Introduction

Diabetes mellitus (DM) is a syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both. It affects more than 220 million people worldwide, and it is estimated that it will affect 440 million by the year 2030. Diabetes is usually irreversible and, although patients can lead a reasonably normal lifestyle, its late complications result in reduced life expectancy and major health costs. These include macrovascular disease, leading to an increased prevalence of coronary artery disease, peripheral vascular disease and stroke, and microvascular damage causing diabetic retinopathy and nephropathy. Neuropathy is another major complication.

Insulin structure and secretion

Insulin is the key hormone involved in the storage and controlled release within the body of the chemical energy available from food. It is coded for on chromosome 11 and synthesized in the beta cells of the pancreatic islets (Fig. 20.1). The synthesis, intracellular processing and secretion of insulin by the beta cell is typical of the way that the body produces and manipulates many peptide hormones. Figure 20.2 illustrates the cellular events triggering the release of insulin-containing granules. After secretion, insulin enters the portal circulation and is carried to the liver, its prime target organ. About 50% of secreted insulin is extracted and degraded in the liver; the residue is broken down by the kidneys. C-peptide is only partially extracted by the liver (and hence provides a useful index of the rate of insulin secretion) but is mainly degraded by the kidneys.

Figure 20.1 Part of a beta cell. The ribosomes manufacture pre-proinsulin from insulin mRNA. The hydrophobic ‘pre’ portion of pre-proinsulin allows it to transfer to the Golgi apparatus, and is subsequently enzymatically cleaved off. Proinsulin is parcelled into secretory granules in the Golgi apparatus. These mature and pass towards the cell membrane where they are stored before release. The proinsulin molecule folds back on itself and is stabilized by disulphide bonds. The biochemically inert peptide fragment known as connecting (C) peptide splits off from proinsulin in the secretory process, leaving insulin as a complex of two linked peptide chains. Equimolar quantities of insulin and C-peptide are released into the circulation via the ‘regulated pathway’. A small amount of insulin is secreted by the beta cell directly via the ‘constitutive pathway’, which bypasses the secretory granules.

Figure 20.2 Local forces regulating insulin secretion from beta cells. Glucose enters the beta cell via the GLUT-2 transporter protein, which is closely associated with the glycolytic enzyme glucokinase. Metabolism of glucose within the beta cell generates ATP. ATP closes potassium channels in the cell membrane (a). If a sulfonylurea binds to its receptor, this also closes potassium channels. Closure of potassium channels predisposes to cell membrane depolarization, allowing calcium ions to enter the cell via calcium channels in the cell membrane (b). The rise in intracellular calcium triggers activation of calcium-dependent phospholipid protein kinase which, via intermediary phosphorylation steps, leads to fusion of the insulin-containing granules with the cell membrane and exocytosis of the insulin-rich granule contents. Similar mechanisms produce hormone-granule secretion in many other endocrine cells.

An outline of glucose metabolism

Blood glucose levels are closely regulated in health and rarely stray outside the range of 3.5–8.0 mmol/L (63–144 mg/dL), despite the varying demands of food, fasting and exercise. The principal organ of glucose homeostasis is the liver, which absorbs and stores glucose (as glycogen) in the post-absorptive state and releases it into the circulation between meals to match the rate of glucose utilization by peripheral tissues. The liver also combines 3-carbon molecules derived from breakdown of fat (glycerol), muscle glycogen (lactate) and protein (e.g. alanine) into the 6-carbon glucose molecule by the process of gluconeogenesis.

Glucose production

About 200 g of glucose is produced and utilized each day. More than 90% is derived from liver glycogen and hepatic gluconeogenesis, and the remainder from renal gluconeogenesis.

Glucose utilization

The brain is the major consumer of glucose, and its function depends upon an uninterrupted supply of this substrate. Its requirement is 1 mg/kg bodyweight per minute, or 100 g daily in a 70 kg man. Glucose uptake by the brain is obligatory and is not dependent on insulin, and the glucose used is oxidized to carbon dioxide and water. Other tissues, such as muscle and fat, are facultative glucose consumers. The effect of insulin peaks associated with meals is to lower the threshold for glucose entry into cells; at other times, energy requirements are largely met by fatty-acid oxidation. Glucose taken up by muscle is stored as glycogen or metabolized to lactate or carbon dioxide and water. Fat uses glucose as a source of energy and as a substrate for triglyceride synthesis; lipolysis releases fatty acids from triglyceride together with glycerol, a substrate for hepatic gluconeogenesis.

