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even inadvertent intravenous injection, can also pre-

cipitate hypoglycemia. Similarly, exercise, as well as

lowering blood glucose in its own right, may provoke

hypoglycemia by increasing the rate of absorption of

insulin from an injection site. A further important

cause of hypoglycemia is alcohol which, by inhibiting

gluconeogenesis, potentiates the action of insulin and

delays recovery from hypoglycemia.

0027 The onset of hypoglycemic symptoms is usually

rapid. The pattern of symptoms varies from patient

to patient but is usually constant for any individual.

The symptoms are those of neuroglycopenia (inco-

ordination, impaired intellectual function, confusion,

inability to concentrate, blurring of vision) and of

sympathoadrenal activity (sweating, anxiety, tremor,

hunger, palpitations). Unless treated by immediate

ingestion of carbohydrate (preferably sucrose or glu-

cose), the patient may lose consciousness. Untreated,

the resultant coma may last for several hours, but

spontaneous recovery owing to counterregulatory

hormone (epinephrine (adrenaline), glucagon, corti-

sol, and vasopressin) and sympathetic stimulation of

gluconeogenesis is the rule. Treatment of the coma-

tose patient consists of glucose gel smeared inside the

mouth, intramuscular glucagon (1 mg) or intravenous

glucose. It is important to avoid giving excess intra-

venous glucose, particularly in young children in

whom the osmotic effects of resultant hyperglycemia

can result in cerebral damage. The dose of intraven-

ous glucose in an adult should not normally exceed

50 ml of a 20% solution. Prolonged coma is occasion-

ally seen in association with massive (sometimes in-

tentional) insulin overdosage, with alcohol and with

sulfonylurea-induced hypoglycemia, and may require

prolonged intravenous glucose infusion.

0028 Particular care should be taken to identify noctur-

nal hypoglycemia. This frequently occurs during sleep

without waking the patient, and therefore may not

give rise to typical symptoms. It commonly causes

restlessness or sweating at night, vivid dreams or

nightmares, and morning headaches or ‘hangover.’ It

is often associated with paradoxically high and/or

rising morning blood glucose levels. This phenom-

enon (the Somogyi effect) is probably caused by a

combination of declining insulin levels and a marked

counterregulatory (particularly growth hormone)

response.

0029 A distressing experience of some patients is that

of hypoglycemic unawareness, which can be both

alarming and potentially dangerous. This is known

to occur in over 20% of patients after 20 years of

diabetes and is frequently associated with autonomic

neuropathy and impaired counterregulatory response

to hypoglycemia. It is also encountered in patients

taking nonselective b-blocking drugs. More recently,

it has been reported by a number of patients who

underwent a change in treatment from animal to

human insulin. The reasons for this phenomenon (if,

indeed, it is real) are unclear. Human insulin given by

subcutaneous injection produces a slightly faster fall

in blood glucose than animal insulin but the pattern

of both glycemic and counterregulatory response is

otherwise virtually identical. Double-blind studies

have generally failed to reproduce an association be-

tween human insulin and hypoglycemic unawareness

even in patients who have reported the condition.

Part of the explanation for the loss or, at least, change

in symptoms may be attributable to the fact that,

when patients were transferred to human insulin,

the opportunity was taken to review and, frequently,

to encourage stricter glycemic control, which is

known to be associated with a reduction in hypo-

glycemic awareness.

0030Hypoglycemia is unpleasant and distressing for

patients and their families. It also causes swings in

blood glucose control because of both the physio-

logical response and overcompensation by the pa-

tient. It should be avoided as far as possible, but not

at the expense of abandoning attempts to obtain good

control.

Diabetic Ketoacidosis

0031DKA is the most serious metabolic emergency associ-

ated with type 1 diabetes. It is the largest single cause

of death in young diabetics and, although uncommon

in older patients, when it does occur, it has a very high

mortality in this age group. The fundamental cause is

either absolute insulin deficiency or, less commonly,

relative deficiency associated with an acute physio-

logical stress, in association with increased secretion

of counterregulatory catabolic hormones. The result-

ant metabolic effects consist of the following:

0032Hyperglycemia, owing to grossly impaired periph-

eral glucose uptake and utilization, plus continu-

ing, uninhibited gluconeogenesis, leading to

increased polyuria and severe fluid and electrolyte

loss.

0033Ketoacidosis, owing to accelerated lipolysis and

ketogenesis, with production of excess acetyl co-

enzyme A, which is partially oxidized to the keto-

acids acetoacetic and b-hydroxybutyric acid.

Along with acetone derived from acetoacetate,

these ‘ketone bodies’ accumulate in larger

amounts than can be metabolized, and are ex-

creted unchanged in urine and on the breath.

