular disease owing to a

greatly

increased

predisposition

to

atheroscle-

rosis. Several factors contribute to this. Because of

their more active lipid metabolism, people with

diabetes have raised plasma levels of triglycerides

and lowered HDL, producing an unfavourable,

atherogenic

lipoprotein

ratio (see

Chapter 4,

Figure 4.28). Furthermore, many type 2 patients

are initially hyperinsulinaemic and insulin may

itself be a growth factor for atheroma. Platelet

aggregating

ability

is

also

usually

raised,

and

hypertension is common. Thus major risk factors

for atherosclerosis are intensified and cerebro-

vascular disease, stroke, IHD and peripheral vas-

cular disease are common. Macroangiopathy also

contributes to kidney disease.

Other mechanisms

As illustrated in Figure 9.6, other complications of diabetes occur, the pathogenesis of which remain obscure.

Moreover,

different

complications may

be inter-related or coexistent. Neuropathy may result partly from direct neuronal damage and partly from impaired blood supply to the

nerve

sheaths.

Microangiopathy

may

result partly from glycation, partly from polyol accu-

mulation

and

partly

from

hyperinsulinaemia. Once nephropathy

is

established,

it

promotes hypertension and vascular disease.

Diabetes

and

hypertension.

There

is

an

association between diabetes (especially type 2)

and

hypertension,

as

part

of

the

metabolic

syndrome.

The

precise

cause

and

effect

relationships

have

not

yet

been

elucidated.

Many

hypertensives

have

insulin

resistance,

hyperinsulinaemia and impaired glucose toler-

ance, and insulin may have several hypertensive

actions including promoting renal sodium reten-

tion,

increasing

sympathetic

vasconstrictor

activity and directly increasing vascular reac-

tivity,

via

an

effect

on

sodium

handling.

In

some cases hypertension may be secondary to

diabetic kidney disease, although the converse

may

also

be

true (see

Chapter 4,

p. 213).

Alternatively,

it

may

be

that

a

third,

as

yet

unknown, independent factor first causes insulin

resistance,

which

then

leads

to

both

type 2

diabetes and hypertension. Hyperinsulinaemia

could

then

be

a

common

link

in

the

vascular

complications

of

both

diabetes

and

hypertension.

The UKPDS (1998) found that rigorous control of blood pressure in diabetes reduced complica-

tions.

However,

prolonged

therapy

with

two common

antihypertensive

agents,

thiazide diuretics

and

beta-blockers,

while

effectively lowering blood pressure, can also lead to glucose intolerance

or

even

overt

diabetes.

For

this reason beta-blockers are not recommended as first-line treatment for hypertension in diabetes, and extra care is needed with both.

Clinical consequences

Almost any system in the body may be affected

by diabetic complications, which is why diabetes

is regarded as a multisystem disease (Table 9.13).

Eyes.

Diabetes is the most common cause of

acquired blindness in developed countries. After

30 years of diabetes, about 50% of patients have

some degree of retinopathy, and up to 10%

become blind. The blindness is due to small-

vessel damage in the retina, with dilatation,

haemorrhage, infarction and ultimately exces-

sive proliferation of new vessels that project

into the vitreous humour (neovascularization).

Retinopathy

is

frequently

associated

with

nephropathy. People with diabetes also have an

increased incidence of glaucoma and cataract.

Nervous

system.

Diabetic

neuropathy

may

affect any part of the peripheral nervous system,

but most commonly starts with the peripheral

sensory nerves, causing tingling and numbness

(paraesthesias), loss of vibration sense or the

sense of balance and limb position. It may inter-

fere

with

the

ability

of

blind

people

with

diabetes

in

reading

Braille.

Autonomic

neuropathy

is

potentially

devastating

because

it can seriously disturb cardiovascular, gastro-

intestinal

or

genitourinary

function,

causing

numerous symptoms; postural hypotension and

impotence are common. Voluntary motor nerves

are less commonly affected.

Complications

601

Renal.

Diabetic nephropathy is the cause of

death in about 25% of type 1 diabetes. Predomi-

nantly a form of sclerosis of the glomerular base-

ment membrane, it develops very slowly and so

most commonly occurs in type 1 patients, up to

40% of whom may be affected. The increased

glomerular filtration rate (‘hyperfiltration’) in

early diabetes, which is due to hypertension and

to the osmotic loading of hyperglycaemia, may

overload

renal

capillaries.

Nephropathy

is

heralded by microalbuminuria, with increasing

proteinuria frequently progressing to end-stage

renal failure, associated with worsening hyper-

tension. Diabetic nephropathy is one of the most

common causes of chronic renal failure, with

people with diabetes comprising about 15% of

the caseload of UK renal replacement therapy

units. Renal decline is hastened by inadequate or

tardy treatment of associated hypertension.

Cardiovascular.

About half of diabetic deaths

are from the consequences of macroangiopathy.

People with diabetes have a twofold greater risk of

stroke and a fivefold greater risk of MI compared

with matched non-diabetic subjects. Peripheral

vascular disease is also common, with a 50-fold

higher risk of peripheral gangrene. Some patients

undergo

progressively

extensive

amputation;

usually the lower limbs (especially the feet; see

below) are affected, but fingers are also at risk.

Hypertension is often associated with diabetes.

Up to 50% of type 1 patients have it, and it is

probably secondary to nephropathy. About a fifth of type 2 patients are hypertensive; the aeti-

ology is uncertain but related to the metabolic syndrome, with obesity and hyperinsulinaemia contributing.

A rare complication is diffuse cardiac fibrosis

(cardiomyopathy),

which

may

lead

to

heart

failure.

Locomotor.

The ‘diabetic foot’ is a common

problem. In normal people minor foot injuries,

such as a blister or a lesion from ill-fitting foot-

ware, usually heal before being noticed. In people

with diabetes, however, these often develop into

non-healing painless ulcers that become infected

and irreversible damage sometimes occurs before

medical attention is sought. In some cases this

results

in

osteomyelitis

or

gangrene,

both

of

which can lead to amputation. This results from

a combination

of

poor

peripheral

sensation

(neuropathy, so that the wound is not felt), poor

peripheral

circulation

(angiopathy,

so

that

healing is impaired) and reduced resistance to

infection. All people with diabetes should see a

chiropodist regularly. Correctly fitting footwear is

essential. No pharmacist should attempt to treat

any foot problem in a diabetic, or sell them ‘corn

plasters’ or similar products. Any foot problem,

however

minor,

should

be

referred

to

their

chiropodist or doctor urgently.

Diabetes can also cause soft tissue damage

resulting in limited joint mobility (stiffness), and

a characteristic arthropathy, usually in the feet,

where angiopathy and sensory neuropathy also

contribute (Charcot joints; see Chapter 12).

Systemic.

People with diabetes are very prone

to infections owing to an impaired immune

response

caused

by

defects

in

immune

and

inflammatory cells. Recurrent bladder infection

is

common,

which

can

ascend

to

cause

pyelonephritis: urinary retention and stasis due

to autonomic neuropathy exacerbate this. Skin

infections are also frequent, and contribute to

foot problems.

Management of complications

General strategy

The

overall

approach

to

preventing

diabetic

complications,

minimizing

them

or

delaying

m

their onset combines control of blood glucose, risk factor reduction and regular monitoring.

Optimal

glycaemic

control.

Although

the

aetiology and pathogenesis of the complications

are still uncertain and likely to be multiple, the

main

clinical

approach

has

been

to

aim

for

scrupulous

control

of

blood

glucose

levels,

keeping them within the normal range, in an

attempt to mimic physiological normality. This

is based on the assumption that complications

are due to hyperglycaemia. This seems to be

particularly likely for the microvascular, possibly

polyol-related, complications in nerves, eyes and

kidney.

Evidence

derives

from

clinical

trials,

including those using the more ‘physiological’

treatments such as continuous SC insulin infu-

sion (p. 624) or other methods of achieving

‘tight’ glycaemic control. This means keeping

fasting blood glucose levels below 7 mmol/L and

not exceeding 11 mmol/L after meals, and may

necessitate

conversion

to

insulin

therapy

in

poorly controlled type 2 patients.

Good

control

has

been

shown

to

reduce

the

incidence

of

complications.

The

most

convincing evidence in type 1 diabetes was the

DCCT trial, which reported significant slowing

of deterioration in retinopathy, microalbumin-

uria and, to a lesser extent, neuropathy. The

UKPDS trial found broadly similar benefits in

type 2 patients and also strongly demonstrated

the synergistic role of hypertension in exacer-

bating

complications

and

the

importance

of

achieving normotension as well as normogly-

caemia. Unfortunately, this study failed to iden-

tify clearly the treatment mode that offered the

best protection, although this had been one of

its aims.

An unwanted side-effect of tight control is that

by keeping the average blood glucose low the

incidence of hypoglycaemia is increased, espe-

cially among elderly and unstable diabetics. In

the DCCT trial there was a threefold increase in

the incidence of hypoglycaemia when under

tight control. This means that in some circum-

stances a compromise is necessary because of the

acute

and

the

long-term

complications

of

frequent

hypoglycaemic

attacks.

Thus,

older

patients in whom the diabetes onset occurred

quite late, i.e. type 2, are usually allowed to run

higher average levels. The long delay in onset of complications will mean that life expectancy

may be little reduced, whereas quality of life

would

be

markedly

reduced

by

frequent hypoglycaemia.

For the macrovascular complications (cardio-

vascular, cerebrovascular and peripheral athero-

sclerosis) this approach is less successful, perhaps

because insulin and related endocrine abnormal-

ities and hypertension may contribute directly,

independently of glycaemia. It is still unknown

whether the generally higher insulin levels asso-

ciated with tight control regimens can actually

exacerbate some macrovascular problems.

Minimize

risk

factors.

It

is

important

to

control any additional risk factors that could

exacerbate organ damage, especially via athero-

sclerosis. These include smoking, hypertension,

obesity, hyperlipidaemia and hyperuricaemia.

Monitoring.

This

essential

component

in minimizing

complications

is

discussed

below (see also Table 9.22).

Reduce

polyol

accumulation.

According to

the polyol hypothesis for certain of the compli-

cations,

it

should

be

possible

to

impede

this process by interfering with the metabolism

of

polyols.

Unfortunately,

aldose

reductase

inhibitors (e.g.

sorbinil),

although

they

do

minimize

sorbitol

accumulation

and

prevent

myoinositol depletion, have not proven clini-

cally successful in reversing or even retarding

neuropathy,

cataract,

nephropathy

or

retino-

pathy. Dietary myoinositol supplementation has

also been unsuccessful.

Specific complications

Nephropathy.

There

are

currently

four

methods that have been shown to slow the rate of deterioration in renal function:

•

Careful glycaemic control. •

Control of hypertension. •

Use of ACEIs or ARAs.

•

Moderate

protein

restriction

(in

more

advanced nephropathy).

It is essential that people with diabetes are moni-

tored annually for the onset of hypertension and

Complications

603

microalbuminuria.

In

treating

hypertension,

ACEIs (and ARAs) seem to have an additional

direct

beneficial

effect

in

diabetes,

dilating

intrarenal (efferent glomerular) vessels and thus

minimizing glomerular hypertension. ACEIs are

increasingly used early unless contra-indicated

e.g. by bilateral renal artery stenosis, which is

always a possibility in someone with diabetes.

ACEIs are indicated when there is hypertension

with proteinuria or microalbuminuria; in type 1

diabetes their use is recommended if there is

microalbuminuria,

even

with

normotensive

patients.

However,

at

present

there

is

no

evidence

that

ACEIs

benefit

normotensive

diabetes

with

no

evidence

of

nephropathy.

Other antihypertensives may not offer similar

extra

benefits

but

another

antihypertensive

should be used if ACEIs are contra-indicated or

inadequate at reducing pressure.

Once established, renal failure is managed as

usual (see Chapter 14), although haemodialysis

is more difficult because of vascular and throm-

botic

complications.

Continuous

ambulatory

peritoneal

dialysis

is

particularly

suitable

in

diabetes because insulin may be administered

intraperitoneally (thus

directly

entering

the

portal circulation, which is more physiological).

However,

there

may

be

a

problem

with

the

glucose, which is usually added to dialysis fluid

to promote water removal. People with diabetes

are nowadays unlikely to be given low priority

for renal transplantation, as they tended to be in

the past, and this is sometimes combined with

pancreatic transplantation (p. 605). There are

however some problems: the poor general health

of these patients and multiple organ damage

increase

the

operative

risk,

and

there

is

an

increased likelihood of post-transplant infection

owing

to

the

immunosuppression

required.

Nevertheless, graft survival is only about 10-15%

poorer than the average for renal transplants.

Macroangiopathy.

The usual dietary constraints

on saturated fat and cholesterol are important.

Monounsaturated fats, especialy olive oil, are

recommended.

The

HPS

study

supported

the

use

of statins for all people with diabetes of

either

type

at

cardiovascular

risk,

whatever

their lipid level, and this is now accepted. The

CARDS study extended the recommendation in type

2

diabetes

to

those

patients

with

even

normal or low lipids, regardless of CVS risk.

However, such routine use is not yet officially

recommended. In the PROactive trial type 2

patients with pre-existing macrovascular disease

used

pioglitazone

in

addition to their usual

treatment. A small but significant reduction in

all-cause mortality, MI and stroke was achieved

but

at

the

expense

of

weight

gain

and

an

increase in heart failure.