Hormonal regulation

Insulin is a major regulator of intermediary metabolism, although its actions are modified in many respects by other hormones. Its actions in the fasting and postprandial states differ (Fig. 20.3). In the fasting state, its main action is to regulate glucose release by the liver, and in the postprandial state, it additionally promotes glucose uptake by fat and muscle. The effect of counter-regulatory hormones (glucagon, epinephrine (adrenaline), cortisol and growth hormone) is to cause greater production of glucose from the liver and less utilization of glucose in fat and muscle for a given level of insulin.

Figure 20.3 Fasting and postprandial effects of insulin. In the fasting state, insulin concentrations are low and it acts mainly as a hepatic hormone, modulating glucose production (via glycogenolysis and gluconeogenesis) from the liver. Hepatic glucose production rises as insulin levels fall. In the postprandial state insulin concentrations are high and it then suppresses glucose production from the liver and promotes the entry of glucose into peripheral tissues (increased glucose utilization).

Glucose transport

Cell membranes are not inherently permeable to glucose. A family of specialized glucose-transporter (GLUT) proteins carry glucose through the membrane into cells.

GLUT-1 – enables basal non-insulin-stimulated glucose uptake into many cells (see Fig. 6.29).

GLUT-2 – transports glucose into the beta cell, a prerequisite for glucose sensing, and is also present in the renal tubules and hepatocytes.

GLUT-3 – enables non-insulin-mediated glucose uptake into brain neurones and placenta.

GLUT-4 – enables much of the peripheral action of insulin. It is the channel through which glucose is taken up into muscle and adipose tissue cells following stimulation of the insulin receptor (Fig. 20.4).

Figure 20.4 Insulin signalling in peripheral cells (e.g. muscle and adipose tissue). The insulin receptor consists of α- and β-subunits linked by disulphide bridges (top right of figure). The β-subunits straddle the cell membrane. The transporter protein GLUT-4 (bottom left of figure) is stored in intracellular vesicles. The binding of insulin to its receptor initiates many intracellular actions including translocation of these vesicles to the cell membrane, carrying GLUT-4 with them; this allows glucose transport into the cell.

The insulin receptor

This is a glycoprotein (400 kDa), coded for on the short arm of chromosome 19, which straddles the cell membrane of many cells (Fig. 20.4). It consists of a dimer with two α-subunits, which include the binding sites for insulin, and two β-subunits, which traverse the cell membrane. When insulin binds to the α-subunits it induces a conformational change in the β-subunits, resulting in activation of tyrosine kinase and initiation of a cascade response involving a host of other intracellular substrates. One consequence of this is migration of the GLUT-4 glucose transporter to the cell surface and increased transport of glucose into the cell. The insulin-receptor complex is then internalized by the cell, insulin is degraded, and the receptor is recycled to the cell surface.

Epidemiology

Type 1 diabetes is a disease of insulin deficiency. In western countries almost all patients have the immune-mediated form of the disease, otherwise known as type 1A. Type 1 diabetes is a disease of childhood, reaching a peak incidence around the time of puberty, but can present at any age. A ‘slow-burning’ variant with slower progression to insulin deficiency occurs in later life and is sometimes called latent autoimmune diabetes in adults (LADA). LADA may be difficult to distinguish from type 2 diabetes. Clinical clues are: leaner build, rapid progression to insulin therapy following an initial response to other therapies, and the presence of circulating islet autoantibodies. The highest rates of type 1 diabetes in the world are seen in Finland and other Northern European countries, and on the island of Sardinia, which for unknown reasons, has the second highest rate in the world (Fig. 20.5). The incidence of type 1 diabetes appears to be increasing in most populations. In Europe, the annual increase is of the order of 2–3%, and is most marked in children under the age of 5 years. WHO estimated in 1995 that there were 19.4 million people with type 1 diabetes and that the number will rise to 57.2 million by 2025.