Both acetoacetic and b-hydroxybutyric acids are

weak acids, but in the amounts produced lead to a

metabolic acidosis with a concomitant rise in

hydrogen ion concentration (fall in pH).

1786 DIABETES MELLITUS/Chemical Pathology

0034 Precipitating causes include infection (in about one-

third of cases), inappropriate insulin treatment (too

often due to the erroneous advice to reduce insulin

dosage when unwell and not eating) and myocardial

infarction. DKA is occasionally the presenting feature

in new cases of type 1 diabetes. In around 25% of

cases no precipitating factors can be identified.

0035 DKA develops relatively slowly (compared with

hypoglycemic coma), usually over a period of 24–

36 h. Symptoms include an increase in thirst and

polyuria, general ill health, nausea, vomiting, drowsi-

ness, and eventually coma. Clinically, the patient is

often febrile, with evidence of dehydration (thin,

rapid pulse, postural hypotension). Hyperventilation

(owing to the metabolic acidosis) is an important

feature, and there is frequently a strong smell of acet-

one on the breath. Treatment should be instituted as a

matter of urgency as soon as the diagnosis is con-

firmed by the finding of hyperglycemia and ketonuria

without waiting for the results of other laboratory

tests (blood gases and acid–base status; plasma

sodium, potassium, and creatinine; full blood count;

urine, sputum, and blood cultures). Treatment con-

sists of replacement of fluid and electrolyte deficits

which, in established DKA in adults, are in the order

of 5 l of fluid and 500 mmol each of sodium, chloride,

and potassium. It is important to remember that

plasma potassium levels may not reflect this, and

may even be paradoxically high due to the effects of

acidosis. Although there may be a similar theoretical

deficit of bicarbonate, replacement is unnecessary

and even counterproductive; small amounts only

should be given as required to raise the blood pH

above 7.0. Insulin is given in relatively small doses

(5–10 units per hour initially) either by intravenous

infusion or intramuscular injection. Intravenous

potassium should be given either immediately or as

soon as plasma potassium levels start to fall, with

regular laboratory monitoring of plasma levels.

Nonketotic Hyperosmolar Coma

0036 Nonketotic hyperosmolar coma only occurs in type 2

diabetes, sometimes as a presenting feature, and

consists of gross hyperglycemia and dehydration but

without ketosis and significant acidosis. The mechan-

ism of this is uncertain. The condition develops more

insidiously than DKA, allowing time for a greater

degree of dehydration to develop. Treatment consists

of fluid replacement and low-dose insulin therapy.

The prognosis is poor, with a significant mortality

especially in older patients.

See also: Diabetes Mellitus: Etiology; Fatty Acids:

Metabolism; Glucose: Maintenance of Blood Glucose

Level; Hormones: Adrenal Hormones; Pituitary

Hormones; Renal Function and Disorders: Kidney:

Structure and Function

Further Reading

Berger W and Keller U (1992) Treatment of diabetic keto-

acidosis and non-ketotic hyperosmolar coma. Clinical

Endocrinology and Metabolism 6: 1–22.

De Fronzo RA, Ferrannini E and Simonson DC (1989)

Fasting hyperglycaemia in non-insulin dependent dia-

betes. Metabolism 38: 387–395.

Hermans MP, Levy JC, Morris RJ and Turner RC (1999)

Comparison of insulin sensitivity tests across a range of

glucose tolerance from normal to diabetes. Diabetologia

42: 678–687.

Pickup JC and Williams G (eds) (1997) Textbook of Dia-

betes, 2nd edn. Oxford: Blackwell.

Reaven GM (1988) Role of insulin resistance in human

disease. Diabetes 37: 1595–1607.

Young AA (1997) Amylin’s physiology and its role in dia-

betes. Current Opinion in Endocrinology and Diabetes

4: 282–290.

Treatment and Management

J Wright, University of Surrey, Guildford, Surrey, UK

Aims of Treatment

0001The main objectives in the treatment of diabetes can

be summarized as follows:

0002alleviation of symptoms

0003maintenance of good general health

0004prevention of long-term complications.

It is relatively easy to achieve the first of these object-

ives and, in the majority of patients, reasonable or

good general health can be maintained in the short

or medium term without necessarily achieving good

diabetic control. However, there is now convincing

evidence that good control of both blood glucose

and blood pressure influences the development of

microvascular complications (nephropathy and reti-

nopathy) in both type 1 and type 2 diabetes although,

as far as macrovascular disease is concerned, the

situation is more complicated. Coronary heart disease

(CHD) is the major cause of death in long-standing

type 1 diabetes, and in type 2 diabetes even of rela-

tively short duration. Evidence suggests that glycemic

control is not closely related to the risk of athero-

sclerosis and other risk factors such as smoking,

hypertension, dyslipidemia (raised triglycerides and

DIABETES MELLITUS/Treatment and Management 1787

low high-density-lipoprotein (HDL)-cholesterol),

physical inactivity, male-pattern obesity, and ethnic

origin appear to be more important determinants.