Other conventional atheroma risk factors such as

smoking

and

hypertension

must

also

be scrupulously addressed (see Chapter 4).

Neuropathy and neuropathic pain.

Little can

be done for diffuse neuropathy, but neuropathic

pain can be partially relieved and fortunately

severe

attacks,

although

prolonged,

tend

to

remit. Drug therapy may be of help in the some-

times excruciating pain. Conventional analgesic

or anti-inflammatory drugs are generally ineffec-

tive. A variety of other drugs have been tried

and the first-generation tricyclic antidepressants

(e.g. amitriptyline) are standard first-line therapy.

Second-line agents include anticonvulsants such

as carbamazepine, gabapentin or topiramate (see

also Chapter 6).

Retinopathy.

Retinal disease is conventionally treated by laser photocoagulation.

Management

Aims and strategy

Preventative

methods

for

diabetes

are

as

yet

poorly developed. More progress has been made

with potentially curative surgery. However, at

present the vast majority of people with diabetes

require long-term management of established

disease.

The cardinal aim of management in diabetes is

to keep blood glucose levels within the normal

range; this should produce patterns of glucose

and insulin levels in the blood similar to those

that follow normal changes in diet and activity

(see

Figure 9.4).

Blood

glucose

levels

should

remain below the maxima in the WHO defini-

m

tion for impaired glucose tolerance (Table 9.1). Ideally, this would require a continuous basal level of insulin to maintain metabolism, supple-

mented by rapid pulses following meals and a reduced level during exercise.

Optimal

management

should

attain

three

important interlinked aims:

•

Prevent symptoms.

•

Maintain biochemical stability.

•

Prevent long-term complications.

At present, this ideal is not achievable. Even if pancreatic transplantation were to be perfected, insulin

receptor

defects

might

still

remain. Current therapy is limited to artificially manipu-

lating diet and insulin (endogenous or exoge-

nous) in order to mimic normal patterns as

closely as is practicable.

The

older

directive,

paternalistic

medical

model

for

such

manipulation

is

no

longer

acceptable, clinics preferring to negotiate a ‘ther-

apeutic contract’ with the patient. The aim is to

agree

a

desired

level

of

control -

optimal,

prophylactic or perhaps merely symptomatic -

based on the severity of the disease and the

patient’s age, understanding, likely compliance

and normal way of life.

Sometimes it is inadvisable to strive too zeal-

ously to approach the ideal. For the elderly,

where

long-term

complications

are

of

less

concern, keeping symptoms at a tolerable level

without

excessive

disruptions

to

normal

life

patterns may be adequate. For this, the target

need only be to achieve random blood glucose

levels below 12 mmol/L. In some patients the

incidence of hypoglycaemic attacks is unaccept-

ably high if control is too tight. The advent of

the insulin pen has enabled the flexibility to

achieve these differing aims.

Prevention

Because type 1 disease involves immune destruc-

tion of the pancreas, immunotherapy has been

attempted

experimentally,

as

early

as

pos-

sible after initial diagnosis or even in the pre-

symptomatic

stage

in

at-risk

individuals,

e.g.

where there is a strong family history or impaired

glucose

tolerance.

In

animal

models

anti-T

cell antibodies, bone marrow transplantation, thymectomy, azathioprine

and ciclosporin

have been tried. In the Diabetes Prevention Trial-1

early introduction of insulin therapy, to ‘spare’ the beta cells and perhaps to reduce their expres-

sion of autoantigens, was unsuccessful. Another trial using nicotinamide to inhibit macrophages has also failed to reduce progression.

However, considerable pancreatic damage has usually

occurred

by

the

time

symptoms

are noticed. Only about 10% of functional islet cells then remain, so no great improvement can be

expected.

Research

is

now

concentrating

on discovering

reliable

early

prognostic

markers, such as islet cell antibodies. Patients at risk could then be identified by screening.

No specific aetiological agents have been iden-

tified for type 2 diabetes, but risk factors are well

known. These correspond with many of the well-

established cardiovascular risk factors associated

with the lifestyle of industrialized countries, i.e.

diets high in sugar and fats and low in fibre and

slowly absorbable complex carbohydrates, lack

of exercise and obesity. Weight loss in particular

has been shown to delay development of the

disease

in

high-risk

individuals

and

achieve

remission in severely overweight people with

diabetes. In the Diabetes Prevention Programme

both

intensive

lifestyle

intervention

and

metformin significantly reduced the risk of devel-

oping diabetes in people with impaired glucose

tolerance.

Another

trial

showed

benefit

with

acarbose.

In

the

Finnish

Diabetes

Prevention

Study

dietary

modification

and

exercise

was

similarly beneficial. More recently the DREAM

trial with rosglitazone over 3 years showed signif-

icant reduction in progression from impaired

glucose tolerance/impaired fasting glycaemia to

overt type 2 diabetes.

Cure: organ replacement

Pancreatic

transplants

are

now

a

realistic

option. Dual renal plus pancreatic transplanta-

tion is especially considered for people with

diabetes with advanced nephropathy, because

such

patients

are

going

to

have

to

undergo

immunosuppression anyway. One-year patient

survival exceeds 90% and 5-year graft survival

exceeds

50%.

Transplantation

substantially

increases the quality of life, although of course

Management

605

is

still

limited

by

the

risks

of

surgery

and the

penalty

of

lifelong

immunosuppression (Chapter 14).

The implantation of donated beta-islet cells is

still

experimental

but

looks

promising.

Stem

cells may offer even more fundamental a solu-

tion

for

the

future.

A

number

of

artificial

pancreas devices have been devised, although

none is yet available for routine use (p. 624).

Therapeutic strategy

Using conventional methods, the only way for a

diabetic to enjoy relatively normal eating and

activity (i.e.

unpredictable,

unplanned

and

uncontrolled)

would

be

to

have

frequent,

precisely calculated injections of soluble insulin

(or appropriate doses of a rapidly acting oral

hypoglycaemic [insulin secretagogue] drug). The

dose would be based on blood glucose measure-

ment or guided by experience and recent diet

and activity level: thus insulin is supplied on

demand in a manner emulating normal physi-

ology (see Figure 9.4). With the introduction of

insulin pens, such an ‘insulin demand-driven’

strategy

is

becoming

practicable,

although

dosage adjustment is still imprecise. The artificial

pancreas, if perfected, may prove a better option.

‘Insulin supply drive’

The

alternative

(and

original)

approach,

still

used for many older patients, is to turn physi-

ology on its head and to accept a model driven

by insulin supply. Instead of matching insulin

supply to instantaneous changes in demand,

demand

in

the

form

of

diet

and

activity

is

adjusted and controlled to conform to available

insulin (whether endogenous or administered

exogenously). Because both drugs and insulin

must be given prospectively this is in effect

‘feeding the insulin’, as opposed to the normal

situation where insulin follows feeding. Meals

and activity must be regular and of predictable

composition: explicit adjustments in drug or

insulin

dose

must

be

made

to

allow

for

deviations (Figure 9.8).

This

places

considerable

constraints

on

patients, particularly children. Education and

counselling

are

extremely

important

and

Diabetes

UK

performs

a

valuable

role

here.

People

with

type

1

diabetes

are

inevitably reasonable compliers in the strictest sense, in

that the severe metabolic upset precipitated by drug defaulting is a powerful motivator. Never-

theless, excellent compliance with diet, and the very tight control of blood glucose demanded for avoidance of long-term complications, is less common, especially in type 2.

Treatment modes

Dietary management is the bedrock of treat-

ment. All people with diabetes, irrespective of

other treatments, require some control of their

eating and exercise patterns, both in terms of

total

calorific

intake,

types

of

nutrients

and

eating schedule. Indeed, about half of patients

will need no more than this, especially those

who lose weight. A further 25% will need to

augment their natural insulin with drugs. The

remainder will need insulin.

The initial choice is usually related to how the

patient

first

presents (Figure 9.9).

Younger

patients, who are frequently non-obese, usually

present

unambiguously

with

type

1

insulin-

dependent diabetes, although a variable insulin-

independent (‘honeymoon’) period may occur following diagnosis.

Older

patients,

who

are

often

obese,

will

almost always be type 2 and must be tried first

on

diet

alone.

Should

this

fail,

drug

therapy

will

be

added.

All

drugs

used

in

diabetes

are

classed

in

the

BNF

as

antidiabetic,

and

this

term

will

be

used

generically

here (although

NICE refers to these drugs as ‘glucose-lowering

drugs’). The older term ‘oral hypoglycaemic’ is

obsolescent,

owing

to

the

development

of

classes

of

drugs

that

do

not

directly

lower

blood

glucose.

Those

that

do,

i.e.

sulphony-

lureas

and

meglitinides,

are

more

accurately

described as insulin secretagogues.

Type 2 patients are usually to some extent

overweight on presentation, and a biguanide is

the first choice. Otherwise a sulphonylurea is

selected. Sometimes a synergistic combination of

the two types will be required. For those for

whom these measures are ineffective a glitazone

may be added. For some patients even this is

unsatisfactory

and,

especially

if

ketoacidosis

occurs, insulin treatment is needed, as it will be

eventually

in

those

whose

disease

progresses

faster. Type 2 patients may also need insulin

temporarily during periods of increased require-

ment such as major infection, surgery or preg-

nancy.

Combining

antidiabetic

drugs

with

insulin therapy is being used increasingly (see

below).

At any point in this sequence, an adjunctive drug that reduces intestinal glucose absorption or reduces insulin resistance may be added.

Initiation of treatment

On first diagnosis, all patients will be fully exam-

ined

and

investigated

to

establish

baseline measures

for

monitoring

development

and progression

of

any

complications.

This

will include ophthalmological, renal, cardiovascular, neurological, lipid and foot assessment.

Some patients will need to be treated first in

hospital,

especially

type

1

patients

first

presenting

with

ketoacidosis.

Blood

glucose

levels

will

be

measured 3-hourly

during

this

period, to establish the diet and possibly the

drug or insulin dosage necessary to achieve the

agreed level of control. After discharge some will

continue to attend as outpatients. Others will be

managed by general practice clinics, which often

include specialist diabetic nurse practitioners.

However,

regular

diabetic

clinic

visits

are

desirable if they have developed complications

or management becomes difficult. Some type 1

and most type 2 patients without acute compli-

cations may be treated by their GP from the

outset.

Diet

Most type 2 patients must first be encouraged to

try to control their disease on diet alone, and no

patient

taking

antidiabetic

drugs

or

insulin

should believe that these obviate the necessity to

control their diet. Recommendations about diet

have evolved in several important ways. Fats are

now discouraged, while complex carbohydrate

and

fibre

are

encouraged,

and

the

overall

approach is now far less restrictive. The recom-

mended diabetic diet, save in a few respects, now

closely resembles the normal healthy diet that

everyone should eat: regular meals low in fats,

simple sugars and sodium and high in complex

carbohydrate (starch) and fibre.

Formerly, inflexible, unrealistic or impractical

prescriptions

and

restrictions

(diet

sheets,

‘exchanges’) took little or no account of the

psychological importance of individual dietary

habits, dietary preferences and ethnic variations.

The result was poor compliance complicated by guilt and anxiety. The modern approach recog-

nizes that:

•

Dietary records or recall are an imprecise basis

for future modification.

•

Nutrient uptake varies even from precisely

regulated and measured portions, owing to

the

interactions

between

foodstuffs,

varia-

tions

in

temperature,

physical

form

and

degree of chewing, etc.

•

Compromise is needed to devise a regimen

with which the patient can be concordant.

Thus a perfect diabetic diet is difficult to achieve in practice, and although the pursuit of it is

worthwhile, this could be counter-productive in some patients. Rather, efforts are made to ensure that patients understand, in their own fashion, what the aims are. Counselling and education are then used to maximize motivation. Advice from a dietician with experience in modifying diabetic diets to suit individual lifestyles can

help achieve good compliance.

Four aspects of diet need to be considered

(Figure 9.10):

•

Total energy intake. •

Constituents.

•

Timing.

•

Variation.

Energy intake

All patients need to adjust their calorific intake

to achieve and maintain the desired bodyweight

for their size, aiming for a body mass index of

about 22 kg/m2. For most people with type 2

diabetes, who are frequently obese, this implies a

weight-reducing diet. Reliable tables are now

available to predict the required energy intake

according

to

age,

gender,

activity

level

and

lifestyle.

Constituents

Macronutrients

The unselective restriction on carbohydrate that

used to characterize diabetic diets is now consid-

ered misconceived. Carbohydrate is not harmful

if

taken

mainly

as

slowly

absorbed

complex

polysaccharides, e.g. starch. Such carbohydrates

allow people with type 2 diabetes to make best

use of their limited endogenous insulin secretory

capacity

by

not

raising

postprandial

blood

glucose

too

rapidly.

Foods

can

be

classified

according

to

their

glycaemic

index,

which

represents the ratio of the total glucose absorp-

tion they produce compared with that from a

standard

test

meal

of

wholemeal

bread

and

cottage cheese. The lower the index the better,

and representative values are rice 80%, potatoes

77%,

pasta

60%

and

lentils

45%.

Foods

acceptable to various ethnic minorities, such as

chappatis, kidney beans, chickpeas, etc. are also

now encouraged where appropriate.