Figure 20.5 Age-standardized incidence rates of type 1 diabetes (onset 0–14 years) in Europe, per 100 000/year.

(Data courtesy of International Diabetes Federation.)

Causes

Type 1 diabetes belongs to a family of HLA-associated immune-mediated organ-specific diseases. Genetic susceptibility is polygenic, with the greatest contribution from the HLA region. Autoantibodies directed against pancreatic islet constituents appear in the circulation within the first few years of life, and often predate clinical onset by many years. Autoantibodies are also found in older patients with LADA and carry an increased risk of progression to insulin therapy.

Autoimmunity and type 1 diabetes

Pancreatic islet showing infiltration by chronic inflammatory cells (insulitis).

Type 1 diabetes is associated with other organ-specific autoimmune diseases including autoimmune thyroid disease, coeliac disease, Addison’s disease and pernicious anaemia. Autopsies of patients who died following diagnosis of type 1 diabetes show infiltration of the pancreatic islets by mononuclear cells. This appearance, known as insulitis, resembles that in other autoimmune diseases such as thyroiditis. Several islet antigens have been characterized, and these include insulin itself, the enzyme glutamic acid decarboxylase (GAD), protein tyrosine phosphatase (IA-2) (Fig. 20.6) and the cation transporter ZnT8. Recent studies have shown that GAD immunotherapy has no benefit. The observation that treatment with immunosuppressive agents such as ciclosporin prolongs beta-cell survival in newly diagnosed patients has confirmed that the disease is immune-mediated.

Figure 20.6 Islet autoantibodies. Islet cell antibodies are detected by a fluorescent antibody technique which detects binding of autoantibodies to islet cells. Much of this staining reaction is due to antibodies specific for glutamic acid decarboxylase (GAD) and protein tyrosine phosphatase – IA-2 (also known as ICA512). Not all the staining seen with ICA is due to these two autoantibodies, so it is assumed that other islet autoantibodies are also involved. Insulin autoantibodies also appear in the circulation but do not contribute to the ICA reaction.

FURTHER READING

Ludvigsson J et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 2012; 366:433–442.

Nathan DM. Navigating the choices for diabetes prevention. N Engl J Med 2010; 362:1533–1535.

Epidemiology

Type 2 diabetes is a common condition in all populations enjoying an affluent lifestyle, and has increased in parallel with the adoption of a western lifestyle and increasing obesity. The four major determinants are increasing age, obesity, ethnicity and family history. In poor countries, diabetes is a disease of the rich, but in rich countries, it is a disease of the poor; obesity being the common factor. Glucose intolerance or frank diabetes may be present in a subclinical or undiagnosed form for years before diagnosis, and 25–50% of patients already have some evidence of vascular complications at the time of diagnosis. Onset may be accelerated by the stress of pregnancy, drug treatment or intercurrent illness. The overall prevalence within the UK is 4–6%, and the lifetime risk is around 15–20%. Type 2 diabetes is 2–4 times as prevalent in people of South Asian, African and Caribbean ancestry who live in the UK, and the life-time risk in these groups exceeds 30%. High rates also affect people of Middle Eastern and Hispanic American origin living western lifestyles. Obesity increases the risk of type 2 diabetes 80–100 fold, and this is reflected by the increasing prevalence of diabetes in different populations. On average, the inhabitants of affluent countries gain almost 1 g daily between the ages of 25 and 55 years. This gain, due to a tiny excess in energy intake over expenditure – 90 kcal or one chocolate-coated digestive biscuit per day – is often due to reduced exercise rather than increased food intake. Further, our sedentary lifestyle means that the proportion of obese young adults is rising rapidly, and epidemic obesity will create a huge public health problem for the future. The increasing numbers of obese adolescents presenting with type 2 diabetes, particularly within high-risk ethnic groups, is a matter for concern.