The presence of microalbuminuria (which is probably

a marker of generalized arterial endothelial damage)

is a particularly strong marker of risk from ischemic

heart disease. (See Atherosclerosis; Coronary Heart

Disease: Intervention Studies.)

0005 Thus it is clear that, if a major objective of treat-

ment is to prevent long-term or associated compli-

cations, as much attention must be paid to these other

risk factors as to control of blood glucose.

Choice of Treatment Regimen

0006 Diet, oral hypoglycemic agents, and insulin

remain the cornerstones of treatment of diabetes.

Dietary advice is required by all patients, but the

selection of other treatment measures is largely

based on individual clinical assessment along with

measures of glycemic control. The criteria used

in the selection of treatment are summarized in

Table 1.

0007 With the exception of pregnancy, in which strict

criteria are generally agreed, the classification of

hyperglycemia into mild, moderate, or severe is per-

sonal to both the physician and the individual patient.

A common dilemma is the overweight patient with

uncontrolled hyperglycemia in whom treatment with

insulin, while improving glycemic control, frequently

results in increasing weight gain and little in the way

of symptomatic improvement. (See Glucose: Main-

tenance of Blood Glucose Level; Pregnancy:

Nutrition in Diabetic Pregnancy.)

Diabetic Diet

0008Although the importance of diet in the treatment of

diabetes has been recognized for centuries, fashions

have changed considerably, even in recent years. Prior

to the introduction of insulin treatment, a number

of desperate dietary measures were tried, including

semistarvation (leading to such gross reduction in

body fat that severe ketoacidosis could not occur).

With insulin, it became possible to liberalize energy

consumption but, with continuing carbohydrate

restriction, diets were inevitably high in fat. The

evolution in dietary policy since 1921 is illustrated

in Table 2. After 1950, in response to the perception

that a high-carbohydrate diet does not have a dele-

terious effect on diabetic control, and that high-fat

diets may contribute to the risk of CHD, there was a

marked swing away from carbohydrate restriction,

and the promotion of diets high in carbohydrate (par-

ticularly complex carbohydrate and fiber) and lower

in fat than previously. More recently, a number of

studies have shown that high-carbohydrate diets

may in fact increase insulin resistance and adversely

affect the lipoprotein profile, while diets high in

monounsaturated fatty acid (MUFA) result in an im-

proved lipoprotein profile (lower triacylglycerols and

higher HDL-cholesterol) without loss of glycemic

control. (High-polyunsaturated fat diets have a simi-

lar effect but are not recommended because of con-

cerns that they result in increased lipid peroxidation.)

An opposing view is that high-carbohydrate diets in

which most of the carbohydrate has a low glycemic

index achieve at least similar metabolic control.

However, many people find such diets difficult to

manage and unpalatable, and, given the low level of

compliance with high-carbohydrate diets, there are

both practical and evidential reasons for recommend-

ing an increase in the (monounsaturated) fat content

of the diet. As yet, however, a number of national

diabetic associations have not modified their guide-

lines, and the one recommendation with respect to fat

which remains universally accepted is that saturated

tbl0001 Table 1 Treatment options in diabetes

Treatment option Criteria

Diet alone Moderate hyperglycemia only

Obesity

Oral hypoglycemic drugs

Sulfonylureas Moderate to severe hyperglycemia

Near-normal body weight

Biguanides Moderate to severe hyperglycemia

Obesity

Insulin resistance

Insulin

Severe hyperglycemia

Ketosis

Unintentional weight loss

Nonspecific symptoms (general

ill health, tiredness)

Specific symptoms (painful

neuropathy, amyotrophy)

Pregnancy

Intercurrent illness, surgery,

myocardial infarction

Plus diet.

tbl0002Table 2 Historical perspective of dietary recommendations for

diabetes

Distribution of calories (% dietary energy)

Year Carbohydrate Protein Fat

Pre-1921 Starvation diets

1921 20 10 70

1950 40 20 40

1971 45 20 35

1986 Up to 60 12–20 <30

1994

10– 20

a,b

Based on individual assessment and goals.

Less than 10% calories from saturated fat.

1788 DIABETES MELLITUS/Treatment and Management

fat should be restricted to less than 10% of dietary

energy. (See Glucose: Glucose Tolerance and the

Glycemic (Glycaemic) Index.)