The relatively high fat content of early dia-

betic diets, which was needed in a carbohydrate-

reduced diet to provide calories more cheaply

than with protein, is now seen to be danger-

ously atherogenic. A reduced fat intake, low in

saturated fats and comprising about one-third

polyunsaturated

and

one-third

monounsatu-

rated

fat (e.g.

nuts,

fish,

olive

oil)

is

now

encouraged. Cholesterol itself is usually reduced

inherently along with saturated fats. There are

no particular constraints on protein except for

patients

with

suspected

nephropathy,

when

restriction is indicated.

Other nutrients

A small amount of simple sugar (sucrose) is now

considered acceptable, if the calorific content is

accounted for. This is usually consumed as a

constituent,

e.g.

of

baked

products.

Artificial

non-nutritive sweeteners are still preferred and

patients must be advised to monitor their intake

of ‘hidden’ sugar in processed foods. So-called

‘diabetic foods’ often contain sorbitol or fructose

and, while they may not raise blood glucose as

much as sucrose, have a high energy content and

cause diarrhoea in excess. They are also expen-

sive, offer nothing that a well-balanced diabetic

diet cannot offer, and are not recommended by

Diabetes UK.

Alcohol is not prohibited if its high calorific

content is accounted for and its hypoglycaemic

effect is appreciated, i.e. it should be taken with

some carbohydrate. Recent evidence of its protec-

tive effect against heart disease suggests that

once

again

similar

recommendations

should

apply to the diabetic population as to the popu-

lation as a whole. There should be little added

salt, to minimize rises in blood pressure.

Fibre is extremely important. Although fibre

is primarily carbohydrate, the terminology is

Management

609

somewhat

inconsistent;

however,

the

distinc-

tions are relevant (Figure 9.11). Starch, in staple

foods like bread, potatoes and rice, is the main

digestible

carbohydrate

energy

source.

Older

classifications

grouped

all

other

indigestible

matter together as ‘dietary fibre’, but there are

important and distinct components. The non-

starch

polysaccharides (NSP)

are

now

known

to be particularly important in diabetes. They

provide no energy but further delay absorption

of glucose from starch digestion (see above), and

by forming intestinal bulk promote a feeling of

satiety that may reduce appetite and therefore

help weight control.

The (semi)soluble or viscous fibres and gums

found

in

fruit,

vegetables

and

pulses (Figure

9.11) produce in addition a modest reduction in blood cholesterol, possibly by binding bile salts and thereby preventing their enterohepatic recir-

culation. The insoluble NSP fibres, as in bran and unmilled cereals and grains, have little effect on cholesterol, but contribute to stool bulk along with other fibrous residues, e.g. lignin. Although undigested in the ileum, some of this material is hydrolysed by colonic flora to release absorbable and metabolizable carboxylic acids.

Proportions

The

recommended

proportions

of

macronu-

trient energy intake are approximately 60:30:10

(carbohydrate:fat:protein;

Table

9.14);

tradi-

tional diabetic diets used to be nearer 25:65:10.

Within the fats, only a third should be saturated

fats. How the patient implements this has also

changed. Clinics no longer issue rigid menus,

kitchen scales and detailed tables of what can be

exchanged for what. More generalized recom-

mendations

with

much

wider

variability

are

found to be more successful.

One such approach simply visualizes a meal

plate divided into segments (Figure 9.12). About

two-thirds contains polysaccharide: equal parts

staple carbohydrate sources such as rice, pasta or

potatoes starch and fibre such as fruit or vegeta-

bles. The remainder is mostly composed of fats

and protein sources such as meat, fish and dairy

products. A small amount of sugar is allowed.

The patient is advised to construct each meal in

these proportions. This roughly conforms to the

recommended proportions, allowing for some

fat

and

protein

being

included

along

with

the carbohydrate.

Timing

Small,

regular,

frequent

meals

are

important.

This means similar calorific intake at all main

meals and regular snacks in between. For type 2

patients

this

minimizes

the

load

put

on

the

pancreas

at

any

one

time.

For

both

types

it

helps to keep blood glucose levels within closer

limits,

minimizing

the

risk

of

hypoglycaemia

between drug or insulin doses and the risk of

postprandial

hyperglycaemia.

There

is

some

evidence that this too is a pattern that might

benefit

the

general

population.

Nibbling

or

‘grazing’

appears

to

produce

lower

average

plasma lipid and blood glucose levels and less

obesity compared with a similar calorific intake

obtained from intermittent, larger meals.

Variation

People with diabetes need to understand that

these constraints do not prevent them having a

varied,

appetizing

and

nutritious

diet.

They

should also understand how to augment their

diet to match any unplanned or unusual exercise

or stress so as to avoid hypoglycaemia. Tempo-

rary changes in a patient’s metabolic require-

ments (as in serious illness) or oral absorptive

capacity (e.g. gastroenteritis) require appropriate

adjustment,

which

may

involve

temporary

insulin therapy in a type 2 patient, and regular

blood glucose monitoring is then essential.

Type 1 patients using the ‘insulin pen’ will

generally be even more flexible (see below). In

mildly diabetic elderly patients the diet will also

be far less rigid, for reasons already discussed. On

the other hand, the diets of growing children

need constant reassessment. The availability of

nutrients

and

the

habits

and

constraints

of different ethnic groups also need to be taken

into account. Dieticians are an essential part of the diabetic team.

Diet as sole management may fail in up to

two-thirds of type 2 patients. Primary failure is usually due to poor compliance, poor motiva-

tion

or

inadequate

counselling.

Secondary failure usually results from disease progression, with falling insulin production. The next stage is to introduce oral antidiabetic drugs.

Oral antidiabetic drugs

Aim and role

Oral antidiabetic drugs (OADs) are used as the

next step for type 2 patients in whom diet has

failed to control their condition adequately. The

majority may then be controlled by a combina-

tion of diet and oral drugs for a number of years,

but some type 2 patients may eventually require

insulin treatment.

There are four main therapeutic targets for

OADs (Table 9.15). Doubts over the safety of

some of these drugs have now been resolved.

The results of the University Group Diabetes

Programme (UGDP) trial in the 1970s, which

suggested significant toxicity in the sulphonyl-

ureas, are now discredited. Phenformin, an early

biguanide, caused numerous deaths from lactic

acidosis and was withdrawn. Newer biguanides

are

much

safer:

only

metformin

is

currently

available in the UK; elsewhere buformin is used.

Novel incretin analogues are undergoing trials.

Incretin is a newly discovered peptide hormone,

secreted in the small intestines following food

intake, which enhances insulin secretion and

suppresses

glucagon,

slows

gastric

emptying

and reduces food intake. It was isolated from a

lizard that eats only four times a year. Exenatide

has been shown to lower glycated Hb levels and

weight. Sitagliptin inhibits incretin inactivation.

All

OAD

strategies

depend

on

endogenous insulin secretion and are therefore effective only in patients with type 2 disease who retain appre-

ciable beta-cell function. Ketosis-prone patients, patients

with

brittle

disease

or

those

whose fasting

blood

glucose

exceeds 15-20 mmol/L, almost invariably need exogenous insulin, in

both type 1 and type 2 patients.

m

Action

These

drugs

have

different,

albeit

comple-

mentary

and

sometimes

overlapping,

actions on

the

underlying

abnormalities

in

type 2

diabetes, so combination therapy is indicated if monotherapy fails.

Alpha-glucosidase

inhibitors

(acarbose)

inhibit the final stage of the digestion of starch

within the intestine by blocking the enzyme

disaccharidase. This reduces the rate of glucose

absorption and thus the postprandial glucose

load presented to the islet cells. Thus, a pancreas

with a limited insulin secretory rate might be

better

able

to

handle

this

load

with

less

hyperglycaemia.

It

can

be

regarded

as

anti-

hyperglycaemic

rather

than

a

hypoglycaemic

agent.

It

has

a

relatively

small

effect

on

glycaemia and is used only as an adjunct to other

therapy,

but

may

be

added

at

any

stage

to

improve control.

Sulphonylureas

enhance

the

release

of

preformed

insulin

in

response

to

circulating

glucose,

partly

by

increasing

beta-cell

sensi-

tivity to blood glucose. This mimics the acute

phase of the normal response to hyperglycaemia.

However, sulphonylureas do not directly stim-

ulate subsequent insulin synthesis. Inhibition of

glucagon has also been suggested. Pharmacody-

namically, they differ only in relative potency but there are important pharmacokinetic differences between them. Sulphonylureas can be combined with most other OADs except the meglitinides. Although some doubt was cast over the safety of the long-established combination with metformin by the UKPDS, this has not been confirmed and the combination is still widely used.

Meglitinides (prandial glucose regulators) also

stimulate insulin release but not at the sulpho-

nylurea receptor. They are claimed to do so more

specifically in response to the blood glucose level

and thus to mealtime glucose load, making them

more

glucose-sensitive.

They

have

two

main

advantages over sulphonylureas. A more rapid

onset means they can be given 15 min or less

before a meal, giving patients more flexibility

and control; and their shorter duration of action

reduces the likelihood of postprandial hyper-

insulinaemia and between-meals hypoglycaemia.

In addition, if a meal is missed they can easily

be

omitted.

Nateglinide

has

a

prompter

and

shorter

action

than

repaglinide.

Currently

nateglinide

is

only

licensed

for

use

with

metformin, whereas repaglinide can be substituted

for sulphonylureas at any stage. The combina-

tion of a meglitinide with a sulphonylurea is

irrational.

Biguanides do not stimulate or mimic insulin

but are insulin sensitizers. They have two main

actions: they increase peripheral glucose uptake

and utilization and they inhibit hepatic gluco-

neogenesis and release of glucose from the liver

into the blood. The underlying effect is probably

via a general inhibitory action on membrane

transport.

Intracellularly,

this

would

prevent

glucose entering mitochondria, thus promoting

anaerobic glycolysis in the cytosol. Because this

is less efficient than aerobic glycolysis, cellular

glucose uptake and utilization are increased. This

may also account for a tendency to cause lactic

acidosis. In the intestine, reduced membrane

transport may be useful in slowing and reducing

glucose absorption. There may also be intestinal

lactate

production.

They

may

also

have

an

anti-obesity action. Only metformin is licensed in

the UK.

Biguanides can be combined with most other OADs.

Management

613

Glitazones

(thiazolidinediones:

rosiglitazone

and

pioglitazone)

are

also

insulin

sensitizers.

They activate a nuclear transcription regulator

for

an

insulin-responsive

gene (peroxisome

proliferators-activated receptor-gamma, PPAR ),

which has numerous complex effects on lipid

and glucose metabolism. An important compo-

nent

is

to

promote

triglyceride

uptake

and

peripheral adipose growth. The effect of this is to

reduce triglyceride availability, increase glucose

utilization, reduce insulin resistance and thus

reduce insulin levels. They also shift fat from

visceral, muscle and hepatic sites to peripheral

adipose tissue, which although resulting in an

increase

in

weight,

produces

a

more

favour-

able cardiovascular risk. This is partly because

they

alter

blood

lipids

favourably,

lowering

triglyceride and raising HDL levels.

The PROactive study suggested this group may

reduce complications, both macrovascular (by

reducing insulin and lipid levels) and microvas-

cular (by reducing hyperglycaemia) complica-

tions, but this has not yet been confirmed. The

prototype, troglitazone, was withdrawn soon after

release owing to liver toxicity but rosiglitazone

and

pioglitazone

are

safe

and

effective

either

alone or in combination if other OADs fail to

achieve control, although their precise role has

not

yet

been

determined.

Currently

NICE

recommends that they should not be added as

second-line

drugs

to

either

metformin

or

a

sulphonylurea,

except

when

these

latter

two

drugs cannot be used in combination owing to

contra-indications or intolerance.

Biopharmacy and pharmacokinetics

Sulphonylureas

are

generally

well

absorbed although

potential

bioavailability

differences mean

that

patients

should

avoid

changing formulation or brand. Most sulphonylureas are more than 90% protein-bound (except tolaza-

mide, 75%), and so are liable to competitive

displacement interactions.

There are important differences in clearance,

half-life and duration of action, which deter-

mine frequency of administration, precautions

and

contra-indications.

Clearance

is

usually

hepatic with subsequent excretion of inactive or

less active metabolites (Table 9.16; Figure 9.13),

usually

renally.

The

older

chlorpropamide

is partially

cleared

renally

and

also

has

active metabolite, which accounts for its long half-life. Those

with

inactive

metabolites (e.g.

tolbu-

tamide) generally have the shortest half-lives. Some sulphonylureas have metabolites that are chiefly excreted in the bile, which makes them more reliant on hepatic function.

The duration of action, or biological half-life,

is related to the plasma half-life but is often

longer, owing partly to the activity of metabo-

lites. Chlorpropamide has too long a duration of

action and frequently produces between-meals

hypoglycaemia; it has little if any role now and

is

contra-indicated

in

the

elderly.

The

other

popular

first-generation

sulphonylurea,

tolbu-

tamide, fell from favour because its action was

felt to be too short, requiring frequent dosing.

However, for this reason it may be useful in the

elderly, to minimize hypoglycaemia. Most newer

m

second-generation drugs avoid these problems, but there are wide interpatient variations in the handling of all sulphonylureas and dose regi-

mens must be individualized. Glibenclamide is a special case because it is concentrated within

beta-cells so its biological half-life is considerably longer than its plasma half-life. For this reason, it too is avoided in the elderly.