Type 2 diabetes is associated with central obesity, hypertension, hypertriglyceridaemia, a decreased HDL-cholesterol, disturbed haemostatic variables and modest increases in a number of pro-inflammatory markers. Insulin resistance is strongly associated with many of these variables, as is increased cardiovascular risk. This group of conditions is referred to as the metabolic syndrome (see p. 223). The International Diabetes Federation has proposed criteria based on increased waist circumference (or BMI >30) plus two of the following: diabetes (or fasting glucose >6.0 mmol/L), hypertension, raised triglycerides or low HDL cholesterol. On this definition, about one-third of the adult population has features of the syndrome, not necessarily associated with diabetes. Critics would argue that the metabolic syndrome is not a distinct entity, but one end of a continuum in the relationship between exercise, lifestyle and bodyweight on the one hand, and genetic make-up on the other, and that diagnosis adds little to standard clinical practice in terms of diagnosis, prognosis or therapy.

Causes

Acute presentation

Young people often present with a 2–6-week history and report the classic triad of symptoms:

Ketonuria is often present in young people and may progress to ketoacidosis if these early symptoms are not recognized and treated.

Subacute presentation

The clinical onset may be over several months or years, particularly in older patients. Thirst, polyuria and weight loss are typically present but patients may complain of such symptoms as lack of energy, visual blurring (owing to glucose-induced changes in refraction) or pruritus vulvae or balanitis that is due to Candida infection.

Complications as the presenting feature

These include:

Asymptomatic diabetes

Glycosuria or a raised blood glucose may be detected on routine examination (e.g. for insurance purposes) in individuals who have no symptoms of ill-health. Glycosuria is not diagnostic of diabetes but indicates the need for further investigations. About 1% of the population have renal glycosuria. This is an inherited low renal threshold for glucose, transmitted either as a Mendelian dominant or recessive trait.

Other investigations

No further tests are needed to diagnose diabetes. Other routine investigations include urine testing for protein, a full blood count, urea and electrolytes, liver biochemistry and random lipids. The latter test is useful to exclude an associated hyperlipidaemia and, if elevated, should be repeated fasting after diabetes has been brought under control. Diabetes may be secondary to other conditions (see Table 20.1), may be precipitated by underlying illness and be associated with autoimmune disease or hyperlipidaemia. Hypertension is present in 50% of patients with type 2 diabetes and a higher proportion of African and Caribbean patients.

The role of patient education and community care

The care of diabetes is based on self-management by the patient, who is helped and advised by those with specialized knowledge. The quest for improved glycaemic control has made it clear that whatever the technical expertise applied, the outcome depends on willing cooperation by the patient. This in turn depends on an understanding of the risks of diabetes and the potential benefits of glycaemic control and other measures such as maintaining a lean weight, stopping smoking and taking care of the feet. If accurate information is not supplied, misinformation from friends and other patients will take its place. For this reason the best time to educate the patient is soon after diagnosis. Organized education programmes involve all healthcare workers, including nurse specialists, dieticians and podiatrists, and should include ongoing support and updates wherever possible.

Carbohydrates

The glucose peak seen in the blood after eating pasta is much flatter than that seen after eating the same amount of carbohydrate as white potato. Pasta has a lower ‘glycaemic index’. Foods with a low glycaemic index prevent rapid swings in circulating glucose, and are thus preferred to those with a higher glycaemic index.

Prescribing a diet

Most people find it extremely difficult to modify their eating habits, and repeated advice and encouragement are needed if this is to be achieved. A diet history is taken, and the diet prescribed should involve the least possible interference with the person’s lifestyle. Advice from dieticians is more likely to affect medium-term outcome than advice from doctors. People taking insulin or oral agents have traditionally been advised to eat roughly the same amount of food (particularly carbohydrate) at roughly the same time each day, so that treatment can be balanced against food intake and exercise. Knowledgeable and motivated patients with type 1 diabetes, who get feedback from regular blood glucose monitoring, can vary the amount of carbohydrate consumed, or meal times, by learning to adjust their exercise pattern and treatment. This is the basis of the DAFNE (Dose Adjustment For Normal Eating) regimen.

