DIABETES MELLITUS INTRODUCTION

DIABETES MELLITUS

INTRODUCTION

Before the discovery of insulin, type 1 diabetes – where insulin

deficiency can lead to ketoacidosis – was invariably fatal. Since

the introduction of insulin, the therapeutic focus has broadened

from treating and preventing diabetic ketoacidosis to preventing

long-term vascular complications. Type 2 diabetes – where

Insulin resistance and a relative lack of insulin lead to hyperglycemia

– not only causes symptoms related directly to hyperglycemia

(polyuria, polydipsia and blurred vision – see below),

but is also a very powerful risk factor for atheromatous disease.

Glucose intolerance and diabetes mellitus are increasingly

prevalent in affluent and developing countries, and represent a

major public health challenge. Addressing risk factors distinct

from blood glucose, especially hypertension, is of paramount

importance and is covered elsewhere (Chapters 27 and 28). In

this chapter, we focus mainly on the types of insulin and oral

hypoglycaemic agents.

PATHOPHYSIOLOGY

Insulin is secreted by β-cells (also called B-cells) of the islets of

Langerhans. It lowers blood glucose, but also modulates the

metabolic disposition of fats and amino acids, as well as carbohydrate.

It is secreted together with inactive C-peptide, which

provides a useful index of insulin secretion: its plasma concentration

is low or absent in patients with type 1 diabetes, but

very high in patients with insulinoma (an uncommon tumor

which causes hypoglycaemia by secreting insulin). This should

not be confused with ‘C-reactive peptide’ (CRP) which is an

acute phase protein synthesized by the liver and used as a nonspecific

index of inflammation. C-peptide concentration is not

elevated in patients with hypoglycaemia caused by injection of

insulin.

Diabetes mellitus (fasting blood glucose concentration

of
7 mmol/L) is caused by an absolute or relative lack of

insulin. In type 1 diabetes there is an absolute deficiency of

insulin. Such patients are usually young and non-obese at

presentation. There is an inherited predisposition. However,

concordance in identical twins is somewhat less than 50%, so

it is believed that genetically predisposed individuals must

also be exposed to an environmental factor. Viruses (including

Coxsackie and Echo viruses) are one such factor and may initiate

an autoimmune process that then destroys the islet cells.

In type 2 diabetes there is a relative lack of insulin secretion,

coupled with marked resistance to its action. The circulating

concentration of immunoreactive insulin measured by standard

assays (which do not discriminate well between insulin

and pro-insulin) may be normal or even increased, but more

discriminating assays indicate that there is an increase in proinsulin,

and that the true insulin concentration is reduced.

Such patients are usually middle-aged or older at presentation,

and obese. Concordance of this form of diabetes in identical

twins is nearly 100%. Type 2 diabetes is rarely if ever associated

with diabetic ketoacidosis, although it can be complicated by

non-ketotic hyperosmolar coma or, rarely (in association with

treatment with a biguanide drug such as metformin, see

below), with lactic acidosis.

An increased concentration of glucose in the circulating

blood gives rise to osmotic effects:

1. diuresis (polyuria) with consequent circulating volume

reduction, causing thirst and polydipsia;

2. the refractive index of a high glucose concentration

solution in the eye differs from healthy aqueous humor,

causing blurred vision.

In addition, glycosuria predisposes to Candida infection, especially

in women. The loss of calories in the urine is coupled

with inability to store energy as glycogen or fat, or to lay down

protein in muscle, and weight loss with loss of fat and muscle

(‘Amyotrophy’) is common in uncontrolled diabetics.

Both types of diabetes mellitus are complicated by vascular

complications. Microvascular complications include retinopathy,

which consists of background retinopathy (dot and

blot hemorrhages and hard exudates which do not of themselves

threaten vision), and proliferative retinopathy which

can cause retinal hemorrhage and blindness. Cataracts are

common. Diabetic neuropathy causes a glove and stocking

distribution of loss of sensation with associated painful

paraesthesiae. Approximately one-third of diabetic patients

develop diabetic nephropathy, which leads to renal failure.

Microalbuminuria is a forerunner of overt diabetic

nephropathy.