Biguanides

differ

substantially

from

the

sulphonylureas,

being

poorly

absorbed,

little

protein-bound

and

cleared

predominantly

by

renal

excretion (with

about 30%

cleared

by

hepatic metabolism). Metformin has a short half-

life and may require thrice daily dosing at higher

doses.

However,

modified-release

preparations

are available for dosages up to 1 g twice daily;

higher

doses

need

standard-release

therapy.

Buformin is longer-acting.

Renal

clearance

of

biguanides

may

exceed

glomerular filtration rate, implying some tubular

secretion. Thus minor renal impairment, un-

noticed because of a normal serum creatinine

level, might still permit significant accumula-

tion, and renal function monitoring is essential

with their use.

Meglitinides are rapidly absorbed, reaching a peak within 1 h and have a very short half-life, being cleared and eliminated hepatically. This means they may be useful in controlling blood glucose in close association with meals.

Glitazones

(thiazolidinediones)

are

rapidly

absorbed

and

hepatically

metabolized.

Although

the

half-life

is

less

than 24 h,

and once

or

twice

daily

dosing

is

adequate,

full effect takes at least a week, owing to the slow speed of fat redistribution.

Alpha-glucosidase

inhibitors

are

not

absorbed, acting slowly within the gut.

Adverse reactions

Sulphonylureas are well tolerated and free from

serious long-term adverse effects. The principal

problem

is

hypoglycaemia,

which

may

be

protracted and even fatal. A related drawback is

the tendency to produce or maintain obesity.

Both effects can be linked to increased insulin

levels, which also are giving concern over a

possible exacerbation of macrovascular compli-

cations, insulin being a possible growth factor in

arterial walls.

Hypoglycaemia may be caused by an overdose,

an interaction, a missed meal or unexpected

activity and occurs more commonly with the

longer-acting

drugs (glibenclamide

and

chlor-

propamide), especially in the elderly, who must

avoid them. (The possible compliance advantage

is far outweighed by the likelihood that a meal

will be forgotten while plasma drug levels are

still significant.) With the newer, shorter-acting

drugs any hypoglycaemia that does occur is brief

and more easily rectified.

Chlorpropamide can occasionally cause a mild

disulfiram-like

flush

with

alcohol (due

to

acetaldehyde

dehydrogenase

inhibition),

and

occasionally

hyponatraemia

and

a

syndrome

of

inappropriate

secretion

of

ADH.

These

effects,

as

well

as

minor

idiosyncratic

reac-

tions,

are

uncommon

with

second-generation

sulphonylureas.

Management

615

Meglitinides do not present such risks of hypo-

glycaemia and weight gain as the sulphonyl-

ureas.

No

serious

class

effects

have

become apparent so far.

Biguanides (with the exception of phenformin)

cause minor adverse effects, being somewhat less

well tolerated than sulphonylureas. The nausea,

diarrhoea,

muscle

discomfort

and

occasional

malabsorption experienced may be due to the

membrane effects inherent in their mode of

action. Malabsorption of vitamin B12

can occur.

Biguanides are best taken with food, the dose

being increased gradually to improve tolerance.

Iatrogenic

lactic

acidosis,

which

has

a

high

mortality, occurs rarely with metformin and the

risk can be further reduced by careful monitoring

of

renal

and

hepatic

function

and

ensuring

that

it

is

avoided

in

patients

with

renal

impairment

and

hypoxic/hypoxaemic

condi-

tions

such

as

cardiopulmonary

insufficiency.

Because biguanides do not release insulin, they

cannot cause hypoglycaemia and they do not

cause weight gain.

Alpha-glucosidase

inhibitors

frequently

cause uncomfortable and sometimes unaccept-

able

or

intolerable

gastrointestinal

problems

owing to the increased carbohydrate load deliv-

ered

to

the

large

bowel.

Subsequent

bacterial

fermentation causes distension, pain, flatulence

and diarrhoea.

Glitazones can cause a number of problems.

Fluid retention results in oedema, and heart

failure in up to 3% of patients: this is potentiated

in combination with insulin. There may also be

a mild dilutional anaemia. Hypoglycaemia is rare

but

weight

gain

is

common.

In

view

of

the

hepatotoxicity of the withdrawn troglitazone,

monitoring of hepatic function and avoidance

in hepatic impairment is needed, but they are

safe in renal impairment if allowance is made for

the fluid retention.

Interactions

Interactions with OADs are potentially serious

because

the

patient’s

delicate

biochemical

balance is maintained by a specific dose. Potenti-

ation can rapidly cause hypoglycaemia, whereas

antagonism could lead, more slowly, to a loss

of glycaemic control and a return of polyuric symptoms.

Pharmacokinetic

interference

with

absorption, binding or clearance occurs almost

exclusively with the sulphonylureas, when the

temporary introduction of an interacting drug

can alter the free OAD plasma level, with poten-

tially

dangerous

consequences.

A

number

of

drugs cause a pharmacodynamic interaction by a

direct effect on glucose tolerance (Table 9.17).

Fortunately, clinically significant problems are

relatively rare, and certainly far fewer than the

theoretical

possibilities.

Moreover,

different

drugs, especially among the sulphonylureas, have

different tendencies to show a given interaction.

m

Pharmacokinetic potentiation

Drugs that increase gastric pH may enhance

absorption

of

sulphonylureas.

Highly

plasma

protein-bound drugs can theoretically displace

sulphonylureas. However, following redistribu-

tion and alterations in clearance there may be

little overall change in free drug levels. More-

over, the newer sulphonylureas bind to different

plasma protein sites and are less prone to this

effect. The hepatic clearance of sulphonylureas

can

be

reduced

by

severe

liver

disease

and

by enzyme-inhibiting drugs and enhanced by

enzyme inducers; similar considerations apply to

the meglitinides. The glitazones have not been

reported to cause any hepatic enzyme interac-

tions. The renal clearance of unchanged drug or

active metabolites of any of these drugs can be

reduced by renal impairment and by certain

drugs that cause fluid retention (e.g. NSAIDs).

Pharmacodynamic potentiation

Alcohol

is

directly

hypoglycaemic

in

fasting

conditions,

and

it

may

also

potentiate

biguanide-induced lactic acidosis. Both MOAIs

and beta-blockers tend to cause hypoglycaemia;

the

former

may

inhibit

glucagon

secretion

and the latter inhibit hepatic glycogenolysis.

Beta-blockers can ‘mask’ the effects of hypo-

glycaemia

as

perceived

by

the

patient.

Beta-

blocker

interactions

are

seen

mainly

with

non-cardioselective agents if at all, but aside

from those with propranolol they are rare and

usually

insignificant.

ACEIs

enhance

glucose

uptake and utilization by cells, although the

effect may diminish with continued therapy and

is of uncertain significance.

Antagonism

Drugs that induce liver enzymes can increase the

clearance of hepatically metabolized sulphonyl-

ureas. Various drugs tend to raise blood glucose,

either directly or via the suppression of insulin

release. Paradoxically, given the masking effect

referred to above, beta-blockers can block insulin

release.

As a consequence of the inhibited disaccharide digestion, oral treatment of hypoglycaemia in patients

taking

glucosidase

inhibitors

should preferably be with glucose/dextrose rather than sucrose preparations.

Contra-indications and cautions

The main precautions may be summarized thus:

•

People with diabetes need to take particular

care when changing dose, brand or type of

antidiabetic medication.

•

Medication records should be monitored to

identify

the

introduction

of

potentially

interacting drugs.

•

The elderly are particularly prone to hypo-

glycaemia

with

the

longer-acting

OADs;

Management

617

these patients may be forgetful about meals, less

able

to

recognize

hypoglycaemia,

and less

tolerant

of

it

homeostatically

and neurologically.

•

Alcohol

use

must

be

carefully

controlled:

although

initially

it

may

cause

hypergly-

caemia

(owing

to

its

caloric

content),

it enhances hypoglycaemia and may impair the ability to respond to it.

•

Alcohol

also

dangerously

enhances

the

possibility of lactic acidosis with biguanides

and

it

causes

unwelcome

flushing

with

sulphonylureas, particularly chlorpropamide.

•

Some

clinicians

manage

all

patients

with

significant

renal

impairment

(common

in people with diabetes) or hepatic impairment (less common) with insulin.

Selection

Combinations

Most

type

2

patients

are

overweight

and

a

biguanide is the preferred first choice. It is also

satisfactory for others but a sulphonylurea might

be started in the non-obese. Patients who fail to

achieve blood glucose control on either regimen

use a biguanide in combination with a sulpho-

nylurea. Meglitinides, with their faster, shorter

action may be substituted for the sulphonylurea

at any stage if the patient prefers it, especially if

they

are

tending

to

suffer

hypoglycaemia

or

weight gain. A glitazone can be added as a third

agent when dual therapy fails, especially if the

patient has persistent postprandial or between-

meals

hyperglycaemia,

both

of

which

imply

insulin resistance. However, if metformin plus a

sulphonylurea

combined

fail

to

control

the

patient, it is likely that they have very little beta-

cell capacity left and the introduction of insulin

should be considered rather than adding a third

drug (see below).

Acarbose could be added at any of these stages to improve control but has a limited benefit and is often poorly tolerated. Sitagliptin and exenatide (p. 612) are available as third-line agents.

Constraints

In addition to these pharmacodynamic consider-

ations, the choice of any OAD must take account

of:

•

duration of action;

•

mode of clearance;

•

age;

•

renal and hepatic function;

•

tolerance of adverse effects;

•

patient preference for number of daily doses.

The elderly must avoid the longer-acting drugs,

while other patients may have particular reasons

for preferring more or less frequent dosing. By

analogy with insulin regimens, a combination of

a

single

daily

dose

of

a

long-acting

drug,

combined with regular top-up doses of a short-

acting one, has been recommended, but is little

used. In general there is little to choose between

the

sulphonylureas,

but

patients

with

renal

impairment

might

do

better

with

gliquidone

(Figure 9.13).

Some

patients

cannot

be

controlled

on

maximal

tolerated

doses

of

combined

OADs.

This may occur after many years of therapy as

the beta-cell function inexorably declines (i.e.

secondary failure), occurring in up to one-third

of type 2 patients within 5 years of diagnosis.

Alternatively some patients present late, when

there has already been considerable degenera-

tion (primary failure). In either case the situation

signifies that there remains insufficient residual

beta-cell

function,

and

exogenous

insulin

supplement becomes mandatory.

At that stage small doses of insulin may be

added to OAD therapy to provide a basal level.

This may delay the onset of full insulin therapy,

and may be preferred by patients anxious about

full insulin dependence. When type 2 patients

eventually need to be controlled with insulin

they do not of course become type 1, and they

may more accurately be referred to as having

insulin-requiring

type 2

diabetes.

Insulin-

augmented

OAD

therapy

will

be

considered

below

after

insulin

has

been

discussed (see

p. 627).

Insulin

About

two-thirds

of

people

with

diabetes

are

treated

with

insulin,

about

half of

whom

are

truly

insulin-dependent

type 1 and

others

are type 2 in secondary failure of OAD therapy.

m

Patients

using

insulin

require

much

finer

control

of

all

aspects

of

management,

including diet, activity and dose measurement,

than other people with diabetes. There is less

margin

for

error

because

patients

rely

totally

on

the

injected

dose.

In

contrast

to

type 2

patients, they lack the small basal insulin secre-

tion

that,

although

insufficient

to

prevent

hyperglycaemia, keeps the type 2 patient free

from metabolic complications like weight loss

and ketosis.

Aims and constraints

In

theory,

it

should

be

possible

to

attain

glycaemic

control

with

insulin

that

closely mimics the natural physiological variations in response to food intake, exercise and metabolic requirement. However, until recently it was not possible even to approach that.

Recall that natural insulin secretion from the

pancreas

into

the

portal

vein

is

finely

and

continuously

tuned

to

variations

in

blood

glucose level (p. 586; see Figure 9.3): this is very

different

from

the

usual

exogenous

insulin

therapy. An approximation might be attained

with a continuous basal injection plus regular IV

boluses of a rapidly acting insulin preparation to

coincide with meals and, ideally, continuously

titrated against the blood glucose level. This

would resemble the natural pattern except for

the portal delivery to the liver. However, such a

regimen is impractical for most patients.

Absorption from the usual SC injection sites,

whether as depot injections or by continuous

delivery, can vary in any one patient from time

to time and from site to site, particularly with

the

otherwise

more

convenient

longer-acting

preparations.

Moreover,

whereas

exercise

inhibits normal insulin secretion, it tends to

speed

absorption

from

an

injection

site

by

promoting peripheral circulation; thus when less

insulin

is

required,

more

is

delivered

exoge-

nously. It is also likely that SC injections admin-

istered by some patients are effectively IM now

that perpendicular injection is recommended,

changing

absorption

characteristics.

Alterna-

tively,

some

patients

retard

absorption

by

injecting into fat, which is less painful. Further-

more, the clearance of most forms of injected

insulin

is

generally

slower

than

endogenous insulin, the half-life of soluble insulin after SC injection being about 1 h.

Until recently the most common compromise

was to give a mixture of a fast-acting and a

moderately

long-acting

preparation

before

breakfast (e.g. soluble plus lente), perhaps with a

booster dose of soluble in the evening. With

appropriate ‘feeding the insulin’ throughout the

day (p. 605) acceptable control can be achieved.

However, it results in relative hyperinsulinaemia,

a tendency to hypoglycaemia during the day and

after midnight (especially if a meal or snack is

missed or there is unanticipated exertion), and

hyperglycaemia before breakfast (Figure 9.8).