0009 There are no great differences between the general

principles of dietary treatment in insulin-dependent

diabetes mellitus (IDDM) and those in noninsulin-

dependent diabetes mellitus (NIDDM), although

there is frequently more emphasis on weight loss in

NIDDM, while meal distribution may be more im-

portant in IDDM. In patients treated with insulin, the

importance of timing of meals and of taking snacks

between meals in order to prevent hypoglycemia

should be stressed. Overall energy intake should be

determined on an individual basis, and the diet

designed to achieve and maintain desired body

weight. (See Energy: Energy Expenditure and Energy

Balance.)

0010 The place of fish oils (high in long-chain n-3 fatty

acids) in the diabetic diet is unclear. There has been

concern that fish oils may have an adverse effect on

glycemic control, but there is a growing consensus

that this potential adverse effect is offset by a greater

beneficial effect of fish oils on lipid profile and

cardiovascular disease risk. Cholesterol intake should

be less than 300 mg day

1

.(See Fats: Requirements;

Fish Oils: Dietary Importance.)

0011 High salt intake should be discouraged, particu-

larly in hypertensive patients. At the same time, a

relatively high potassium intake (particularly from

vegetable sources) should be encouraged. (See Potas-

sium: Physiology; Sodium: Physiology.)

0012 In patients with early nephropathy, protein intake

should not exceed 12% of total dietary energy. (See

Protein: Requirements.)

Alcohol

0013 Guidelines are similar to those for the general adult

population, i.e., a maximum of 30 g (3 units) per day

for men, and 20 g (2 units) per day for women.

Patients taking insulin need to be especially careful

since alcohol, by inhibiting gluconeogenesis, can

predispose to severe hypoglycemia, especially at

night. (See Alcohol: Alcohol Consumption.)

Special Foods

0014In general, special ‘diabetic’ foods are not recom-

mended. Artificial sweeteners are acceptable in

moderation.

Individualization

0015The most important of all the recommendations is

that diets should be specifically tailored for individual

patients. This is critical in certain groups, such as

growing children, pregnant women, and the elderly,

in whom restrictive diets may be inappropriate.

Oral Hypoglycemic Agents

0016Oral hypoglycemic agents rely on residual insulin

secretion for their action. Their use is largely re-

stricted to the management of type 2 diabetes. The

number of classes of oral agents has increased in

recent years, and further developments are antici-

pated in the near future. Those currently available

are summarized in Table 3.

Sulfonylureas

0017The sulfonylurea group comprises a large number of

closely related compounds (Table 4). The important

clinical differences between individual drugs are

related to differences in half-lives, in route of metab-

olism and excretion, and in receptor binding (second-

generation drugs bind more avidly to the specific

sulfonylurea receptor on pancreatic B cells and are

effective at lower doses).

0018The major effect of the sulfonylureas is to stimulate

insulin secretion, an effect which appears to be main-

tained in the long term. The glucose-lowering potency

of sulfonylureas is directly related to the starting

blood glucose level – the higher the fasting blood

glucose, the greater the decrease achieved by sulfonyl-

urea treatment.

tbl0003 Table 3 Oral antidiabetic agents

Class of drug Example(s) Mode(s) of action

Sulfonylureas Chlorpropamide Enhance insulin secretion

Tolbutamide

Glyburide (glibenclamide)

Gliclazide

Biguanides Metformin Increase peripheral insulin sensitivity

Inhibit gluconeogenesis

a-Glucosidase inhibitor Acarbose Impairs starch digestion and glucose absorption

Thiazolidenediones Troglitazone

Pioglitazone

Increase adipocyte differentiation and net triglyceride deposition;

reduce plasma nonesterified fatty acids; increase insulin sensitivity

Rosiglitazone

Non S-U insulin secretagogue Repaglinide Enhances insulin secretion

DIABETES MELLITUS/Treatment and Management 1789

0019 The fact that the sulfonylureas increase insulin se-

cretion means that, if anything, they tend to encour-

age weight gain. They are therefore most suitable for

lean patients and should be used sparingly in the

obese. Weight gain may be less marked with those

drugs which have a shorter half-life; if given before

meals, these have been claimed to enhance the insulin

response to food without inducing sustained hyper-

insulinemia.

0020 The major adverse effect of the sulfonylureas is

hypoglycemia which may be both profound and pro-

longed. This is seen particularly with those drugs

which have a longer half-life or where this is pro-

longed by hepatic or renal dysfunction. Chlorpropa-

mide, for example, should be used with caution in the

elderly and should be avoided in patients with renal

impairment. Other adverse effects are uncommon

and include nausea, dizziness, blood dyscrasias,

cholestatic jaundice, skin rashes, and water retention

(particularly with chlorpropamide, which can be used

in the treatment of diabetes insipidus). Flushing with

alcohol (probably owing to inhibition of acetalde-

hyde metabolism) is common in patients taking chlor-

propamide and can usually be improved by transfer

to an alternative sulfonylurea preparation.