Macrovascular disease is the result of accelerated atheroma

and results in an increased incidence of myocardial infarction,

peripheral vascular disease and stroke. There is a strong association

(pointed out by Reaven in his 1988 Banting Lecture at

the annual meeting of the American Diabetes Association)

between diabetes and obesity, hypertension and dyslipidemia

(especially hypertriglyceridemia), and type 2 diabetes is

strongly associated with endothelial dysfunction, an early

event in atherogenesis (Chapter 27).

PRINCIPLES OF MANAGEMENT

It is important to define ambitious but achievable goals for each

patient. In young type 1 patients there is good evidence that

improved diabetic control reduces microvascular complications.

It is well worth trying hard to minimize the metabolic derangement

associated with diabetes mellitus in order to reduce the

development of such complications. Education and support are

essential to motivate the patient to learn how to adjust their

insulin dose to optimize glycaemic control. This can only be

achieved by the patient performing blood glucose monitoring at

home and learning to adjust their insulin dose accordingly. The

treatment regimen must be individualized. A common strategy

is to combine injections of a short-acting insulin before each

meal with a once daily injection of a long-acting insulin to provide

a low steady background level during the night. Follow up

must include structured care with assessment of chronic glycaemic

control using HbA1c and regular screening for evidence

of microvascular disease. This is especially important in the case

of proliferative retinopathy and maculopathy, because prophylactic

laser therapy can prevent blindness.

By contrast, striving for tight control of blood sugar in type 2

patients is only appropriate in selected cases. Tight control

reduces macrovascular complications, but at the expense of

increased hypoglycemic attacks, and the number of patients

that needs to be treated in this way to prevent one cardiovascular

event is large. In contrast, aggressive treatment of hypertension

is of substantial benefit, and the target blood pressure

should be lower than in non-diabetic patients (

130 mmHg systolic

and

80 mmHg diastolic, see Chapter 28). In older type 2

patients, hypoglycemic treatment aims to minimize symptoms

of polyuria, polydipsia or recurrent Candida infection, and to prevent

hyperosmolar coma.

DIET IN DIABETES MELLITUS

It is important to achieve and maintain ideal body weight on a

non-atherogenic diet. Caloric intake must be matched with

insulin injections. Patients who rely on injected insulin must

time their food intake accordingly. Simple sugars should be

restricted because they are rapidly absorbed, causing postprandial

hyperglycemia, and should be replaced by foods

that give rise to delayed and reduced glucose absorption,

analogous to slow release drugs (quantified by nutritionists as

‘glycaemic index’). (Artificial sweeteners are useful for those

with a ‘sweet tooth’.) A fiber-rich diet reduces peak glucose

levels after meals and reduces the insulin requirement. Beans

and lentils flatten the glucose absorption curve. Saturated fat

and cholesterol intake should be minimized. Low fat sources

of protein are favored. There is no place for commercially

promoted ‘special diabetic foods’, which are expensive and

also often high in fat and calories at the expense of complex

carbohydrate.

DRUGS USED TO TREAT DIABETES MELLITUS

INSULINS

Insulin is a polypeptide. Animal insulins have been almost

entirely replaced by recombinant human insulin and related

analogues. These are of consistent quality and cause fewer

allergic effects. Insulin is available in several formulations

(e.g. with protamine and/or with zinc) which differ in pharmacokinetic

properties, especially their rates of absorption

and durations of action. So-called ‘designer’ insulins are synthetic

polypeptides closely related to insulin, but with small

changes in amino acid composition which change their properties.

For example, a lysine and a proline residue are

switched in insulin lispro, which consequently has a very

rapid absorption and onset (and can therefore be injected

immediately before a meal), whereas insulin glargine is very

slow acting and is used to provide a low level of insulin activity

during the 24-hour period.

Use

Insulin is indicated in all patients with type 1 diabetes mellitus

(although it is not strictly necessary during the early ‘honeymoon’

period before islet cell destruction is complete) and

in about one-third of patients with type 2 disease. Insulin is

usually administered by subcutaneous injection, although

recently an inhaled preparation has been licensed for use in

type 2 diabetics. (Note: This was not commercially successful,

and has been withdrawn in the UK for this reason.) The effective

dose of human insulin is usually rather less than that of

animal insulins because of the lack of production of blocking

antibodies. Consequently, the dose is reduced when switching

from animal to human insulin.