Three

recent

advances

have

brought

treat-

ment

closer

to

the

ideal

for

many

patients. Ultra-short-acting analogues such as lispro allow closer matching to meals; long-acting analogues such as glargine provide more consistent basal levels; and ‘insulin pen’ systems permit easier and more accurate injection.

Insulin types

Developments

in

insulin

technology

have

produced a range of chemically pure, immuno-

logically

neutral

preparations

of

standard

strength (100 units/mL in the UK and North

America) with a wide range of pharmacokinetic

parameters.

Pharmacokinetic differences

Formulations of insulin can be divided into four

broad groups depending on their duration of

action; their times of onset and periods of peak

activity also vary considerably (Table 9.18). The

fastest action is provided by solutions of insulin.

In solution, insulin molecules normally associate

non-covalently

into

hexamers,

which

are

progressively

dissociated

by

dilution

in

body

fluids

to

the

active

monomer.

This

process,

which delays onset and prolongs duration, can

be

accelerated

by

small

rearrangements

of

molecular structure that affect association char-

acteristics but not pharmacodynamic activity.

Increased

duration

may

also

be

provided

by

forming

stable

suspensions

of

carefully

controlled particle size that gradually dissolve in

a uniform manner. Alternatively, solubility char-

Management

619

acteristics can be manipulated. Other chemical

manipulation produces ultra-long-acting (basal)

formulations. A number of premixed formula-

tions provide combinations of these properties.

Ultra-short

(rapid)

action.

By

substituting

different amino acids at key positions, insulin

analogues

have

been

produced

that

exist

in

monomeric form with little tendency to asso-

ciate but retain full activity at insulin receptors.

In insulin lispro lysine and proline are placed at

positions B28 and B29 near the end of the B

chain; insulin aspart

has aspartic acid at B28.

These agents have an onset of less than 15 min,

reach a higher peak within about half the time of

conventional soluble insulin (1 h as opposed to

1.5-2.5 h) and a duration of action little greater than 5 h (as opposed to 6-10 h). Thus, they can be injected less than 15 min before a planned

meal, or even just after one has been started; the optimal time will need to be determined for each patient. The advantages include:

•

Less imposed delay between injection and

food

intake (especially

breakfast),

and/or

reduction of postprandial hyperglycaemia if delay not observed.

•

Convenient pre-meal bolus doses, as part of

basal-bolus regimen (below).

•

Easier adjustment for unexpected food intake

or missed meal.

•

Reduction of between-meals hypoglycaemia,

caused in some patients by excessive duration

of action on regular short-acting preparations.

•

Less reliance on foods with a low glycaemic

index.

However, there is no advantage in using these

intravenously instead of soluble insulin in emer-

gencies or as part of a ‘sliding scale’ regimen (see

below). Patients who switch need careful re-

education about the relative timing of injection

and food intake.

Short

action.

Clear

solutions

of

soluble

(neutral) insulin act less rapidly than ultra-short

analogues and are cleared within 6-10 h. They

are useful:

•

when IV use is required, e.g. for ketoacidosis; •

when titrating a newly diagnosed patient’s

requirement;

•

in a continuous SC infusion system;

•

for the temporary insulin therapy of type 2

patients during pregnancy, surgery or severe illness.

Soluble insulin is being replaced by ultra-short-

acting

preparations

when

a

booster

dose

is needed rapidly, or when frequent injections are needed for patients with brittle diabetes.

Soluble

insulin

to

cover

a

particular

meal

should be injected 15-30 min, or occasionally

45 min,

beforehand.

When

newly

diagnosed

type 1

patients

are

being

assessed

they

are

usually put on an insulin sliding scale regimen,

with 4-hourly

soluble

insulin

doses

adjusted

according to the current blood glucose level.

Intermediate

and

prolonged

action.

Many

patients still receive part of their daily insulin

dose as a depot injection. This is intended to

provide a continuous basal level of insulin for

metabolic activity, with little effect on postpran-

dial glucose disposal. The particular regimen is

dictated partly by life pattern and patient prefer-

ence, but ultimately by trial and error. Depot

preparations

are

formulated

by

complexing

insulin with either zinc or protamine, a non-

allergenic

fish

protein.

This

produces

a

fine

suspension that is assimilated at a rate that is

dependent on particle size and injection site

perfusion. Being a suspension, it cannot be given

intravenously. Available products span a wide

spectrum of times of onset, peak activity and

duration,

allowing

flexibility

in

tailoring

regimens (Table 9.18).

The insulin zinc suspension (IZS) range contains

an insulin-zinc complex in either crystalline or

amorphous form, the latter being more readily

absorbed. Insulin zinc suspension mixed is 30%

crystalline and 70% amorphous, and insulin zinc

suspension crystalline

is 100% crystalline, with

proportionate increases in duration of activity.

(Insulin zinc suspension amorphous, which is no

longer

available,

was

purely

amorphous

and

combined prompt onset with quite prolonged,

but

rather

variable,

action).

Isophane

insulin

containing protamine as the retarding agent also

has an intermediate activity.

Protamine zinc insulin and insulin zinc suspen-

sion

crystalline

are

the

longest-acting

prepara-

Management

621

tions available. If an excessive dose of this type

is

injected,

the

hypoglycaemic

effect

is

corre-

spondingly prolonged and glucose or glucagon

injection may be needed to reverse it. Because

the

variability

in

response

between

different

preparations

increases

with

the

duration

of

action

(even

in

the

same

patient),

these

very

long-acting forms are little used unless patients

of long standing are stabilized on them.

A variety of premixed biphasic

preparations

(compatible

combinations,

usually

of

soluble

and isophane forms) are available to provide

further flexibility. Some patients mix specific

combinations immediately before injection.

Basal.

A

more

physiological

approach

to

insulin

provision

has

recently

evolved.

The

basal-bolus regimen is designed to provide a

continuous backgound level of insulin supple-

mented by bolus doses at mealtimes. Existing

prolonged

action

formulations,

while

lasting

24 h

or

more,

did

not

provide

the

required

consistency of release: they all tended to give a

peak at 6-12 h (Table 9.18). Two different strate-

gies have been devised to solve this problem. In

insulin glargine, amino acid substitutions have

changed the isoelectric point of the molecule

from below pH 7 to neutral. As a result it is

soluble when administered in a slightly acid

solution but precipitates out as microcrystals at

body pH after injection. Subsequent dissolution

and

absorption

from

the

depot

provides

a

predictable, consistently sustained action with

an essentially flat activity profile for up to 24 h

(Table 9.18). In insulin detemir, attaching a C14

fatty acid chain to the insulin molecule substan-

tially increases reversible binding to albumin in

body tissue, with a similar result.

Purity and antigenicity

There are two significant factors here: chemical,

and

therefore

immunological,

similarity

to

human insulin; and contamination with extra-

neous antigenic material. Originally, all insulin

was extracted from ox or pig pancreases supplied

by slaughterhouses. (Approval for insulin treat-

ment from these sources has been obtained from

most

major

religions,

but

strict

vegans

may

present a problem.) Beef insulin differs from the

human insulin polypeptide sequence by three amino acids, and porcine by just one. These

differences affect antigenicity but not hypogly-

caemic potency. As may be expected, porcine is

the better tolerated, but neither causes great

problems.

Contaminants

derived

from

the

extraction

process (e.g.

pro-insulin),

insulin

breakdown

products and other unrelated proteins, can stim-

ulate the production of insulin antibodies, and

allergic

reactions

used

to

be

quite

common.

Consequently, chromatographic purification is

now

used

giving

highly

purified

or

mono-

component animal insulins that cause far fewer

problems.

Human

insulin

is

made

either

semi-

synthetically,

by

chemically

modifying

the

single variant amino acid in purified porcine

insulin (emp,

enzyme-modified

porcine),

or

biosynthetically (crb, chain recombinant-DNA

bacterial;

prb,

proinsulin

recombinant-DNA

bacterial;

pyr,

precursor

yeast

recombinant).

Biosynthesis is becoming the preferred process

and human insulin now costs less than animal

forms.

Unfortunately, the expectation that human

insulin would be vastly superior has not been

realized. Anti-insulin antibodies are not signifi-

cantly less common with human insulin than

with

the

highly

purified

porcine

form,

and allergic phenomena still occur, probably due to breakdown products occurring during manufac-

ture, storage, etc. Nevertheless, almost all new patients are started on human insulin, and use of animal-derived insulin is now rare.

Human insulin is slightly more hydrophilic

than animal forms. Thus, although it has an

identical biological action to pork insulin when

given

intravenously,

it

is

assimilated

more

rapidly from SC sites and acts more quickly in

otherwise

identical

formulations.

It

is

also

cleared more rapidly, possibly by binding more

avidly to those hepatic and renal enzymes that

destroy it. These differences are slight and only

relevant to patients transferring from one form

to the other.

Adverse reactions

The chief adverse effects of insulin are hypogly-

caemia, injection site problems, immunological

m

phenomena

and

resistance.

These

may

be partially inter-related.

Hypoglycaemia

This

is

the

most

common

complication

of

insulin

therapy

and

potentially

the

most

harmful; the clinical aspects were discussed on

pp. 596-598. Insulin can cause hypoglycaemia

either through an excessive (e.g. mis-measured)

dose

or

through

an

unexpectedly

reduced

insulin requirement (most commonly, a missed

meal).

Human insulin has been associated with an

apparent increase in the incidence of hypogly-

caemic attacks, including some deaths. This was

initially attributed to a reduced hypoglycaemic

awareness,

i.e.

hypoglycaemia

is

not

more

common

but

is

permitted

to

progress

more

frequently. The autonomic warning symptoms

of hypoglycaemia (see Table 9.12) seemed to be

experienced less intensely or at a later stage

when using human insulin, perhaps owing to

autonomic (sympathetic) neuropathy.

There is no pharmacodynamic rationale for

this phenomenon and it has been suggested that

it is only incidentally related to human insulin

use. The change to human insulin came at a time

when

the

need

for

tighter

control

became

apparent and aids to this, e.g. injector pens and

home blood glucose monitoring, were devel-

oped. Improved control produces lower mean

glucose levels and therefore an increased risk of

hypoglycaemia. Thus it is not now regarded as a

serious problem of human insulin, although it is

stressed that great care is necessary in transfer-

ring a patient to human insulin. Close moni-

toring is essential and the daily dose may need to

be reduced, particularly when changing from

beef insulin or for patients with a higher than

average daily insulin requirement.

Injection site lipodystrophy

Some patients develop unsightly lumps (lipo-

hypertrophy)

or

hollows

(lipoatrophy)

at

frequently used injection sites if they fail to

rotate the sites regularly. These are not due to

scar tissue but are caused by local disturbances of

lipid metabolism. Lipoatrophy seems to be an

immunological phenomenon; immune complex

deposition may possibly stimulate lipolysis in SC

adipose tissue. It responds to changing to a purer

form of insulin, initially injected around the

depression. Lipohypertrophy is more common

with the newer insulins and may result from

enhanced

local

lipogenesis,

a

known

insulin

action. It is reversed when the site is no longer

used. Although patients may prefer to inject at

these easily penetrated, relatively painless sites,

such an approach results in delayed and erratic

absorption.

Insulin antibodies and insulin resistance

Insulin

antibodies

(insulin-binding

globulins)

occur in up to 50% of insulin-treated patients. It

might be expected that they would speed the

clearance

of

insulin

by

forming

immune

complexes that would be eliminated in the usual

way

by

the

monocyte-macrophage

system.

However, on the contrary, insulin antibodies

delay assimilation and prolong the action and so

are potentially beneficial. They are otherwise

usually harmless, although they may sometimes

be responsible for insulin resistance (see below).

Insulin allergy ranges from minor local irrita-

tion to, very rarely, full-blown anaphylaxis. The

less

serious

reactions

commonly

remit

on

prolonged use and are minimized by using the

highly purified modern insulin formulations as

first choice. The size of the insulin molecule is

borderline

for

antigenicity.

Hyposensitization

has

been

used

to

treat

insulin

allergy,

by

injecting extremely dilute insulin solutions at

Management

623

progressively higher concentrations to induce tolerance.

Very

occasionally,

local

steroid injections need to be given with the insulin.

The term insulin resistance tends to be used in

an ambiguous manner (Table 9.19). In patho-

genetic terms, it refers to one of the common

underlying problems of type 2 diabetes, namely

reduced receptor sensitivity. As an adverse effect

of insulin treatment, it refers to the requirement

in some insulin-dependent diabetes for doses of

insulin far above the physiological norm.

In the latter sense, insulin resistance occurs

only rarely and may be defined as an insulin

requirement ÷1.5 units/kg/day (about 100 units

daily in an average patient). There are many

possible causes; probably the most common is

simply

obesity,

but

poor

injection

technique

may be an unsuspected problem. Insulin resis-

tance

is

less

common

now

with

the

use

of

the

monocomponent

and

human

formula-

tions.

Treatment

involves

eliminating

any

obvious cause and then gradually switching to

highly

purified

or

human

insulin.

As

a

final

resort, systemic steroids, which are themselves

diabetogenic, may be needed.

Administration

Delivery systems

Pen

injectors.