Exercise

Diet treatment is incomplete without exercise. Any increase in activity levels is to be encouraged, but participation in more formal exercise programmes is best. Where facilities for this exist, exercise should be prescribed for everyone with diabetes. Several trials have shown that regular exercise reduces the risk of progression to type 2 diabetes by 30–60%, and the lowest long-term morbidity and mortality is seen in those with established disease who have the highest levels of cardiorespiratory fitness. Both aerobic and resistance training improve insulin sensitivity and metabolic control in type 1 and type 2 diabetes, although reported effects on metabolic control are inconsistent. Patients on insulin or sulfonylureas should be warned that there is an increased risk of hypoglycaemia for up to 6–12 h following heavy exertion.

Biguanide (metformin)

Metformin is the only biguanide currently in use, and remains the best validated primary treatment for type 2 diabetes. It activates the enzyme AMP-kinase, which is involved in regulation of cellular energy metabolism, but its precise mechanism of action remains unclear. Its effect is to reduce the rate of gluconeogenesis, and hence hepatic glucose output, and to increase insulin sensitivity. It does not affect insulin secretion, does not induce hypoglycaemia and does not predispose to weight gain. It is thus particularly helpful in the overweight, although normal weight individuals also benefit, and may be given in combination with sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors or insulin. Metformin was as effective as sulfonylurea or insulin in glucose control and reduction of microvascular risk in the UK Prospective Diabetic Study (UKPDS), but proved unexpectedly beneficial in reducing cardiovascular risk, an effect that could not be fully explained by its glucose-lowering actions. Adverse effects include anorexia, epigastric discomfort and diarrhoea, and these prohibit its use in 5–10% of patients. Diarrhoea should never be investigated in a diabetic patient without testing the effect of stopping metformin or changing to a slow release preparation. Lactic acidosis has occurred in patients with severe hepatic or renal disease, and metformin is contraindicated when these are present. A Cochrane review showed little risk of lactic acidosis with standard clinical use, but most clinicians withdraw the drug when serum creatinine exceeds 150 µmol/L.

Sulfonylureas (Table 20.6)

These act upon the beta cell to promote insulin secretion in response to glucose and other secretagogues. They are ineffective in patients without a functional beta-cell mass, and they are usually avoided in pregnancy. Their action is to bind to the sulfonylurea receptor on the cell membrane, which closes ATP-sensitive potassium channels and blocks potassium efflux. The resulting depolarization promotes influx of calcium, a signal for insulin release (Fig. 20.2). Sulfonylureas are cheap and more effective than the other agents in achieving short-term (1–3 years) glucose control, but their effect wears off as the beta-cell mass declines. There are theoretical concerns that they might hasten beta-cell apoptosis and they promote weight gain, and are best avoided in the overweight. They can also cause hypoglycaemia and although the episodes are generally mild, fatal hypoglycaemia may occur. Severe cases should always be admitted to hospital, monitored carefully, and treated with a continuous glucose infusion since some sulfonlyureas have long half-lives. Sulfonylureas should be used with care in patients with liver disease. Patients with renal impairment should only be given those primarily excreted by the liver. Tolbutamide is the safest drug in the very elderly because of its short duration of action.

Table 20.6 Properties of the most commonly used sulfonylureas

Meglitinides

Meglitinides, e.g. repaglinide and nateglinide, are insulin secretagogues. Meglitinides are the non-sulfonylurea moiety of glibenclamide. As with the sulfonylureas, they act via closure of the K+-ATP channel in the beta cells (see Fig. 20.2). They are short-acting agents that promote insulin secretion in response to meals. Their effects are similar to that of the short-acting sulfonylurea tolbutamide, but they are much more costly.

Thiazolidinediones

The thiazolidinediones (more conveniently known as the ‘glitazones’) reduce insulin resistance by interaction with peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor which regulates large numbers of genes including those involved in lipid metabolism and insulin action. The paradox that glucose metabolism should respond to a drug that binds to nuclear receptors mainly found in fat cells is still not fully understood. One suggestion is that they act indirectly via the glucose-fatty acid cycle, lowering free fatty acid levels and thus promoting glucose consumption by muscle. They reduce hepatic glucose production, an effect that is synergistic with that of metformin, and also enhance peripheral glucose uptake. Like metformin, the glitazones potentiate the effect of endogenous or injected insulin. The glitazones have yet to demonstrate unique advantages in the treatment of diabetes, and their place in routine diabetes care remains uncertain. Troglitazone and rosiglitazone have been withdrawn for safety concerns (liver failure and increased cardiovascular risk, respectively), and pioglitazone is the only remaining agent in this class. Unwanted effects of pioglitazone include weight gain of 5–6 kg, together with fluid retention and heart failure. Mild anaemia and osteoporosis resulting in peripheral bone fractures have also been reported, and there is a possible increase in the risk of bladder cancer.