Soluble insulin is the only preparation suitable for intravenous

use. It is administered intravenously in diabetic emergencies

and given subcutaneously before meals in chronic

management. Formulations of human insulins are available in

various ratios of short-acting and longer-lasting forms (e.g.

30:70, commonly used twice daily). Some of these are marketed

286 DIABETES MELLITUS

in prefilled injection devices (‘pens’) which are convenient for

patients. The small dose of soluble insulin controls hyperglycemia

just after the injection. The main danger is of hypoglycaemia

in the early hours of the morning. When starting a

diabetic on a two dose per day regime, it is therefore helpful to

divide the daily dose into two-thirds to be given before breakfast

and one-third to be given before the evening meal. If the

patient engages in strenuous physical work, the morning dose

of insulin is reduced somewhat to prevent exercise-induced

hypoglycaemia.

Insulin is also required for symptomatic type 2 diabetics

in whom diet and/or oral hypoglycemic drugs fail.

Unfortunately, insulin makes weight loss considerably more

difficult because it stimulates appetite, but its anabolic effects are

valuable in wasted patients with diabetic amyotrophy. Insulin is

needed in acute diabetic emergencies such as ketoacidosis, during

pregnancy, peri-operatively and in severe intercurrent disease

(infections, myocardial infarction, burns, etc.).

Insulin requirements are increased by up to one-third by

intercurrent infection and patients must be instructed to intensify

home blood glucose monitoring when they have a cold or

other infection (even if they are eating less than usual) and

increase the insulin dose if necessary. The dose will subsequently

need to be reduced when the infection has cleared. Vomiting

often causes patients incorrectly to stop injecting insulin (for

fear of hypoglycaemia) and this may result in ketoacidosis.

Patients for elective surgery should be changed to soluble

insulin preoperatively. During surgery, soluble insulin can be

infused i.v. with glucose to produce a blood glucose concentration

of 6–8 mmol/L. This is continued post-operatively until

oral feeding and intermittent subcutaneous injections

of insulin can be resumed. A similar regime is suitable for

emergency operations, but more frequent measurements of

blood glucose are required. Patients with type 2 diabetes can

sometimes be managed without insulin, but the blood glucose

must be regularly checked during the post-operative period.

Ketoacidosis

The metabolic changes in diabetic ketoacidosis (DKA) resemble

those of starvation since, despite increased plasma glucose concentrations,

glucose is not available intracellularly (‘starving

amidst plenty’). Hyperglycemia leads to osmotic diuresis and

electrolyte depletion. Conservation of K is even less efficient

than that of Na in the face of acidosis and an osmotic diuresis,

and large amounts of intravenous K are often needed to

replace the large deficit in total body K. However, plasma K

concentration in DKA can be increased due to a shift from the

intracellular to the extracellular compartment, so large amounts

of potassium chloride should not be administered until plasma

electrolyte concentrations are available and high urine output

established. Fat is mobilized from adipose tissue, releasing free

fatty acids that are metabolized by β-oxidation to acetyl coenzyme

A (CoA). In the absence of glucose breakdown, acetyl CoA

is converted to acetoacetate, acetone and β-hydroxybutyrate

(ketones). These are buffered by plasma bicarbonate, leading to

a fall in bicarbonate concentration (metabolic acidosis – with an

increased ‘anion gap’ since anionic ketone bodies are not

measured routinely) and compensatory hyperventilation

(‘Küssmaul’ breathing). There are therefore a number of metabolic

abnormalities:

• Sodium and potassium deficit A generous volume of

physiological saline (0.9% sodium chloride), given

intravenously, is crucial in order to restore extracellular

fluid volume. Monitoring urine output is necessary. When

blood glucose levels fall below 17 mmol/L, 5% glucose is

given in place of N-saline. Potassium must be replaced

and if the urinary output is satisfactory and the plasma

potassium concentration is

4.5 mEq/L, up to

20 mmol/hour KCl can be given, the rate of replacement

being judged by frequent measurements of plasma

potassium concentration and ECG monitoring.

• Hyperglycemia Intravenous insulin is infused at a rate of

up to 0.1 unit/kg/hour with a syringe pump until ketosis

resolves (judged by blood pH, serum bicarbonate and

blood or urinary ketones).

• Metabolic acidosis This usually resolves with adequate

treatment with physiological sodium chloride and insulin.

