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 phar- macokinetic properties, especially their rates of absorption and durations of action. So-called ‘designer’ insulins are syn- thetic polypeptides closely related to insulin, but with small changes in amino acid composition which change their prop- erties. 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 glargineis very slow acting and is used to provide a low level of insulin activ- ity during the 24-hour period.
Use
Insulinis indicated in all patients with type 1 diabetes melli- tus (although it is not strictly necessary during the early ‘honey- moon’ period before islet cell destruction is complete) and in about one-third of patients with type 2 disease. Insulinis 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 (Note: This was not commercially successful, and has been withdrawn in the UK for this reason.)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 effec- tive 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 intra- venous use. It is administered intravenously in diabetic emer- gencies 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 hyper- glycaemia just after the injection. The main danger is of hypo- glycaemia 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 break- fast and one-third to be given before the evening meal. If the patient engages in strenuous physical work, the morning dose ofinsulin is reduced somewhat to prevent exercise-induced hypoglycaemia.
Insulinis also required for symptomatic type 2 diabetics in whom diet and/or oral hypoglycaemic 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. Insulinis needed in acute diabetic emergencies such as ketoacidosis, dur- ing pregnancy, peri-operatively and in severe intercurrent dis- ease (infections, myocardial infarction, burns, etc.).
Insulinrequirements are increased by up to one-third by intercurrent infection and patients must be instructed to inten- sify home blood glucose monitoring when they have a cold or other infection (even if they are eating less than usual) and increase the insulindose 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 insulinpreoperatively. During surgery, soluble insulincan be infused i.v. with glucose to produce a blood glucose concentra- tion of 6–8 mmol/L. This is continued post-operatively until oral feeding and intermittent subcutaneous injections
of insulincan 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 con- centrations, glucose is not available intracellularly (‘starving amidst plenty’). Hyperglycaemia leads to osmotic diuresis and electrolyte depletion. Conservation of Kis even less efficient than that of Nain 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 coen- zyme 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 meta- bolic abnormalities:
• Sodium and potassium deficitA 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 is4.5 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.
• HyperglycaemiaIntravenous 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 acidosisThis 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 is7.0, the patient is often given bicarbonate, should be managed on an intensive care unit if possible and may need inotropic support.
• Other measuresinclude 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).
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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 self- monitoring 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
Lessinsulinis required in this situation, as the blood pH is normal and insulinsensitivity 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 com- mon, contributes to the difficulty of correcting the potassium deficit, and should be treated provided renal function is nor- mal. In this hyperosmolar state, the viscosity of the blood is increased and a heparinpreparation (Chapter 30) should be considered as prophylaxis against venous thrombosis.
Mechanism of action
Insulinacts by binding to transmembrane glycoprotein recep- tors. 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 insulintreatment. 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-hypoglycaemic hyperglycaemia (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 tumours occur if repeated injections are made at the same site.
5. Insulinresistance, 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
Insulinis broken down in the gut and by the liver and kidney, and is given by injection. The t1/2is three to five minutes. It is metabolized to inactive α and β peptide chains largely by hepatic/renal insulinases (insulin glutathione transhydroge- nase).Insulinfrom the pancreas is mainly released into the por- tal 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 insulinand 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 hypoglycaemic 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 con- trol 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 insulinis 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
Metforminis 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 contraindica- tions. 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 (insulinshould be substituted).
288 DIABETES MELLITUS
Metforminshould be withdrawn and insulinsubstituted 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 hypo- glycaemia and are effective in pancreatectomized animals.
Effects of metformininclude:
• 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
Metformincauses nausea, a metallic taste, anorexia, vomiting and diarrhoea. The symptoms are worst when treatment is ini- tiated 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 haemodialysis 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 B12is reduced bymetformin, 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. Metforminaccumulates in patients with renal impairment. The plasma t1/2ranges from 1.5 to 4.5 hours, but its duration of action is considerably longer, permitting twice daily dosing.
Drug interactions
Other oral hypoglycaemic drugs are additive with metformin.
Ethanolpredisposes 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. Tolbutamideandgliclazideare shorter act- ing 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 hypoglycaemic effect of these drugs depends on the pres- ence 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 acti- vates voltage-sensitive Ca2channels, in turn causing entry of Ca2ions and insulinsecretion.
Adverse effects
Sulphonylureas can cause hypoglycaemia. Chlorpropamide, the longest-acting agent, was responsible for many cases. It also causes flushing in susceptible individuals when ethanolis con- sumed, and can cause dilutional hyponatraemia (by potentiat- ing ADH, see Chapter 42). Allergic reactions to sulphonylureas include rashes, drug fever, gastrointestinal upsets, transient jaundice (usually cholestatic) and haematopoietic 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 rela- tive 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 approxi- mately 55 minutes after an oral dose) and elimination (half-life approximately three hours). These features lead to short dura- tion 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 hypoglycaemic effects of sulphonylureas by virtue of their actions on insulinrelease or sensitivity.
THIAZOLIDINEDIONES (GLITAZONES)
Glitazones (e.g. piolitazone, rosiglitazone) were developed from the chance finding that a fibrate drug (Chapter 27) increased insulinsensitivity.
DRUGSUSED TOTREATDIABETESMELLITUS 289
Use
Glitazones lower blood glucose and haemoglobin A1c (HbA1c) in type 2 diabetes mellitus patients who are inadequately con- trolled on diet alone or diet and other oral hypoglycaemic 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 insulinpossibly 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 rosiglita- zone 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 PPARγrecep- tors on renal tubular sodium ion absorption. They can also exac- erbate cardiac dysfunction and are therefore contraindicated in heart failure. Recently, an association with increased bone frac- tures and osteoporosis has been noted. They are contraindicated during pregnancy. A possible increase in myocardial infarction withrosiglitazonehas been noted, but the data are controversial.
Pharmacokinetics
Bothrosiglitazoneandpioglitazoneare well absorbed, highly protein bound and subject to hepatic metabolism.
Drug interactions
Glitazones are additive with other oral hypoglycaemic drugs.
They potentiate insulin, but this combination is contraindi- cated 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
Acarboseis used in type 2 diabetes mellitus in patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic agents. Acarboseis a reversible competi- tive 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 carbohy- drate in the intestine leads to increased gas formation which results in flatulence, abdominal distension and occasionally diarrhoea. As with any change in a diabetic patient’s medica- tion, diet or activities, the blood glucose must be monitored.
290 DIABETES MELLITUS
Key points
Type 2 diabetes mellitus and oral hypoglycaemic 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 hypoglycaemic 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.
Diarrhoea 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 diarrhoea associated with carbohydrate malabsorption.
• Sulphonylureas (e.g. tolbutamide) and related drugs (e.g. nateglinide) release insulin from β-cells by closing ATP-sensitive Kchannels, 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 PPARγreceptors 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 dia- betes 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 haemoglobin 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 hyperglycaemia is still not improved, metformin (which reduces appetite) would be appropriate.