Dipeptidyl peptidase-4 (DPP4) inhibitors

These enhance the incretin effect (Box 20.2). The enzyme dipeptidyl peptidase 4 (DPP4) rapidly inactivates GLP-1 as this is released into the circulation. Inhibition of this enzyme thus potentiates the effect of endogenous GLP-1 secretion. Four agents are currently available (linagliptin, saxagliptin, sitagliptin and vildagliptin) with more likely to be available in the future. They have a moderate effect in lowering blood glucose and are weight neutral. They are most effective in the early stages of type 2 diabetes when insulin secretion is relatively preserved, and are currently recommended for second-line use in combination with metformin or a sulfonylurea. Adverse events are uncommon: the main side-effect is nausea, and there have been occasional reports of acute pancreatitis. Their place in the management of type 2 diabetes has yet to be fully established. Although the short-term safety record is good, DPP4 is widely distributed in the body, and the long-term consequences of inhibition of this enzyme in other tissues are unknown.

GLP-1 agonists

Exenatide and liraglutide are injectable long-acting analogues of GLP-1, which enhance the incretin effect (Box 20.2). They promote insulin release, inhibit glucagon release, reduce appetite and delay gastric emptying, thus blunting the postprandial rise in plasma glucose and promoting weight loss. Their main clinical disadvantage is the need for subcutaneous injection (twice daily for exenatide and once daily for liraglutide), and their major advantage is improving glucose control whilst inducing useful weight reduction. They work well in 70% but have limited benefit in 30% of those treated. Side-effects include nausea, acute pancreatitis and acute kidney injury. At present they are used as an alternative to insulin, particularly in the overweight. A once weekly version of exenatide has been developed.

GLP-1 promotes beta-cell replication in immature rodents, but there is no evidence to suggest that it can do so in adult humans. GLP-1 receptors are also present in the exocrine pancreas, and the long-term clinical implications of this observation remain unclear.

Other therapies

Injections

The needles used to inject insulin are very fine and sharp. Even though most injections are virtually painless, patients are understandably apprehensive and treatment begins with a lesson in injection technique. Insulin is usually administered by a pen injection device but can be drawn up from a vial into special plastic insulin syringes marked in units (100 U in 1 mL). Injections are given into the fat below the skin on the abdomen, thighs or upper arm, and the needle is usually inserted to its full length. Slim adults and children usually use a 31 gauge 6 mm needle and fatter adults a 30 gauge 8 mm needle. Both reusable and disposable pen devices are available, together with a range of devices to aid injection. The injection site used should be changed regularly to prevent areas of lipohypertrophy (fatty lumps). The rate of insulin absorption depends on local subcutaneous blood flow, and is accelerated by exercise, local massage or a warm environment. Absorption is more rapid from the abdomen than from the arm, and is slowest from the thigh. All these factors can influence the shape of the insulin profile.

Insulin administration

In healthy individuals a sharp increase in insulin occurs after meals; this is superimposed on a constant background of secretion (Fig. 20.7). Insulin therapy attempts to reproduce this pattern, but ideal control is difficult to achieve for four reasons:

A multiple injection regimen with short-acting insulin and a longer-acting insulin at night is appropriate for most younger patients (Fig. 20.10b). The advantages of multiple injection regimens are that the insulin and the food go in at roughly the same time so that meal times and sizes can vary, without greatly disturbing metabolic control. The flexibility of multiple injection regimens is of great value to patients with busy jobs, shift workers and those who travel regularly. Some recovery of endogenous insulin secretion may occur over the first few months (the ‘honeymoon period’) in type 1 patients and the insulin dose may need to be reduced or even stopped for a period. Requirements rise thereafter. Strict glucose control from diagnosis in type 1 diabetes prolongs beta-cell function, resulting in better glucose levels and less hypoglycaemia. Target blood glucose values should normally be 4–7 mmol/L before meals and 4–10 mmol/L after meals, assuming that this can be achieved without troublesome hypoglycaemia.