Bicarbonate treatment to reverse the extracellular

metabolic acidosis is controversial, and may paradoxically

worsen intracellular and cerebrospinal fluid acidosis. If

arterial pH is

7.0, the patient is often given bicarbonate,

should be managed on an intensive care unit if possible

and may need inotropic support.

• Other measures include aspiration of the stomach, as

gastric stasis is common and aspiration can be severe and

may be fatal, and treatment of the precipitating cause of

coma (e.g. antibiotics for bacterial infection).

DRUGS USED TO TREAT DIABETES MELLITUS 287

Key points

Type 1 diabetes mellitus and insulin

• Type 1 (insulin-dependent) diabetes mellitus is caused

by degeneration of β-cells in the islets of Langerhans

leading to an absolute deficiency of insulin.

• Without insulin treatment, such patients are prone to

diabetic ketoacidosis (DKA).

• Even with insulin treatment, such patients are

susceptible to microvascular complications of

retinopathy, nephropathy and neuropathy, and also to

accelerated atherosclerotic (macrovascular) disease

leading to myocardial infarction, stroke and gangrene.

• Management includes a healthy diet low in saturated

fat (Chapter 27), high in complex carbohydrates and

with the energy spread throughout the day.

• Regular subcutaneous injections of recombinant human

insulin are required indefinitely. Mixtures of soluble

and longer-acting insulins are used and are given using

special insulin ‘pens’ at least twice daily. Regular selfmonitoring

of blood glucose levels throughout the day

with individual adjustment of the insulin dose is

essential to achieve good metabolic control, which

reduces the risk of complications.

• DKA is treated with large volumes of intravenous

physiological saline, intravenous soluble insulin and

replacement of potassium and, if necessary, magnesium.

Hyperosmolar non-ketotic coma

Less insulin is required in this situation, as the blood pH is

normal and insulin sensitivity is retained. Fluid loss is restored

using physiological saline (there is sometimes a place for half strength,

0.45% saline) and large amounts of intravenous

potassium are often required. Magnesium deficiency is common,

contributes to the difficulty of correcting the potassium

deficit, and should be treated provided renal function is normal.

In this hyperosmolar state, the viscosity of the blood is

increased and a heparin preparation (Chapter 30) should be

considered as prophylaxis against venous thrombosis.

Mechanism of action

Insulin acts by binding to transmembrane glycoprotein receptors.

Receptor occupancy results in:

1. activation of insulin-dependent glucose transport

processes (in adipose tissue and muscle) via a transporter

known as ‘Glut-4’;

2. inhibition of adenylyl cyclase-dependent metabolism

(lipolysis, proteolysis, glycogenolysis);

3. intracellular accumulation of potassium and phosphate,

which is linked to glucose transport in some tissues.

Secondary effects include increased cellular amino acid

uptake, increased DNA and RNA synthesis and increased

oxidative phosphorylation.

Adverse reactions

1. Hypoglycaemia is the most important and severe

complication of insulin treatment. It is treated with

an intravenous injection of glucose in unconscious

patients, but sugar is given as a sweet drink in those

with milder symptoms. Glucagon (1 mg intramuscularly,

repeated after a few minutes if necessary) is useful if

the patient is unconscious and intravenous access is

not achievable (e.g. to ambulance personnel or a family

member).

2. Insulin-induced post-hypoglycemic hyperglycemia

(Somogyi effect) occurs when hypoglycaemia (e.g. in the

early hours of the morning) induces an overshoot of

hormones (adrenaline, growth hormone, glucocorticosteroids,

glucagon) that elevate blood glucose (raised blood glucose

on awakening). The situation can be misinterpreted as

requiring increased insulin, thus producing further

hypoglycaemia.

3. Local or systemic allergic reactions to insulin, with

itching, redness and swelling at the injection site.

4. Lipodystrophy: the disappearance of subcutaneous fat at

or near injection sites. Atrophy is minimized by rotation of

injection sites. Fatty tumors occur if repeated injections

are made at the same site.

5. Insulin resistance, defined arbitrarily as a daily

requirement of more than 200 units, due to antibodies, is

unusual. Changing to a highly purified insulin

preparation is often successful, a small starting dose being

used to avoid hypoglycaemia.