Biguanides

0021 The two drugs in this group are phenformin and

metformin. Phenformin has now been withdrawn in

most countries because of its association with severe

and occasionally fatal lactic acidosis.

0022 Metformin reduces both fasting and postprandial

blood glucose levels in diabetics but rarely causes

hypoglycemia. The precise mechanism of its action

is uncertain but the major effect appears to be an

increase in glucose uptake and enhanced glycogen

secretion in skeletal muscle, resulting in an increase

in insulin sensitivity. Metformin also inhibits gluco-

neogenesis and thus reduces hepatic glucose output.

(This results in a small increase in blood lactate

concentration but less than that produced by phen-

formin and rarely sufficient to cause significant lactic

acidosis.) Unlike the sulfonylureas, metformin does

not cause weight gain; in fact, it often helps with

weight loss, and is therefore most suitable in over-

weight patients. The drug is not metabolized but is

excreted unchanged via the kidney and must there-

fore be used with caution in patients with renal im-

pairment. The major side-effects of metformin are

dose-related and include gastrointestinal discomfort

and diarrhea. To minimize gastointestinal side-

effects, treatment with metformin should begin with

a low dose (500 mg daily) building to a maximum of

1000 mg three times per day as tolerated.

Thiazolidenediones

0023The thiazolidenediones are a new class of drug re-

cently introduced for the treatment of type 2 diabetes.

They bind to a novel nuclear receptor, the peroxisome

proliferator activated receptor (PPAR-g), which initi-

ates effects on fat metabolism, including adipocyte

differentiation and lipoprotein lipase (LPL) gene

expression. The major effect of the thiazolidene-

diones is probably on the adipocyte, and their ability

to increase muscle insulin sensitivity probably results

from a reduction in circulating nonesterified fatty

acid (NEFA) levels. Their effect on adipocyte differ-

entiation and triglyceride deposition probably ex-

plains their tendency to encourage weight gain. It

is unclear whether they also have direct effects on

hepatic carbohydrate metabolism, such as induction

of glucose transporter expression and inhibition of

gluconeogenesis.

0024Troglitazone was the first of the thiazolidenediones

to become available for clinical use but was with-

drawn after only a short time in the UK because of

concerns over liver damage; it remains in use in many

other countries, including the USA. A number of

other thiazolidenediones have been introduced re-

cently, these include pioglitazone, ciglitazone, and

rosiglitazone. Experience indicates that the glucose-

lowering effect of the thiazolidenediones is less than

that of sulfonylureas, although they may have a

greater effect on lipid parameters. Like metformin,

they can also be used in combination with insulin in

type 2 diabetes.

0025The starting and maximal daily doses of the thia-

zolidenediones are 400 and 600 mg for troglitazone,

15 and 45 mg for pioglitazone, and 2 and 8 mg for

pioglitazone.

Prandial Glucose Regulators

0048A new class of insulin secretagogs has recently

been introduced, the so-called prandial glucose regu-

lators. Those currently available are repaglinide and

tbl0004 Table 4 Examples of sulfonylurea drugs

Drug Half-life

(h)

Duration of

action (h)

Daily

dose (mg)

Doses

per day

First-generation

Chlorpropamide 35 60 100–375 1

Acetohexamide 4–6 12–18 250–1500 2

Tolbutamide 3–8 6–12 500–2500 2–3

Tolazamide 4–7 12–24 100–1000 1–2

Second-generation

Glyburide

(glibenclamide)

5 12–24 2.5–15 1–2

Glipizide 1–5 12–24 2.5–40 1–2

Gliclazide 12 10–15 40–320 1–3

Gliquidone 4 6–8 15–60 1–3

1790 DIABETES MELLITUS/Treatment and Management

nateglinide. These are chemically dissimilar to the

sulfonylureas but may act via the sulfonylurea recep-

tor on the B cell. These drugs are rapidly absorbed

and have a short plasma half-life (< 1 h). Given before

meals they produce a rapid release of insulin which

helps control ‘prandial’ glucose levels. This may

prove valuable since there is increasing concern that

postprandial peaks in blood glucose may be an im-

portant risk factor for the development of microvas-

cular complications.

0049 The starting doses of repaglinide and nateglinide

are respectively 0.5 mg and 60 mg three times daily

with meals, rising to maximum total doses of 4 mg

and 180 mg three times daily respectively.