Multidose

insulin

reservoir

injector pens are now the most popular delivery

system. Each pen has a replaceable cartridge

loaded with up to 300 units (3 mL), representing

up to 1 week’s supply for some patients. There

are various forms of metered-dose injectors. One

automatically delivers a 2-unit dose for each

depression of a trigger, i.e. 2 units per ‘click’, a

situation that is particularly beneficial to visually

impaired people with diabetes; another form

permits full doses to be preset visually on a

digital scale, which may be palpable or audible.

Most have a maximum deliverable single dose to

minimize the risk of overdose. Each type of pen

should

only

be

used

with

the

appropriate

cartridge. The main advantages are correct dose

measurement,

and

hence

less

error,

and

the

facilitation of multiple daily dosing as part of a

basal-bolus regimen.

Standard syringe.

The use of disposable plastic

syringes with fixed needles is no longer the norm

in the UK. If stored in a fridge, these syringes may

be re-used for up to 1 week, without significant

contamination

of

the

vial

contents (which

contain a bacteriostat) and no increase in skin

reactions. Patients change the syringe when the

needle

is

blunted

or

the

barrel

graduations

become unclear. Injection through clothing, long

practised by some people with diabetes, has also

been reported to not cause significant problems.

Patients must use a safe method of contaminated

waste and ‘sharps’ disposal.

Artificial

pancreas.

The

ideal

replacement

pancreas

has

not

yet

been

constructed.

One

experimental

approach

involves

a

feedback-

controlled, blood-glucose driven ‘closed loop’

system. A sensor in an IV catheter monitors

blood glucose continuously and the results are

fed

to

a

microprocessor

that

calculates

the

instantaneous insulin requirement. This drives a

portable pump, strapped to or implanted in the

patient,

delivering

the

appropriate

dose.

The

main problem is in designing a suitably sensitive

indwelling

blood

glucose

sensor.

In

another

experimental

system,

an

implanted

insulin

reservoir

enclosed

in

a

glucose-sensitive

gel

membrane permits insulin diffusion in propor-

tion

to

external

glucose

concentration.

The

reservoir is replenished percutaneously.

Continuous SC insulin infusion is a more

practicable but still relatively expensive ‘open

m

loop’

option,

without

the

automatic

dosage

control. An external reservoir/pump strapped to

the body delivers a continuous basal level of

insulin via an indwelling catheter, with meal-

time boosts being activated manually. Modifica-

tions include an implanted pump, contolled by

radio, and the use of an intraperitoneal catheter,

which has the theoretical advantage of more

closely mimicking the natural insulin secretion.

Clearly this method would only suit patients

who are able to manage the technology and

understand

the

relationship

between

blood

glucose, diet, activity and insulin dose. However,

current prototypes are as yet too bulky, expen-

sive and demanding of patients’ motivation for

general use.

Other

forms.

Simple oral administration of

insulin

is

impossible

owing

to

intragastric

enzymic destruction. Systems are being devel-

oped that avoid this but do not require the

complications of injection. One approach is to

incorporate insulin into liposomes that would be

taken orally. The lipid coat would act as an

enteric

coating

and

the

liposomes

would

be

absorbed

unchanged

from

the

gut,

as

are

chylomicrons. Percutaneous jet

injection

has

also been tried. Intranasal administration

is

being explored, using a liposomal or polymer

vehicle.

People

with

diabetes

with

advanced

nephropathy

on

peritoneal

dialysis

find

it

convenient to add insulin to their dialysis fluid.

A metered dose inhaler (inhaled human insulin,

Exubera) for pulmonary absorption is now avail-

able in the UK. It seems to offer an activity

profile

similar

to

injection

with

the

rapidly

acting

insulin

analogues

but

may

be

more

acceptable to some patients in combination with

a single basal insulin dose by injection. Concerns

remain

over

cost

and

possible

lung

damage,

especially in smokers, who should not use it.

Moreover, bioequivalence is an issue for patients

switching to inhaler, not least because the dose is

expressed in milligrams, 1 mg being equivalent

to 3 units.

Storage

Insulin

should

always

be

kept

cool,

but

is

stable

at

room

temperatures

for

up

to 28

days. Formulations incorporating polyethylene- polypropylene

glycol,

specially

developed

for

prolonged

reservoir

use,

are

stable

for

even

longer.

Thus,

insulin

may

safely

be

used

in

pens

and

continuous

SC

infusion,

etc.

and

while travelling. Pharmacy stocks and patients’

reserve

supplies

are

refrigerated

(but

not

frozen).

Before

withdrawing

a

dose,

the

vial

should

be

warmed

to

body

temperature

and

gently mixed by inversion or rotation (but not

shaken).

Mixing

If a combination of two preparations of different

durations

is

required,

specially

formulated

proprietary mixtures should be used whenever

possible, and extemporaneous mixing avoided.

The

insulin

zinc

suspension

formulations

are

intended

to

be

stable

after

intermixing

but

others are not, and mixtures of these must be

injected

within 5 min.

One

problem

is

the

adsorption of the soluble form onto the retar-

dant from the longer-acting one, which may

seriously interfere with the expected rapid action

of the former. The order of mixing is important:

the soluble form is drawn up first, then the depot

form. This avoids contamination of the whole

vial of soluble insulin with zinc or protamine.

Injection

Now

shorter

needles

have

become

available,

deep SC injection perpendicular to the skin is

Management

625

universally recommended. Most patients cope

well, but instruction and counselling when treat-

ment is started are clearly important, especially

with children. Diabetes UK and a number of

interested

manufacturers

produce

helpful

literature on this and all other aspects of diabetes

care.

Equally important is the need to rotate the site

of injection regularly so that any one site is only

used once in 10-20 injections. Seven general

areas are recommended by Diabetes UK (upper

arms, thighs, buttocks, abdomen), but within

these areas the precise injection site used on one

occasion

can

be

avoided

on

the

next;

they

provide a template to assist such variation. This

minimizes skin reactions, especially lipohyper-

trophy. Patients can also use the slower assimila-

tion sites, e.g. thighs, for the overnight dose.

Sites usually covered by clothing are preferred.

Factors

that

may

alter

absorption

from

the

injection

site,

possibly

upsetting

control,

are

summarized in Table 9.20.

Dosage regimens

An initial dose titration period on first starting

insulin

will

indicate

the

total

daily

dose

required, but decisions on how this is to be

distributed throughout the day require discus-

sion

with

the

patient.

With

fewer,

medium-

acting injections overall control is poorer and

there is the added risk of hypoglycaemia, with

the threat of coma if a meal is missed. However,

when multiple injections are linked with close

blood glucose monitoring, aimed at achieving

lower glucose levels (so-called ‘tight glycaemic

control’)

there

is

the

risk

of

more

frequent

episodes of hypoglycaemia. On the other hand,

use of multiple short-acting regimens can lead to

hyperglycaemia between injections and poorer

control. For each patient a balance must be

struck that imposes no more restriction on their

life than they are prepared to tolerate, which as

closely as possible meets their treatment objec-

tives.

Achieving

this

is

not

easy.

Factors

to

consider are:

•

the

patient’s

pattern

of

glycaemia

(e.g.

nocturnal

hypoglycaemia,

morning

hyper-

glycaemia); •

age;

•

severity of complications;

•

occupation, social habits and routine; •

compliance;

•

physical disabilities;

•

comprehension of disease, prescribed regimen

and associated equipment;

•

patient preference;

•

ethnic and religious constraints.

The blood glucose targets are usually:

•

never below 4 mmol/L;

•

fasting (preprandial) 4-7 mmol/L;

•

postprandial and bedtime

9 mmol/L.

Specialized units can organize test periods of

24-h blood glucose monitoring via temporary

indwelling sensors to plot the patient’s pattern

of

glycaemia.

However,

the

interpretation

of

these data is complex and it is an uncommon

technique. Somewhat easier is for the patient to

perform a short period of self-monitoring and

recording, the results of which can be discussed

with their diabetologist.

There are also more general considerations,

especially

when

first

starting

insulin.

Many

people have a distaste for injections or fear them,

and the psychological stress of accepting reliance

on injections for life can be substantial. This is

more of an issue with type 2 patients as they

approach secondary failure on OADs, which is

considered below.

m

The choice ranges from multiple daily injec-

tions of short-acting insulin closely co-ordinated with eating and activity pattern, to a convenient but very unphysiological single daily dose of a longer-acting preparation (Table 9.21).

Whatever the regimen, the total daily dose

required

is

usually

0.5-1.0 unit/kg(about

50 units). This is usually divided as 2⁄3

during the

day and 1⁄3 at night for minimum frequency

regimens and 50/50 for basal-bolus regimens.

Minimum dose frequency regimen

Because of the potential compliance benefits of fewer daily injections, this method used to be favoured.

However

it

is

no

longer

preferred because

it

imposes

inflexibility

on

activity patterns and mealtimes, and risks both poor

control

and

episodes

of

hypoglycaemia.

The regimen

usually

consists

of

morning

and evening doses of a combination of short- and

medium-acting preparations, the relative doses being determined by trial and error.

There are numerous possible variations. For

example, the morning dose could be a mix of

about one-third soluble and two-thirds interme-

diate-acting forms, which covers breakfast and

provides a sustained level throughout the day.

This may be repeated in the evening, or later in

those

patients

who

get

serious

pre-breakfast

hyperglycaemia. Alternatively there may simply

be a booster dose of soluble before the evening

meal.

If

one

of

the

commercially

available

premixed

combinations

can

be

used

it

is

certainly

convenient,

especially

with

a

pen.

More

flexibility

is

provided

by

individually

determined

combinations,

but

a

pen

cannot

then be used.

Some patients can be controlled satisfactorily

with just a single dose of a long-acting form. This

includes type 2 patients with significant residual

endogenous insulin production in whom OADs

have failed, and some elderly patients requiring

only symptomatic relief and for whom the threat

of long-term complications is less critical.

Multiple injections

These are now preferred for all patients who can

manage to self-inject frequent doses of short-

acting insulin throughout the day, before each

food intake. In addition, an evening dose of -acting insulin is given for basal needs. The most recent variation of this basal-bolus regimen utilizes

ultra-short-acting

and

long-acting analogues, e.g. Table 9.21, regimen 5.

A

multiple

injection

regimen

is

especially

useful for brittle patients requiring close control,

or for temporary transfer of patients to insulin,

e.g. type 2 patients during pregnancy or with

serious infections. However, many clinics are

starting most new patients on such a regimen,

for

which

injector

pens

are

ideal.

Existing

patients are also being converted. Many patients

can,

with

experience,

finely

judge

the

dose

required according to their food intake and exer-

cise. Others, more committed, will measure their

blood glucose level immediately before the next

scheduled

dose

and

adjust

the

insulin

dose

accordingly.

The

improved,

more

physiological

control provided by this type of regimen reduces the

development or progression of complications; in some trials they have even remitted. Such regi-

mens can also, if used properly, minimize the risk of hypoglycaemia between meals and of

overnight hyperglycaemia.

Insulin for type 2 patients

Most type 2 patients will eventually need insulin

as

their

beta-cell

capacity

become

exhausted

(secondary failure). Owing to the insulin resis-

tance common in type 2, their insulin require-

ment

when

they

become

completely

insulin

dependent will often exceed that of a type 1

patient. However, it may be preferable not to

wait

until

insulin

is

absolutely

necessary

to

initiate

treatment.

It

may

be

psychologically

preferable to start patients on a combination of

oral agents and small insulin doses. They will

invariably note an improvement in their well-

being and can adjust to insulin injections before

becoming

completely

reliant

on

them.

The

combination can also be helpful in difficult to

control type 2 patients with high insulin resis-

tance, or those with persistent morning hyper-

glycaemia.

Another

situation

where

the

combination is useful is with patients who are

already using insulin but are showing resistance:

adding

metformin

may

reduce

their

insuin

requirement.

The most logical combination is insulin plus

an

insulin

sensitizer.

Metformin

is

the

usual

choice. Combining insulin with a secretagogue such as a sulphonylurea or a meglitinide is irra-

tional. One regimen is to add a small dose of

about 15 units of medium-acting insulin each

evening. When switching to this regimen, OAD doses are reduced.

Summary

Diabetes

therapy

must

be

individualized

following

regular

close

consultation

between

patients and their clinicians. To a certain extent

the optimal result is found by trial and error, but

this must be supported by diligent monitoring of

blood

glucose

and

reporting

of

all

hypogly-

caemic

episodes

and

other

disturbances

of

control.

Monitoring

People with diabetes require self-monitoring of their biochemical control, and regular assess-

ment

by

a

clinician

of

the

development

or progress of long-term complications. The former has

recently

been

much

simplified

and

improved. Type 1 patients need much closer

monitoring than type 2.

Biochemical control

While

even

moderate

control

relieves

symp-

toms

and prevents serious biochemical abnor-

malities, tight control is believed to be essential

if complications are to be minimized. In general,

diligent monitoring is more important for type 1

diabetes, but all patients should record all test

results.

Glucose

Urine glucose

This has been the traditional way of assessing control. A few elderly patients still use the colour reaction based on Benedict’s test for reducing substances.

It

is

imprecise,

non-specific

and cumbersome,

even

with

the

ingeniously

formulated Clinitest reagent tablets.

m

Urine glucose estimations can never provide

precise information about current blood glucose

levels,

particularly

low,

potentially

hypogly-

caemic ones. Urinary concentrations will vary

according

to

urine

volume

independently

of

blood

glucose.

Furthermore,

aglycosuria

does

not

necessarily

guarantee

normoglycaemia,

owing to differences in renal threshold between

patients and in the same patient at different

times.