Pharmacokinetics

Insulin is broken down in the gut and by the liver and kidney,

and is given by injection. The t1/2 is three to five minutes. It is

metabolized to inactive α and β peptide chains largely by

hepatic/renal insulinases (insulin glutathione transhydrogenase).Insulin

from the pancreas is mainly released into the portal

circulation and passes to the liver, where up to 60% is

degraded before reaching the systemic circulation (presystemic

metabolism). The kidney is also important in the metabolism of

insulin and patients with progressive renal impairment often

have a reduced requirement for insulin. There is no evidence

that diabetes ever results from increased hepatic destruction of

insulin, but in cirrhosis the liver fails to inactivate insulin, thus

predisposing to hypoglycaemia.

ORAL HYPOGLYCAEMIC DRUGS AND

TYPE 2 DIABETES

Oral hypoglycemic drugs are useful in type 2 diabetes as

adjuncts to continued dietary restraint. They fall into four

groups:

1. biguanides (metformin);

2. sulphonylureas and related drugs;

3. thiazolidinediones (glitazones);

4. α-glucosidase inhibitors (acarbose).

Most type 2 diabetic patients initially achieve satisfactory control

with diet either alone or combined with one of these agents.

The small proportion who cannot be controlled with drugs at

this stage (primary failure) require insulin. Subsequent failure

after initially adequate control (secondary failure) occurs in

about one-third of patients, and is treated with insulin. Inhaled

insulin is effective but expensive. Its bioavailability is affected

by smoking and by respiratory infections, and currently should

only be used with great caution in patients with asthma/

COPD.

BIGUANIDES: METFORMIN

Uses

Metformin is the only biguanide available in the UK. It is used

in type 2 diabetic patients inadequately controlled by diet. Its

anorectic effect aids weight reduction, so it is a first choice drug

for obese type 2 patients, provided there are no contraindications.

It must not be used in patients at risk of lactic acidosis and

is contraindicated in:

• renal failure (it is eliminated in the urine, see below);

• alcoholics;

• cirrhosis;

• chronic lung disease (because of hypoxia);

• cardiac failure (because of poor tissue perfusion);

• congenital mitochondrial myopathy (which is often

accompanied by diabetes);

• acute myocardial infarction and other serious intercurrent

illness (insulin should be substituted).

288 DIABETES MELLITUS

Metformin should be withdrawn and insulin substituted

before major elective surgery. Plasma creatinine and liver

function tests should be monitored before and during its use.

Mechanism of action

This remains uncertain. Biguanides do not produce hypoglycaemia

and are effective in pancreatectomized animals.

Effects of metformin include:

• reduced glucose absorption from the gut;

• facilitation of glucose entry into muscle by a non-insulin responsive

mechanism;

• inhibition of gluconeogenesis in the liver;

• suppression of oxidative glucose metabolism and

enhanced anaerobic glycolysis.

Adverse effects

Metformin causes nausea, a metallic taste, anorexia, vomiting

and diarrhoea. The symptoms are worst when treatment is initiated

and a few patients cannot tolerate even small doses.

Lactic acidosis, which has a reported mortality in excess of 60%,

is uncommon provided that the above contraindications are

respected. Treatment is by reversal of hypoxia and circulatory

collapse and peritoneal or hemodialysis to alleviate sodium

overloading and removing the drug. Phenformin (withdrawn

in the UK and USA) was more frequently associated with this

problem than metformin. Absorption of vitamin B12 is reduced

by metformin, but this is seldom clinically important.

Pharmacokinetics

Oral absorption of metformin is 50–60%; it is eliminated

unchanged by renal excretion, clearance being greater than the

glomerular filtration rate because of active secretion into the

tubular fluid. Metformin accumulates in patients with renal

impairment. The plasma t1/2 ranges from 1.5 to 4.5 hours, but

its duration of action is considerably longer, permitting twice

daily dosing.

Drug interactions

Other oral hypoglycemic drugs are additive with metformin.

Ethanol predisposes to metformin-related lactic acidosis.

SULPHONYLUREAS AND RELATED DRUGS

Use

Sulphonylureas (e.g. tolbutamide, glibenclamide, gliclazide)

are used for type 2 diabetics who have not responded

adequately to diet alone or diet and metformin with which

they are additive. They improve symptoms of polyuria and

polydipsia, but (in contrast to metformin) stimulate appetite.