All patients need careful training for a life with insulin. This is best achieved outside hospital, provided that adequate facilities exist for outpatient diabetes education. A scheme for adjusting insulin regimens is given in Table 20.7. DAFNE is described on page 1010.

Table 20.7 Guide to adjusting insulin dosage according to blood glucose test results

When to use insulin analogues

Hypoglycaemia between meals and particularly at night is the limiting factor for many patients on multiple injection regimens. The more expensive rapid-acting insulin analogues (Fig. 20.10c) are a useful substitute for soluble insulin in some patients. They reduce the frequency of nocturnal hypoglycaemia due to reduced carry-over effect from the day-time. They are often used on grounds of convenience, since patients can inject shortly before meals but standard insulins injected at the same time give equivalent overall control. High or erratic morning blood sugar readings can prove a problem for about a quarter of all patients on conventional multiple injection regimens, because the bedtime intermediate-acting insulin falls and the absorption is variable. The long-acting insulin analogues insulin glargine and insulin detemir may help to overcome these problems and reduce the risk of nocturnal hypoglycaemia.

Infusion devices

CSII (continuous subcutaneous insulin infusion) is delivered by a small pump strapped around the waist that infuses a constant trickle of insulin via a needle in the subcutaneous tissues. Meal-time doses are delivered by the user telling the pump to deliver a bolus of insulin at the start of a meal.

This approach is particularly useful in the overnight period, since the basal overnight infusion rate can be programmed to fit each patient’s needs. Disadvantages include the nuisance of being attached to a gadget, skin infections, the risk of ketoacidosis if the flow of insulin is broken (since these patients have no protective reservoir of injected depot insulin) and cost. Infusion pumps should only be used by specialized centres able to offer a round-the-clock service to their patients. This form of treatment has revolutionized the lives of some people with type 1 diabetes.

Urine tests

Urine dipstick tests, although less informative than blood tests, offer some feedback on metabolic control. Patients with consistently negative tests and no symptoms of hypoglycaemia are generally well controlled. Nevertheless, the correlation between urine tests and simultaneous blood glucose is poor for three reasons:

Home blood glucose testing

Blood tests offer invaluable feedback to everyone affected by diabetes, but their routine use varies according to need. Patients soon learn to provide their own profiles using finger-prick blood samples and reagent strips which can be read with the aid of a meter. Blood is taken from the side of a finger tip (not from the tip, which is densely innervated) using a special lancet usually fitted to a spring-loaded device, a range of which are available. The fasting blood glucose concentration is reproducible in diet or tablet-treated type 2 diabetes, and is therefore a useful guide to therapy, supplemented by occasional tests after meals. Those on insulin treatment require more frequent testing in order to adjust their therapy and avoid hypoglycaemia. Regular profiles (e.g. four daily samples on at least two days each week) are needed in those on intensified therapy, and should be recorded electronically or in a record book. Patients on insulin are encouraged to adjust their insulin dose as appropriate (Table 20.7) and should be able to obtain advice over the telephone when needed. Blood glucose monitoring does not in itself result in better control, but is essential to those wishing to achieve it.

Glycosylated haemoglobin (HbA₁ or HbA_1c) and fructosamine

Glycosylation of haemoglobin occurs as a two-step reaction, resulting in the formation of a covalent bond between the glucose molecule and the terminal valine of the β chain of the haemoglobin molecule. The rate at which this reaction occurs is related to the prevailing glucose concentration. Glycosylated haemoglobin is expressed as a percentage of the normal haemoglobin (standardized range 4–6.1%; 20–44 mmol/mol). This test provides an index of the average blood glucose concentration over the life of the haemoglobin molecule (approximately 6 weeks). The figure will be misleading if the life-span of the red cell is reduced or if an abnormal haemoglobin or thalassaemia is present. There is considerable interindividual variation in HbA_1c levels, even in health. Although the glycosylated haemoglobin test provides a rapid assessment of glycaemic control in a given patient, blood glucose testing is needed before the clinician can know what to do about it.