Acarbose

0028 Acarbose is an a-glucosidase inhibitor which com-

petitively inhibits the action of brush-border enzymes

in the digestion of oligo- and disccharides, thereby

preventing the release and absorption of glucose from

dietary carbohydrate. It has only a moderate glucose-

lowering potency which is most marked in the post-

prandial phase. The drug is safe but gastrointestinal

side-effects (abdominal discomfort, diarrhea, and

severe flatulence) are common and frequently limit

the acceptability of the drug to patients. The maximal

tolerable dose is 200–300 mg day

1

Combination Therapy

0029 Oral hypoglycemic agents may be used either alone or

in combination with other agents. The combination

of sulfonylurea and metformin was shown to be ef-

fective in the UK Prospective Diabetes Study. Metfor-

min and insulin are frequently used in combination in

overweight patients with type 2 diabetes. Thiazolide-

nediones may also be used in combination with either

a sulfonylurea or metformin; they have also been used

successfully in combination with insulin but this prac-

tice is not yet universal. Sulfonylureas have also been

used in combination with insulin (for example with

isophane insulin used overnight) but this has not

gained widespread acceptance.

Insulin

0030 Prior to the isolation of insulin in 1921, juvenile-

onset diabetes was an untreatable and rapidly fatal

condition. With well-managed insulin treatment,

such patients can now expect to live a full and virtu-

ally normal life. Until the 1970s, insulin for thera-

peutic use was extracted from either beef or pork

pancreas. The resulting bovine and porcine insulins

differ from human insulin by two and one amino

acids respectively. The majority of insulin is now

bioengineered using recombinant deoxyribonucleic

acid (DNA) technology. The proinsulin thus pro-

duced is cleaved to give insulin which is identical in

its amino acid sequence to human insulin. Regular,

soluble neutral insulin is relatively short-acting and a

number of techniques have been used to produce

preparations with longer duration of action. The

most successful of these are the complexing of insulin

with either zinc or a protein (protamine) to produce

zinc and isophane insulins respectively. Within the

range of zinc insulins, further variations in duration

of activity are achieved by varying the pH and, there-

fore, the particle size to form either amorphous

(microcrystalline, medium-acting semilente) or crys-

talline (long-acting ultralente) preparations. Lente

insulin is a mixture of these two in the ratio 30%

semilente to 70% ultralente; the resultant mixture is

intermediate-acting. Isophane insulin (also known as

neutral protamine Hagedorn, or NPH insulin) is of

standard formulation and has a similar, intermediate

duration of action to lente insulin.

0031A range of premixed insulins, containing from

10% soluble and 90% isophane to 50% of each, is

available. Such premixtures are not possible with zinc

insulins owing to the loss of the short-acting, soluble

component which results from complexing with any

excess zinc present.

0032Several new insulins are currently being developed

and introduced into clinical practice. In these, the

insulin molecule is modified in order to alter either

the duration of action or receptor specificity. The first

of these to be introduced (Lispro and Aspart) are very

fast-acting and can be injected immediately before a

meal (in contrast to soluble insulin which should be

injected 15–20 min before eating). A new, modified

insulin (Glargine) has been introduced recently. This

provides stable ‘background’ plasma insulin levels

over a 24-hour period, and has been used successfully

in combination with very fast-acting soluble insulin

analogs. It is anticipated that insulins with altered

receptor specificity with, for example, differential

activity on hepatocyte or skeletal muscle metabolism,

will have particular advantages in different patterns

of diabetes.

0033A number of patients who were treated initially

with either pork or beef insulin and subsequently

transferred to human insulin reported a marked loss

of hypoglycemic awareness and, largely for such pa-

tients, some animal insulins continue to be manufac-

tured. In total, a bewildering range of preparations is

now available, but can be simplified, as shown in

Table 5.

Choice of Insulin Regime

0034The decision to start insulin treatment is made on

clinical grounds (Table 1). In younger patients with

DIABETES MELLITUS/Treatment and Management 1791

evidence of ketosis, the decision is usually unambigu-

ous. Patients with type 2 diabetes frequently come to

treatment with insulin but the decision to change

from oral agents is often difficult. Unintentional

weight loss is an important criterion, as are nonspe-

cific symptoms such as tiredness and lack of energy

which usually improve on insulin. However, in over-

weight but otherwise asymptomatic patients with un-

controlled hyperglycemia, large doses of insulin are

often required to achieve improved glycemic control,

and this is often at the expense of further weight gain

and little in the way of symptomatic benefit. Age is

certainly not an absolute criterion and, indeed, many

newly diagnosed elderly patients need insulin treat-

ment from the outset. Unfortunately, there are no

objective biochemical criteria (apart from glucose

and ketones) on which to base treatment decisions.

In particular, measurement of endogenous insulin se-

cretion (e.g. C-peptide response to glucagon stimula-

tion), while of interest for research purposes, should

not be used in the decision to treat with insulin or not.