Nevertheless, urine testing remains useful as a

simple initial screen and for type 2 patients not

prone to hypoglycaemia when tight control is

not essential, e.g. the elderly and patients averse

to repeated skin puncturing. A few patients may

be monitored adequately by regular urinalysis

and

occasional

blood

glucose

measurements,

once the relationship between the two has been

established.

Urinary

glucose

measurement

also

has

the

advantage that timing is less important than

with blood testing because urine concentration

reflects control over the previous several hours.

Thus,

newer

glucose

oxidase-based

urine

dipsticks have been developed that are more

specific for glucose and far more convenient

because they can simply be passed through the

urine stream.

Blood glucose

There are three main uses for blood glucose

monitoring: to detect hyperglycaemia or incip-

ient hyoglycaemia; to monitor closely in times of changing glucose/insulin need (e.g. intercur-

rent illness); and to determine a new patient’s diurnal glucose profile so as to construct an

appropriate insulin regimen.

Most patients, especially with type 1 disease,

measure their blood glucose directly using a drop

of blood from a finger prick on a glucose oxidase

stick. This provides an immediate measure of

glycaemia that is reasonably accurate and reli-

able, not overly prone to error from poor tech-

nique, and easy to read. Sticks for unaided visual

reading are being replaced by ones to be inserted

into automated meters that display the result

digitally and may give audible warnings. Some

meters can store the most recent results, for

reporting at clinics.

Various spring-operated skin puncture devices may be used to help obtain the blood drop easily and

safely,

and

percutaneous

techniques

of measurement are being developed.

A few type 1 patients regularly test four times

daily, including at the lowest points, before meals

and in the morning, and at the high point after

meals. This is necessary only in the more erratic,

brittle patients, in intensive multiple-dose regi-

mens in younger patients, or when previously

well-controlled patients start to experience prob-

lems. Others, once stabilized, will test randomly a

few times weekly and some may perhaps use

urine dipsticks daily. The main guideline is to

identify a patient’s risk times (e.g. between-meal

hypoglycaemia or postprandial hyperglycaemia)

and subject those to special scrutiny.

Once type 2 patients have become stabilized, weekly or even monthly fasting blood glucose measurement is usually sufficient.

Dose modification falls into two basic strate-

gies. Well-motivated patients on the basal-bolus regimen who are suitably trained by the diabetic team will be able to modify their next insulin

dose, based on the results of their preprandial glucose level and the glycaemic content of their next meal. This is termed ‘dosage adjustment for normal eating (DAFNE)’.

For

patients

who

prefer

regular

dosing,

frequent

changes

following

this

apparently

logical DAFNE strategy is both inconvenient and

inappropriate. More systematic is to note pre-

meal blood glucose over several days. If it is

consistently unsatisfactory, they must alter the

previous scheduled dose on future days, because

the current pre-meal level is a reflection of the

previous dose.

Glycated (glycosylated) haemoglobin

The

abnormal,

quantitative

glycation

of

systemic

protein

as

a

consequence

of

excess

blood glucose (p. 599) applies also to blood

proteins, including Hb and albumin, as well as to

plasma fructosamine. Because these substances

remain in the blood for long periods (120 days

for Hb, 7-14 days for the others), their glycation

gives a long-term, integrated picture of blood

glucose levels over those periods. This can be

Monitoring

629

measured at diabetic clinics and is useful in

tracing any problems with control that might

not be revealed by patients’ tendency to be extra

meticulous on the few days before each clinic

visit.

Care must be taken to ensure adequate time between

successive

measurements,

especially after a treatment change. This allows the level to restabilize, bearing in mind the normal 120-day red cell lifespan. A reading taken too soon will give a falsely high reading because the glycosy-

lated red cells originally measured will not have died.

One

the

other

hand,

when

there

is

a reduced

red

cell

number

or

increased

cell turnover, e.g. in haemolysis or blood loss, a

falsely low reading may be given.

The glycated Hb level gives the best index of

the control needed to minimize complications

and is now regarded as the ‘gold standard’. Non-

diabetics have about 5% of glycated Hb (HbA1c)

and the target level for optimal diabetes control

is currently

7.5%, or

6.5% in

patients at

increased arterial risk, e.g with hypertension.

Ketones

Regular ketonuria monitoring is unnecessary for

type 2 and most type 1 patients, but is essential

in brittle ketosis-prone people with diabetes, and

in all patients during periods of metabolic stress

such as infection, surgery or pregnancy. Great

accuracy is not required and urine dipsticks are

adequate because any ketonuria at all in the pres-

ence of glycosuria indicates a dangerous loss of

control.

Combined

glucose/ketone

sticks

are

preferred,

especially

as

heavy

ketonuria

may

interfere with some standard glucose sticks.

Clinical monitoring

In addition to biochemical monitoring, regular

medical examination is important in the long-

term care of people with diabetes. This will iden-

tify as early as possible the development of any

of the many possible systemic complications.

Table 9.22

lists

the

factors

that

need

to

be

monitored

at

intervals

that

will

vary

from

patient to patient.

Thyroid disease

Thyroxine is a simple catechol-based hormone

but it has multiple crucial subcellular actions

essential

to

life.

It

is

involved

with

oxygen

utilization within all cells, and thyroid abnor-

malities have profound effects on most organ

systems in the body. Thyroid disease is one of

the

most

common

endocrine

disorders,

yet

fortunately it is relatively straightforward to treat

and

to

monitor.

This

is

partly

because

the

thyroid

axis

is

largely

independent

of

other

endocrine systems and partly because the long

half-life of thyroid hormone means that dosing

is not as critical as for insulin replacement. Thus

frequent variations in thyroid hormone levels do

not normally occur and the acute disturbances

of

control

seen

with

abnormal

insulin

and

glucose levels are rare. Furthermore, long-term

complications are few and uncommon.

Physiological principles

Synthesis

Thyroid

hormone

is

synthesized

from

the

aromatic amino acid tyrosine (closely related to

phenylalanine

and

cathecholamine)

in

the

thyroid gland, which sits across the trachea in

the front of the neck. Iodine is an essential ingre-

dient, and the conversion from dietary inorganic

iodide to iodinated thyroid hormone is termed

the organification of iodine. Ionic iodide in the blood is taken up by the thyroid gland by an

active sodium/iodide symporter (Figure 9.14) then, catalysed by thyroid peroxidase, oxidized to give I2, which is then bound to the aromatic ring of the tyrosine residues.

Mono-

and

di-iodotyrosine

are

covalently attached to thyroglobulin within the colloid-

filled thyroid follicles, dimerized with another tyrosine ring, then further iodinated to either

tri-iodothyronine (T3)

or

thyroid

hormone

(T4). T3

is five times more potent than T4, but 75% of thyroid hormone is synthesized and

transported as T4. This is largely converted in target

tissues

to

T3.

Several

weeks’

supply

is stored in the gland in the bound form, but it is released into the blood as free hormone.

In this chapter the term thyroid hormone(s)

will be used when referring to the natural physi-

ological hormone. Thyroxine (T4) when used as

a

drug

is

officially

termed

levothyroxine,

and

tri-iodothyronine (T3) when used as a drug as

liothyronine.

Control and release

Control of thyroid function is an example of a classic endocrine negative feedback loop, which enables

fine

control

of

many

body

systems according to need. A relatively simple peripher-

ally

active

hormone (thyroid

hormone)

is released from an endocrine gland that is its site

of synthesis, stimulated by a peptide trophic

hormone

(thyroid-stimulating

hormone,

thyrotropin, TSH) from the pituitary and also

under CNS influence via a releasing hormone

(thyrotropin-releasing

hormone,

TRH)

from

the

hypothalamus (Figure 9.15).

Both

the

synthesis and the release of trophic and releasing

hormones are inhibited by the active hormone.

TSH is a 221-amino acid glycoprotein with

receptors on the thyroid that mediate both the

synthesis and the release of thyroid hormones. It

is the main physiological control on thyroid

function,

an

important

clinical

indicator

of

thyroid

malfunction

and

a

component

in

the aetiology of some thyroid diseases. Hypo-

thalamic control via the tripeptide TRH is less

important because low thyroid hormone levels

can stimulate TSH release directly, but it enables

the

CNS

to

exert

an

influence

on

thyroid

function;

it

is

particularly

concerned

with

temperature control. Disease of this arm of the

thyroid axis is rare.

Distribution and metabolism

Approximately 80 lg of thyroid hormones are released

daily,

peaking

overnight

when

TSH levels are highest. It has a biological half-life of about 7 days, being cleared by de-iodination in the liver and kidneys. It is carried in the blood almost

entirely

bound,

mostly

to

thyroid-

binding globulin; only 0.02% is carried as free T3 and free T4 (FT3, FT4). However, only the free hormones are biologically active.

Actions of thyroid hormone

Thyroid hormone enters target cells and after

conversion to T3 interacts with nuclear receptors

to influence the expression of genes coding for

proteins invoved in energy metabolim, oxygen

consumption and general tissue growth; thus it

has far-reaching effects on metabolism, growth

and development (Table 9.23). In some ways the

action

resembles

that

of

catecholamines (e.g

adrenaline), to which it bears a structural resem-

blance, but the effect is far more prolonged and more fundamental, whereas the catecholamines have a very brief action.

Metabolism and growth.

Thyroid hormone

has

a

generally

catabolic

effect,

stimulating

metabolism and increasing oxygen consump-

tion, basal metabolic rate and body temperature.

However, in children there are anabolic effects

leading to protein synthesis and growth. Carbo-

hydrate absorption is increased and plasma lipid

levels fall.

Cardiovascular and renal.

There are inotropic

and

chronotropic

effects

mediated

via

up-

regulation

of

numerous

systems,

including

beta-receptors. In addition the calorigenesis pro-

motes peripheral vasodilatation and secondary

fluid retention to maintain cardiac output and

blood pressure.

CNS.

The

action

on

the

CNS

is

known

mostly

through

the

consequences

of

thyroid

malfunction,

considered

below.

There

are

important effects on mentation and CNS devel-

opment. However, little is known of the precise

mechanisms.

Investigation

The three key parameters of thyroid function are

serum levels of FT3, FT4

and TSH. Older tests

measured

protein-bound

iodine

and

total

thyroid hormone, but now the precise radio-

immunoassay of free hormones and TSH gives a

far

better

correlation

with

physiological

and

clinical

status.

It

is

possible

to

measure

the

binding

proteins,

and

several

factors

can

change

binding,

but

the

feedback

control

is

sensitive and precise, so FT4

levels tend to be

very

stable.

It

is

not

usually

necessary

to

measure

TRH.

The

measurement

of

FT4,

FT3

and TSH together is know as a thyroid func-

tion test (TFT). It has become clear that TSH

levels are the most important index of thyroid

status,

and

management

now

stresses

normal

TSH levels.

In the initial investigation of thyroid disease

an autoantibody screen should be done for anti-

thyroid antibodies, and also for anti-intrinsic

factor and anti-gastric parietal cell antibodies,

because

there

is

an

association

with

other

autoimmune

diseases

including

pernicious

anaemia.

Liver

function,

lipid

profile,

blood

glucose and full blood count are also necessary.

The possibility of primary hypothalamic or

pituitary disease should always be borne in mind when thyroid dysfunction is detected, particu-

larly hypothyroidism. In this case both thyroid hormone and TSH levels will be low.

Thyroid disease

Normal thyroid function is described as euthy-

roidism. Hypothyroidism

(underactivity) and

hyperthyroidism

(overactivity)

are

about

equally common and together constitute the

most prevalent endocrine abnormalities. Usually

the cause is idiopathic, often involving autoim-

muity, although iatrogenic causes occur. Detec-

tion and diagnosis are usually straightforward,

and

management

of

hypothyroidism

is

also

simple. Hyperthyroidism is more complex to

manage and may develop complications.

There are several potentially confusing aspects

to thyroid disease. Firstly, certain aetiological

factors, such as autoantibodies, amiodarone and

iodine, are common to both hypo- and hyper-

thyroidism; similarly, an enlarged thyroid gland

(goitre)

can

occur

in

both.

The

action

of

iodine/iodide

can

seem

paradoxical,

causing

either

stimulation

or

inhibition

in

different

circumstances. Long-term hyperthyroidism can

eventually

evolve

into

hypothyroidism,

and

some

forms

of

hypothyroidism

can

have

a

hyperthyroid phase.

Hypothyroidism

Aetiology and epidemiology

Hypothyroidism is far more common in women

than in men (prevalence 1.5% vs 0.1%) and

more common in the elderly, although it can

affect

the

very

young

and

is

then

far

more

serious. It is usually due to intrinsic thyroid

gland

disease

although

rarely

it

may

occur secondary to hypothalamic or pituitary disease, or to drugs (Table 9.24).

Simple

atrophy

is

the

commonest

cause,

mainly affecting elderly women. There may be

an autoimmune component as it is sometimes

associated with other autoimmune disease, but

no antibodies are found. Autoimmune destruc-

tion

is

the

main

cause

of

Hashimoto’s

thyroiditis, which can affect the middle-aged

and elderly. Also common is hypothyroidism

secondary to the treatment of hyperthyroidism

(see below).

In the developed world dietary iodine defi-

ciency is now almost unknown, partly owing to iodination of salt, but it is far more common in developing

countries.

Congenital

hypothy-

roidism secondary to maternal iodine deficiency affects the developing nervous system of the

fetus to produce cretinism.