Glycosylated plasma proteins (‘fructosamine’) may also be measured as an index of control. Glycosylated albumin is the major component, and fructosamine measurement relates to glycaemic control over the preceding 2–3 weeks. It is useful in patients with anaemia or haemoglobinopathy and in pregnancy (when haemoglobin turnover is changeable) and other situations where changes of treatment need a swift means of assessing progress.

Targets for glucose control

Data from the UK Prospective Diabetic Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT) suggest that patients with both type 1 diabetes and type 2 diabetes should ideally aim to run their glycosylated haemoglobin readings below 7.0% (53 mmol/mol) in order to reduce the risk of long-term microvascular complications (Table 20.8). Hypoglycaemia, patterns of eating and lifestyle, weight problems and problems accepting and coping with diabetes limit what can be achieved (see p. 1017). Some will, but most will not, be able to reach these target values, particularly as their duration of diabetes increases. Realistic goals should be set for each patient, taking into account what is likely to be achievable, and this applies in particular to elderly patients and those with a limited prognosis.

Table 20.8 Target goals of risk factors for diabetic patients

* In women >1.3 mmol/L.

Standards from American Diabetes Association (2003).

Does good glucose control matter?

Blood glucose is just one measure of the diverse metabolic consequences of diabetes which not only affect carbohydrate metabolism but also the metabolism of lipids and proteins.

The DCCT in the USA compared standard and intensive insulin therapy in a large prospective controlled trial of young patients with type 1 diabetes. Despite intensive therapy, mean blood glucose levels were still 40% above the non-diabetic range, but even at this level of control, the risk of progression to retinopathy was reduced by 60%, nephropathy by 30% and neuropathy by 20% over the 7 years of the study. Near-normoglycaemia should, therefore, be the goal for all young patients with type 1 diabetes. The unwanted effects of this policy include weight gain and a two- to three-fold increase in the risk of severe hypoglycaemia. Control should be less strict in those with a history of recurrent severe hypoglycaemia.

The UKPDS compared standard and intensive treatment in a large prospective controlled trial of type 2 diabetes patients. There was a 25% overall reduction in microvascular disease end-points, a 33% reduction in albuminuria and a 30% reduction in the need for laser treatment for retinopathy in the more intensively treated patients. These benefits persisted for many years after conclusion of the trial (the ‘legacy effect’). This study also showed blood pressure control to be equally necessary in the prevention of retinopathy, but there is no legacy effect and good blood pressure control needs to be maintained. There appeared to be little difference in outcome between the agents used to achieve good metabolic control (metformin, sulfonylurea or insulin). Intensive blood pressure control very considerably reduced the cardiovascular risk.

Recent trials in type 2 diabetes. Three large outcome studies in type 2 diabetes have confirmed the benefits of good glucose control upon microvascular complications, although these benefits diminish with increasing age. Glucose control appears to be of less value in prevention of arterial disease, and the current trend is to aim for more relaxed glucose control in older patients (e.g. HbA_1c <8% (<64 mmol/mol)), while attention to blood pressure and lipids should take priority. In the recent ACCORD study the use of intensive therapy to target a glycated hemoglobin level below 6% in people with type 2 diabetes increased 5-year mortality. Such an intensive strategy thus cannot be recommended, particularly for high-risk patients with advanced type 2 diabetes.

Regular checks for patients with diabetes

Box 20.3 is modified from the guidelines set out in The European Patients’ Charter published by the St Vincent Declaration Steering Committee of the WHO. The charter sets out goals for both the healthcare team and the patient.

Problems of management

Subsequent management

Intravenous glucose and insulin are continued until the patient feels able to eat and keep food down. The drip is then taken down and a similar amount of insulin is given as four injections of soluble insulin subcutaneously at meal times and a dose of intermediate-acting insulin at night.

Sliding-scale regimens are unnecessary and may even delay the establishment of stable blood glucose levels.

The mortality of diabetic ketoacidosis is around 5%, and is increased in older patients. Its treatment is incomplete without a careful enquiry into the causes of the episode and advice as to how to avoid its recurrence.