0035 Insulin is usually given by subcutaneous injection.

Examples of injection regimes in current use are

shown in Table 6. A once-daily regime may be used

in the elderly but for the majority of patients, good

control can only be achieved by using at least twice-

daily injections. A number of pen injector devices are

now available for the administration of soluble, iso-

phane, and soluble/isophane mixtures. An alternative

to intermittent insulin injections is the technique of

continuous subcutaneous insulin infusion (CSII)

whereby insulin is infused continuously (with boosts

at meal times) via an indwelling subcutaneous can-

nula from a pump which is worn or carried perman-

ently by the patient. Impeccable glycemic control can

be achieved with pump treatment and although en-

thusiasm for it waned at one time, recent technical

advances have made it a far more acceptable form of

insulin delivery, and it is now widely used in a number

of countries. Of the other alternative methods of

insulin delivery (oral administration, intraperitoneal

injection, nasal spray, implantable programmed infu-

sion devices, etc.), some have been abandoned while

others are still under evaluation. Other techniques,

such as pancreatic transplantation, hold promise, but

the prospects for a practical alternative to insulin

injections in the near future seem remote.

Other Measures

Treatment of Hypertension

0036It is increasingly recognized that control of hyperten-

sion is essential in diabetes, and it has been shown

to reduce the progression of both microvascular and

macrovascular complications in both type 1 and type

2 diabetes. Early studies which indicated that treat-

ment with angiotensin-converting enzyme (ACE)-

inhibitors reduced the progression of nephropathy

(as judged by microalbuminuria) even in normoten-

sive patients suggested that these drugs may have a

particular benefit in diabetes. However, in the UK

Prospective Diabetes Study, there was no difference

in outcome between patients treated with an ACE-

inhibitor (captopril) or a b-blocker. Long-term studies

comparing the effects of newer ACE-inhibitors,

angiotensin receptor antagonists, a-blockers, and cal-

cium channel antagonists are required to decide the

optimum drug(s) for use in diabetes.

Exercise

0037Lack of physical activity is a major factor in the

increased incidence of diabetes in the developing

world. Exercise has been shown not only to have a

beneficial effect on metabolic control in people with

established diabetes but also, in retrospective and

prospective studies, to reduce the risk of developing

type 2 diabetes.

Patient Education

0038Perhaps more than in any other disease, the person

with diabetes needs to participate in treatment and to

take responsibility for the day-to-day management of

tbl0005 Table 5 Major available insulin preparations

Time of action (h)

Formulation Onset Peak Duration Othernames

Crystalline

0.5–1 2–4 8 Regular, soluble,

neutral Humalog

Zinc

Amorphous 1–2 4–6 8–12 Semilen

Crystalline 2–4 14–20 24–36 Ultralente

Mixed

2–4 6–10 12–24 Lente

Protamine

2–4 6–10 12–24 Isophane

Premixed

Dependent on ratios

Approximate times following subcutaneous injection.

Available mixtures contain crystalline and isophane insulin in the ratios

1:9, 2:8, 3:7, 4:6, and 5:5.

Animal (pork or beef) preparation still available.

tbl0006 Table 6 Examples of insulin regimes

Regime Formulation

Once daily Lente, ultralente

Twice daily Soluble plus lente

Soluble plus isophane (premixed or

variable)

Multiple injections

(basal bolus)

Soluble or Humalog two or three times

daily before meals, plus either ultralente

or isophane at bedtime

1792 DIABETES MELLITUS/Treatment and Management

the condition. This cannot be successfully accom-

plished without a clear understanding of treatment

objectives and the means of achieving them.

0039 A successful educational program needs to be care-

fully planned and coordinated, with opportunities for

individual as well as group sessions, and a commit-

ment to long-term reinforcement. The contribution of

the diabetes nurse specialist, who is usually the ideal

person to undertake much of the responsibility for

patient education, has proved invaluable. The trad-

itional hospital diabetic clinic is by no means the best

environment for teaching and in many areas, dedi-

cated diabetic centers have been established for this

purpose. A vast array of literature and audiovisual

aids is available both from support organizations,

such as national diabetic associations, and from

commercial firms.

0040 An essential part of any educational program is

long-term evaluation. Despite the apparently obvious

need for education, the results, when formally

assessed, have not been uniformly encouraging. A

reduction in hospital admissions can be achieved but

this might simply reflect an improvement in care and

support services in general. Furthermore, the effects

may not be sustained in the long term. As yet, there is

no conclusive evidence that improvements in knowl-

edge lead to better metabolic control; poor compli-

ance is usually attributable to factors other than

simple ignorance. Successful self-treatment requires,

in many people, fundamental changes in attitude and

behavior. It is these benefits rather than the acquisi-

tion of knowledge that educational programs can

provide.