Chlorpropamide, the longest-acting agent in this group, has a

higher incidence of adverse effects (especially hypoglycaemia)

than other drugs of this class and should be avoided. This is

because of a protracted effect and reduced renal clearance in

patients with renal dysfunction and the elderly; thus it is

hardly ever used. Tolbutamide and gliclazide are shorter acting

than glibenclamide, so there is less risk of hypoglycaemia,

and for this reason they are preferred in the elderly. Related

drugs (e.g. repaglinide, nateglinide) are chemically distinct,

but act at the same receptor. They are shorter acting even than

tolbutamide, but more expensive. They are given before meals.

Mechanism of action

The hypoglycemic effect of these drugs depends on the presence

of functioning B cells. Sulphonylureas, like glucose,

depolarize B cells and release insulin. They do this by binding

to sulphonylurea receptors (SUR) and blocking ATP-dependent

potassium channels (KATP); the resulting depolarization activates

voltage-sensitive Ca2 channels, in turn causing entry of

Ca2 ions and insulin secretion.

Adverse effects

Sulphonylureas can cause hypoglycaemia. Chlorpropamide,

the longest-acting agent, was responsible for many cases. It also

causes flushing in susceptible individuals when ethanol is consumed,

and can cause dilutional hyponatremia (by potentiating

ADH, see Chapter 42). Allergic reactions to sulphonylureas

include rashes, drug fever, gastrointestinal upsets, transient

jaundice (usually cholestatic) and hematopoietic changes,

including thrombocytopenia, neutropenia and pancytopenia.

Serious effects other than hypoglycaemia are uncommon.

Pharmacokinetics

Sulphonylureas are well absorbed from the gastrointestinal

tract and the major differences between them lie in their relative

potencies and rates of elimination. Glibenclamide is

almost completely metabolized by the liver to weakly active

metabolites that are excreted in the bile and urine. The activity

of these metabolites is only clinically important in patients

with renal failure, in whom they accumulate and can cause

hypoglycaemia. Tolbutamide is converted in the liver to

inactive metabolites which are excreted in the urine. The t1/2

shows considerable inter-individual variability, but is usually

four to eight hours. Gliclazide is extensively metabolized,

although up to 20% is excreted unchanged in the urine. The

plasma t1/2 ranges from 6 to 14 hours. Repaglinide and

nateglinide exhibit rapid onset and offset kinetics, rapid

absorption (time to maximal plasma concentration approximately

55 minutes after an oral dose) and elimination (half-life

approximately three hours). These features lead to short duration

of action and a low risk of hypoglycaemia. They are

administered shortly before a meal to reduce the postprandial

glucose rise in type 2 diabetic patients.

Drug interactions

Monoamine oxidase inhibitors potentiate the activity of

sulphonylureas by an unknown mechanism. Several drugs

(e.g. glucocorticosteroids, growth hormone) antagonize the

hypoglycemic effects of sulphonylureas by virtue of their

actions on insulin release or sensitivity.

THIAZOLIDINEDIONES (GLITAZONES)

Glitazones (e.g. piolitazone, rosiglitazone) were developed

from the chance finding that a fibrate drug (Chapter 27)

increased insulin sensitivity.

DRUGS USED TO TREAT DIABETES MELLITUS 289

Use

Glitazones lower blood glucose and hemoglobin A1c (HbA1c)

in type 2 diabetes mellitus patients who are inadequately controlled

on diet alone or diet and other oral hypoglycemic drugs.

An effect on mortality or diabetic complications has yet to be

established, but they have rapidly become very widely used.

Mechanism of action

Glitazones bind to the peroxisome-proliferating activator

receptor γ (PPARγ), a nuclear receptor found mainly in

adipocytes and also in hepatocytes and myocytes. It works

slowly, increasing the sensitivity to insulin possibly via effects

of circulating fatty acids on glucose metabolism.

Adverse effects

The first two glitazones caused severe hepatotoxicity and are not

used. Hepatotoxicity has not proved problematic with rosiglitazone

or pioglitazone, although they are contraindicated in

patients with hepatic impairment and liver function should be

monitored during their use. The most common adverse effects

are weight gain (possibly partly directly related to their effect on

adipocytes) and fluid retention due to an effect of PPARγ receptors

on renal tubular sodium ion absorption. They can also exacerbate

cardiac dysfunction and are therefore contraindicated in

heart failure. Recently, an association with increased bone fractures

and osteoporosis has been noted. They are contraindicated

during pregnancy. A possible increase in myocardial infarction

with rosiglitazone has been noted, but the data are controversial.