The term myxoedema is sometimes used as a

synonym for hypothyroidism but more precisely

describes one characteristic dermatological sign.

Pathology

Low

levels

of

thyroid

hormone

compromise

many

crucial

metabolic

processes,

as

can

be

inferred

from

Table 9.23.

There

is

a

general

slowing of basal metabolic rate, a fall in temper-

m

ature,

and

slowing

of

physical

and

mental processes. More detail is given on p. 635.

Investigation and diagnosis

The standard thyroid function test is definitive. When

thyroid

hormone

levels

fall

there

is almost invariably a compensatory rise in TSH. However, a small rise in TSH may precede both clinical signs and a fall in thyroid hormone level by many months; this is known as subclinical hypothyroidism (see below).

In

rare

hypothalamic-pituitary

causes

the combination of low FT4

and low TSH levels is diagnostic.

Screening for autoantibodies to thyroid perox-

idase or thyroglobulin is not necessary for diag-

nosis but can indicate a possible cause, and can act as an alert for possible autoimmune compli-

cations in Hashimoto’s thyroiditis. Occasionally there may be anti-TSH receptor antibodies with a blocking effect, although such antibodies are

usually

stimulant,

causing

hyperthyroidism (Graves’ disease, see p. 637).

Hypothyroidism is often diagnosed following

vague generalized complaints of tiredness and

lack of energy. However, these common symp-

toms can of course have many other causes,

which

sometimes

makes

diagnosis

of

mild

disease

problematic.

Thyroid

disease

should always

be

borne

in

mind

as

a

differential

diagnosis of depression in the elderly.

Clinical features

Most of the features of hypothyroidism can be

understood from a knowledge of the physiolog-

ical action of thyroid hormone (Table 9.25). The

overall clinical impression is of slowness and

Hypothyroidism

635

dullnes of intellect combined with an unprepos-

sessing appearance. Therefore a history from a

relative might be helpful, to identify recent or

specific changes, which may be less apparent to

the patient because onset is usually insidious.

The two most common erroneous diagnoses in

mild disease would be simple ageing, owing to

the slowness, stiffness and general aches and

pains, or depression.

The

most

characteristic

symptoms

are

the

general

physical

and

mental

sluggishness,

lethargy, intolerance of cold, weight gain and

coarsening of the skin. The voice is hoarse and

hair is dry, brittle and falling. There may be a

characteristic swollen thyroid, visible in the neck

as a goitre.

The

classic

dermatological

feature

is

myxoedema,

which

is

an

accumulation

of

mucopolysaccharide in the dermis that causes

widespread skin thickening and puffiness. This

form of oedema is non-pitting because it is not

caused by excess fluid accumulation (contrast

with the pitting oedema of heart failure; see

Chapter 4, p. 184).

The heart rate is slowed and this may cause heart failure. The periphery is cold.

Thought processes and memory are impaired

and mild depression is common. There is usually

weight gain and constipation, despite anorexia.

Biochemically,

in

addition

to

abnormal

thyroid functions tests (low FT3

and FT4, raised

TSH),

there

is

usually

hyperlipidaemia

and

possibly abnormal liver enzymes. Haematology

(see Chapter 11) may show a mixed picture of

iron

deficiency

(hypochromic,

microcytic

anaemia), folate and/or B12

deficiency (macro-

cytic

anaemia)

or

simply

a

normochromic,

normocytic pattern.

Subclinical hypothyroidism

In some patients there are few if any symptoms

and FT4/FT3

levels are within normal limits but

TSH is elevated; this might be identified as a

chance finding. The pathogenesis is probably an

early stage of thyroid insufficiency being compen-

sated

by

slightly

elevated

TSH

level,

initally

keeping thyroid hormone levels adequate. Even-

tually the slowly progressive nature of idiopathic

hypothyroidism will lead to frank insufficiency

that does not respond to increasing levels of TSH:

thyroid hormone levels then fall and symptoms

develop. Regular monitoring is all that is required

during the asymptomatic phase.

m

Complications

If thyroid hormone levels are corrected there is no reduction in life expectancy and there are no long-term problems.

Heart failure or ‘myxoedemic’ coma can be

precipitated by severe metabolic stress, such as

trauma, infection or hypothermia, which may

acutely

increase

thyroid

hormone

require-

ment. Psychosis can also occur (‘myxoedemic

madness’). If the fetus is exposed to inadequate

thyroid hormone in utero, irreversible neurolog-

ical damage leads to cretinism. Hypothyroidism

in children results in retardation of mental and

physical development that is partially reversible

on thyroid hormone treatment. Newborn are

routinely screened.

Management

The management of hypothyroidism is relatively

straightforward, simply requiring oral thyroxine

for life. The general aim is to restore T4, T3

and

TSH levels to within the normal ranges. TSH

should

not

be

suppressed

too

much

in

an

attempt to maintain T4/T3 at high-normal levels:

this represents overtreatment and can lead to

long-term cardiovascular complications. Thus a

mid-range TSH level is usually regarded as the

primary objective, ensuring of course that T4/T3

are also within range. However, low-end TSH

levels are regarded by some as preferable.

Levothyroxine

This is the synthetic replacement drug used for

maintenance

therapy,

which

is

identical

to

natural

thyroxine (T4). (This

has

completely

replaced

the

original

dried

thyroid

gland,

a

natural product derived from animal sources,

with all the quality control risks these entail.)

Levothyroxine

is

well

absorbed

on

an

empty

stomach, but absorption is delayed and possibly

reduced by food. Dosing is not nearly as critical

for levothyroxine in hypothyroidism as it is for

insulin in diabetes, because levothyroxine has a

half-life

of

about

7 days

and

a

gentle

dose-response

curve.

Moreover,

day-to-day

requirements do not change even with intercur-

rent illness, nor do they tend to alter over the

long term. Owing to the natural diurnal varia-

tion of TSH secretion, which peaks overnight, a

single dose is usually taken each morning before

breakfast.

Levothyroxine is initialized at 50 lg daily and

increased by 50 lg daily every 2-4 weeks depend-

ing on response. Clinical improvement is usually

evident

within

the

first

month

of

therapy.

Thyroid function testing is required 6 weeks after

each dose change. Most patients are stabilized on

100-200 lg daily; subsequently only annual TFTs

will be needed.

More care is needed when initializing treat-

ment in the elderly or those with known IHD,

using a lower starting dose, e.g. 25 lg on alternate

days, and smaller increments, because the cardiac

over-stimulation

could

precipitate

ischaemic

symptoms or even an MI. Sometimes liothyronine

(T3) is used for its shorter half-life, permitting a more

rapid

correction

of

overdosing.

Regular ECGs are advisable and beta-blocker cover may be needed to limit the heart rate.

Side-effects

The adverse effects of excess levothyroxine (thyro-

toxicosis) are exactly what would be predicted

from

the

physiological

action

of

excess

thyroxine and are described below (p. 640). With

overdosage, as with untreated hyperthyroidism,

there is the possibility of osteopenia or osteo-

porosis in women, which should be monitored.

Cautions and interactions

The dose may require increasing in pregnancy.

Hepatic enzyme inducers (e.g. rifampicin, pheny-

toin)

increase

clearance.

Some

drugs

reduce

absorption, so levothyroxine should be taken at a

different

time

from

sucralfate,

aluminium

hydroxide

and

iron

salts (Table 9.26).

Other

factors that affect the control of hypothyroidism

are also shown in this table.

Hyperthyroidism

637

Liothyronine

Liothyronine (tri-iodothyronine, T3) has a swifter onset and shorter half-life than levothyroxine and it is about five times more potent. It is mainly used

for

emergency

treatment

of

severely hypothyroid states such as coma, or for initi-

ating treatment in those with CVD. It is available in injectable and oral forms.

Hyperthyroidism

For

several

reasons,

hyperthyroidism

is

not

simply

the

opposite

of

hypothyroidism.

The

causes are more diverse, there are more potential

complications

and

there

are

more

treatment

options with worse side-effects. Note that the

term

thyrotoxicosis

is

used

to

describe

the

syndrome

resulting

from

excess

thyroid

hormone

levels,

but

hyperthyroidism

refers

specifically to when the syndrome is due to

excessive secretion from the thyroid gland.

Aetiology and epidemiology

Hyperthyroidism

is

about

10

times

more common in women, in whom the point preva-

lence is about 1%. However, the lifetime inci-

dence in women is over 2%, some forms being acute or reversible.

Graves’

disease,

caused

by

IgG

auto-

antibodies that stimulate the TSH receptor, is the

commonest form, representing some 75% of all

cases (Table 9.27). It typically follows a fluctating

but

progressive

course,

eventually

leading

to

hypothyroidism, either naturally or as a result ot

treatment.

Autonomous

growth

of

multiple,

hyper-

secreting ‘toxic’ nodules in the thryoid gland is

the second most common form and this is more

often seen in elderly females, but isolated ‘toxic’

adenomas (benign tumours) can also occur. These

are usually associated with goitre. Occasionally

general

thyroid

inflammation

(thyroiditis)

occurs following radiation, childbirth or viral

illness;

there

may

be

an

underlying

auto-

immune

aetiology

to

this.

It

usually

remits

without recurrence. Thyroid cancer is one of

the most common radiation-induced tumours,

via

ingestion

of

radioiodine (131I),

e.g.

after

radiological accidents such as at Chernobyl.

Amiodarone,

which

has

a

high

iodine

con-

tent, frequently causes mild hyperthyroidism,

possibly leading to thyrotoxicosis on prolonged

therapy. It can also cause hypothyroidism (Table

9.24).

Very

rarely

hyperthyroidism

can

be

secondary to pituitary hyperactivity (Table 9.27).

Pathology

High levels of thyroid hormone cause a general acceleration

of

metabolic

processes

with increased metabolic rate and energy utilization, hyperthermia

and

increased

cardiovascular activity (see below). There is a compensatory fall in TSH, often to undetectable levels.

Investigation and diagnosis

Owing to the several possible aetiologies, more

extensive

investigation

is

required

than

for

hypothyroidism.

Typical

clinical

features

will

invariably be borne out by a TFT, which will

usually

show

raised

FT4

and

FT3

and

barely detectable TSH.

Further investigation will depend upon the

degree of suspicion of different aetiologies, but could include:

•

Autoantibody scan; thyroid peroxidase and

thyroglobulin antibodies are usually found,

but

there

is

a

10-20%

false-negative

rate

because they may also occur in unaffected

individuals.

TSH-stimulating

receptor

anti-

bodies

are

difficult

to

assay

and

are

not

routinely sought.

•

Imaging

is

best

done

with

radiolabelled

sodium pertechnetate (99mTc), which is prefer-

entially taken up into the thyroid by the

symporter but not organified. This will show

the overall size of the organ, with concentra-

tion in any nodules, showing their number

and size. It is a prerequisite if ablation therapy

is planned. Ultrasound is less invasive. MRI or

CT scanning is used if ophthalmopathy (see

below) is suspected.

•

Biopsy: if a tumour is suspected.

Clinical features

The clinical features of hyperthyroidism (Table

9.28)

should

be

contrasted

with

those

of

hypothyroidism (Table 9.25):

the

picture

is

strikingly different. The range of features varies

slightly

according

to

aetiology

but

is

broadly

consistent.

Typically

the

patient

is

thin,

nervous, agitated, hyperactive, hot, thirsty and

sweaty.

Examination will show a raised heart rate,

possibly even atrial fibrillation; in severe cases

there may be signs of heart failure. The neck will

usually be swollen and auscultation of the goitre

will reveal bruits (the sound of rapid, excessive

blood flow). There are also usually diarrhoea and

anxiety.

In Graves’ disease the common complication

of

ophthalmopathy (see

below)

will

cause

bulging eyes and an unblinking stare, known as

exophthalmos - the classic sign of thyrotoxi-

cosis. Another characteristic Graves’ feature is

m

pretibial myxoedema, where the deposition of fibrous material causes painless dermal nodules on the shin.

Course

Graves’ disease may follow a relapsing and remit-

ting

course,

with

remissions

facilitated

by therapy. However, remissions become decreas-

ingly likely following each successive relapse. Paradoxically, the end-stage for some patients may be autoimmume hypothyroidism. There is an

increased

risk

of

osteoporosis

and

heart disease in untreated disease.

Complications

Ophthalmopathy (thyroid eye disease)

A characteristic eye disease affects about half of

Graves’ disease patients. It is potentially serious

and

for

unkown

reasons

it

is

associated

with

smoking. The cause is autoimmune inflamma-

tion

of

the

oculomotor

muscles,

with

fibrous

overgrowth. This pushes the eyes forward and

impairs eye movement. The overexposed corneas

can become dry and painful, and there may be

diplopia (double vision). In the most severe form

( 10%

cases)

the

retro-orbital

swelling

can

compress the optic nerve and threaten sight.

It

can

be

detected

by

examination

of

eye

movement and testing for double vision at the

extremes of lateral eye rotation, but MRI scan-

ning is needed for precise assessment. Its severity

is not related to thyroid hormone levels nor is it

relieved if euthyroidism is achieved by medical

or surgical means, probably because it is due to

antithyroid

antibodies

rather

than

excessive

thyroid hormone itself. For most patients it is an

unsightly inconvenience rather than a threat to

sight.

Thyroid crisis (‘storm’)

This rare condition, which occurs when there are

very high levels of thyroid hormone, is poten-