Assessment of Diabetic Control

Glycemic Control

0041 Regular monitoring of diabetes is essential in order to

make short-term adjustments to treatment (particu-

larly insulin dosage) and in order to assess control in

the longer term. Short-term assessment is achieved by

monitoring glucose in urine or blood, and long-term

assessment by measurement of glycated (glycosyl-

ated) proteins. Monitoring diabetes by means of

urine tests was for a long time the only practical

method available, but this must now be considered

crude and often misleading. The renal threshold for

glucose varies widely in diabetes but is frequently

well above target levels for blood glucose; the urine

may therefore be free of glucose when the blood

glucose is higher than desired. At the same time,

urine tests are of no value in detecting hypoglycemia.

Persistent, heavy glycosuria is probably an indication

of poor control (except in those with a very low renal

threshold) but more subtle interpretation of tests is

usually impossible.

0042Occasional, single measurements of blood glucose

are also of very limited value in monitoring control

since there are wide variations in blood glucose

throughout the day in both type 1 and type 2 diabetes.

Once a common feature of diabetic clinics, ‘one-off’

blood glucose measurements have been abandoned in

many centers. Regular measurement of blood glucose

by patients (home monitoring) has become common-

place and is essential in managing changes in insulin

treatment, and in making day-to-day adjustments

in insulin dosage (especially with multiple injection

regimes), particularly during periods of metabolic

instability such as intercurrent illness or pregnancy.

A number of test ‘sticks’ are available (most of which

employ dry-reagent chemistry based upon glucose

oxidase) and these can be read visually or using one

of the many meters designed for the purpose.

0043Measurement of glycated proteins has become the

standard method of monitoring medium-term glyce-

mic control. These compounds result from the non-

enzymatic linkage of glucose to proteins (in the case

of hemoglobin, to the N-terminal valine residue of the

b-chain). The initial aldimine linkage undergoes an

Amadori rearrangement to form a stable ketoamine

product. The rate of glycation depends on the prevail-

ing glucose concentration, and the extent of glycation

of any protein is therefore a function of the average

glucose concentration during its lifetime. Glycated

hemoglobin (HbA

) is most commonly used because

of its availability and because the half-life of the red

blood cell (around 8 weeks) is a convenient period

of time over which to assess control. Laboratories

should now measure the more specific HbA

frac-

tion. The level of HbA

in nondiabetics is around

4.5–5.5%. The results of the DCCT study suggest

that 7% should be the target level in well-controlled

diabetes, although higher levels may be acceptable,

particularly in older patients. Low values may be

found in patients who are experiencing frequent

hypoglycemia. Spuriously low values are found in

conditions associated with reduced red-cell survival

(e.g., hemolytic anemias), while high values are found

in renal failure (owing to the presence of carbamyl-

ated hemoglobin).

0044In situations such as pregnancy, the half-life of

hemoglobin is too long for HbA

to be useful in

monitoring glycemic control as closely as is required.

Glycated albumin (half-life of around 19 days) would

be ideal for this purpose but there are currently no

specific methods for this. As an alternative, measure-

ment of glycated serum proteins or fructosamine

(mostly albumin and, therefore, of similar half-life)

can be used.

DIABETES MELLITUS/Treatment and Management 1793

Nonglycemic Control

0045 In addition to measures of glycemic control, it is

clearly essential to monitor a large number of other

biochemical and clinical parameters on a regular

basis in an attempt to anticipate and, if possible,

prevent the development of complications. Control

of blood pressure is particularly important as this

has been shown to influence the progression of both

nephropathy and retinopathy. Monitoring is best

done as part of a regular (usually annual) formal

review (Table 7).

Prognosis

0046 Despite the advances which have been made over the

last 70 years, life expectancy is still reduced in both

type 1 and type 2 diabetes. This is largely attributable

to arterial disease (especially coronary artery and

peripheral vascular disease), which occurs at an

earlier age than in the nondiabetic population, and

to those complications which are peculiar to diabetes,

i.e., microvascular disease (particularly nephro-

pathy), and both ketoacidosis and hyperosmolar

coma. In type 1 diabetes, life expectancy is reduced

by about 25%, with a peak in mortality occurring

between 15 and 25 years after diagnosis.

0047 There is a common misconception that the situ-

ation is less serious in type 2 diabetes, but this is

clearly not so. Overall life expectancy is reduced by

between 5 and 10 years, largely owing to the very

high incidence of coronary and cerebrovascular dis-

ease. Nephropathy is relatively uncommon in type 2

diabetes, but visual loss resulting from maculopathy

is as common as in type 1 diabetes and frequently

occurs early in the course of the disease. It is import-

ant to remember that type 2 diabetes may be only a

single aspect of a syndrome which comprises, in add-

ition to carbohydrate intolerance, hypertension, dys-

lipidemia, obesity, and marked insulin resistance. The

diabetes itself may be ‘mild,’ but patients should not

be dismissed lightly in view of the high mortality

associated with the syndrome. (See Lipoproteins.)