Pharmacokinetics

Both rosiglitazone and pioglitazone are well absorbed, highly

protein bound and subject to hepatic metabolism.

Drug interactions

Glitazones are additive with other oral hypoglycemic drugs.

They potentiate insulin, but this combination is contraindicated

in Europe because of concerns that it might increase the

risk of heart failure, although the combination is widely used

in the USA. Pioglitazone is an inducer of CYP3A and may

cause treatment failure with concomitantly administered

drugs which are CYP3A substrates (e.g. reproductive steroids).

ACARBOSE

Acarbose is used in type 2 diabetes mellitus in patients who

are inadequately controlled on diet alone or diet and other

oral hypoglycemic agents. Acarbose is a reversible competitive

inhibitor of intestinal α-glucoside hydrolases and delays

the absorption of starch and sucrose, but does not affect the

absorption of ingested glucose. The postprandial glycaemic

rise after a meal containing complex carbohydrates is reduced

and its peak is delayed. Fermentation of unabsorbed carbohydrate

in the intestine leads to increased gas formation which

results in flatulence, abdominal distension and occasionally

diarrhea. As with any change in a diabetic patient’s medication,

diet or activities, the blood glucose must be monitored.

290 DIABETES MELLITUS

Key points

Type 2 diabetes mellitus and oral hypoglycemic agents

• Type 2 (non-insulin-dependent) diabetes mellitus is

caused by relative deficiency of insulin in the face of

impaired insulin sensitivity. Such patients are usually

obese.

• About one-third of such patients finally require insulin

treatment. This is especially important when they are

losing muscle mass.

• The dietary goal is to achieve ideal body weight by

consuming an energy-restricted healthy diet low in

saturated fat (Chapter 27).

• Oral hypoglycemic drugs are useful in some patients as

an adjunct to diet.

• Metformin, a biguanide, lowers blood glucose levels

and encourages weight loss by causing anorexia.

Diarrhea is a common adverse effect. It is

contraindicated in patients with renal impairment,

heart failure, obstructive pulmonary disease or

congenital mitochondrial myopathies because of

the risk of lactic acidosis, a rare but life-threatening

complication.

• Acarbose, an α-glucosidase inhibitor, delays the

absorption of starch and sucrose. It flattens the rise in

plasma glucose following a meal and may improve

control when added to diet with or without other

drugs. However, it can cause bloating, flatulence and

diarrhea associated with carbohydrate malabsorption.

• Sulphonylureas (e.g. tolbutamide) and related drugs

(e.g. nateglinide) release insulin from β-cells by closing

ATP-sensitive K channels, thereby depolarizing the cell

membrane. They are well tolerated and improve blood

glucose at least initially, but stimulate appetite,

promoting weight gain. They differ from one another

in their kinetics, the longer-acting drugs being

particularly likely to cause hypoglycaemia which can be

severe, especially in the elderly and should not be used

in these patients.

• Thiazolidinediones (e.g. pioglitazone, rosiglitazone)

activate PPARγ receptors and increase insulin sensitivity.

They lower blood sugar but cause weight gain and fluid

retention. They are contraindicated in heart failure.

Effects on longevity or complications are unknown.

Case history

A 56-year-old woman with a positive family history of diabetes

presents with polyuria, polydipsia, blurred vision and

recurrent attacks of vaginal thrush. She is overweight at

92 kg, her fasting blood sugar is 12 mmol/L and hemoglobin

A1C is elevated at 10.6%. She is treated with glibenclamide

once daily in addition to topical antifungal treatment for the

thrush. Initially, her symptoms improve considerably and she

feels generally much better, but after nine months the

polyuria and polydipsia recur and her weight has increased

to 102 kg.

Comment

Treatment with a sulphonylurea without attention to diet

is doomed to failure. This patient needs to be motivated to

take dietary advice, restricting her energy intake and

reducing her risk of atherosclerosis. If hyperglycemia is still

not improved, metformin (which reduces appetite) would

be appropriate