DIETARY MODIFICATION
Dietary control is important in bom type 1 and type 2 diabetes. The goals of dietary modification are to maintain glucose concentrations in the normal range or as close to normal as possible, and a lipid and lipoprotein profile and blood pressure mat reduce the risk of macrovascular disease (see Diabetic Complications, below). Correction of obesity is desirable in all patients, and weight loss in patients with type 2 diabetes can decrease insulin resistance, improve gly-caemic and lipid measures, and reduce blood pressure. Anorectic drugs are not appropriate in these patients,although orlistat, a gastric and pancreatic lipase inhibitor, can be used as an adjunctive treatment to reduce weight and improve blood glucose control in overweight patients with type 2 diabetes. A high fibre intake may also lower blood-glucose concentrations and additional fibre is sometimes taken in the form of guar gum. The influence of diet on diabetes is such mat all diabetic patients need to be aware of the composition of foods and to be able to make adjustments to their diet, especially to counteract treatment-induced hypoglycaemia. However, neither protein restriction nor very low calorie diets are recommended.
EXERCISE
All diabetic patients should be encouraged to exercise, according to their age and physical capability. Exercise improves carbohydrate metabolism, insulin sensitivity, and cardiovascular function. It is also a useful component of any weight reduction programme although diet may be more effective in promoting weight loss and metabolic control.
ORAL ANTIDIABETICS
If patients with type 2 diabetes have not achieved suitable control after about 3 months of dietary modification and increased physical activity, men oral antidiabetics (oral hypoglycaemics) may be tried. The two major classes are the sulfonylureas and the biguanides. Sulfonylureas act mainly by increasing endogenous insulin secretion, while biguanides act chiefly by decreasing hepatic gluconeogenesis and increasing peripheral utilisation of glucose. Both types function only in the presence of some endogenous insulin production. More recently developed classes of oral antidiabetics include the alpha-glucosidase inhibitors, the meglitinides, and the thiazolidinediones (see Table: Classification of oral antidiabetics). Alpha-glucosidase inhibitors act by delaying the absorption of glucose from the gastrointestinal tract meglitinides increase endogenous insulin secretion and thiazolidinediones appear to increase insulin sensitivity. Most patients with type 2 diabetes are overweight, and are preferably treated with the biguanide metformin rather man with a sulfonylurea (which can cause weight gain). Results from the UK Prospective Diabetes Study (UKPDS) have suggested that the use of metformin to provide intensive blood-glucose control in overweight diabetic patients substantially reduced the risk of diabetes-related end-points such as myocardial infarction, stroke, amputation, renal failure, blindness, and death.Metformin is as effective as the sulfonylureas in terms of blood-glucose control and is less likely to cause hypoglycaemia, but has a rare tendency to cause lactic acidosis in patients with renal impairment, in whom it should not be used.
Oral treatment of type 2 diabetes in patients who are not overweight may be begun with a sulfonylurea. Chlorpropamide and glibenclamide have long half-lives and hence an increased tendency to cause hypoglycaemia, although a large study reported mat hypoglycaemic episodes were less frequent with chlorpropamide man glibenclamide. These 2 drugs are best avoided in the elderly a sulfonylurea with a short half-life, such as gliclazide or tolbutamide, should be used instead.
There is evidence mat the use of low-dose sulfonylurea therapy in patients with diagnosed type 2 diabetes but near-normoglycaemia due to early remission (the so-called honeymoon period) can delay the onset of hyperglycaemia.
Drug treatment may also involve an alpha-glucosidase inhibitor such as acarbose or miglitol. These have a small but significant effect in lowering blood glucose and do not cause hypoglycaemia when used alone, but they can cause intolerable gastrointestinal effects. Meglitinides such as repaglinide and nateglinide are a new chemical class of antidiabetics which act similarly to sulfonylureas repaglinide has a rapid onset and short duration of action and is given with meals. The thiazolidinediones, such as pioglitazone or rosiglitazone, appear to increase insulin sensitivity and have been the subject of much interest for type 2 diabetes and insulin resistance.
Should treatment with one of the oral antidiabetics fail men a different type or in some instances combinations of different types may produce improvement. Alarming evidence of an increased risk of death in UKPDS patients given intensive therapy with metformin plus a sulfonylurea was not borne out by further analysis, and this combination is widely used. In patients in whom such combinations fail or are contra-indicated, pioglitazone or rosiglitazone may be combined with metformin or a sulfonylurea as an alternative to progressing to insulin. Triple therapy, combining a sulfonylurea, metformin, and either rosiglitazone or pioglitazone has also been shown to be effective. Biguanides may also be added to meglitinide therapy. Alpha-glucosidase inhibitors may improve diabetes control when used as an adjunct to sulfonylureas or biguanides. Guar gum may also be used as an adjunct to any of the oral hypoglycaemics to enhance the improvement in blood-glucose control.
Patients with type 2 diabetes who cannot be controlled adequately by oral therapy and diet need insulin either in addition to or in place of oral therapy. Type 2 diabetes is a progressive disease, and about 30% of those on sulfonylureas will be transferred to insulin treatment within 4 years, a change which now tends to be made earlier owing to increasingly strict criteria for glycaemic control (tight control of blood glucose has now been shown to decrease the risk of complications, see Diabetic Complications, below). However, as insulin therapy is associated with more hypoglycaemic episodes and a greater tendency to weight gain it remains reasonable to begin with oral therapy in type 2 diabetes before proceeding to insulin. Combination of a single insulin injection at bedtime (morning injection is less effective) with oral hypoglycaemics (either a sulfonylurea, metformin, or bom) is as effective as insulin alone, and if metformin is used, is associated with less weight gain. In general, as the disease progresses, the majority of patients need multiple therapies to achieve glycaemic control.Biguanides and alpha-glucosidase inhibitors may also be combined with insulin. There is increasing interest in the use of metformin and other oral hypoglycaemics as potential adjuncts to insulin therapy in patients with type 1 diabetes.
Insulin is also substituted for oral treatment to provide cover during periods of severe stress, as in severe infection, trauma, or major surgery. Type 2 patients who become pregnant should also be switched from oral therapy to insulin (see Pregnancy, below).
INSULIN THERAPY
While insulin may not be a necessary part of the treatment of type 2 diabetes, it is essential in the treatment of patients with type 1, since they have little or no endogenous insulin secretory capacity.The aim of insulin therapy is to achieve the best possible control of blood-glucose concentrations without the risk of the hypoglycaemia that can occur if too fine a degree of control is attempted. Tight control of blood-glucose concentrations can reduce the long-term complications of diabetes such as retinopamy, nephropamy, and neuropathy (see Diabetic Complications, below) but in some patients (such as the elderly, or those who lack motivation) it may be better merely to alleviate symptoms rather man attempt tight control. Exercise and dietary discipline are necessary to maintain normal sensitivity to insulin.
Insulin may be of beef or pork origin, or it may be human insulin produced by gene technology or by modification of porcine insulin. Human and porcine insulin are less immunogenic man bovine insulin and where possible most newly diagnosed type 1 patients are now given human insulin. Modified insulin analogues such as insulin lispro, insulin aspart, insulin detemir, and insulin glargine are now available.
Insulin is available in preparations offering a short, intermediate, or long action. It may be given intramuscularly but the subcutaneous route is usually preferred. Soluble insulin can also be given intravenously. More recently, products delivering insulin for absorption through the buccal mucosa or lungs have been developed. Details of insulin routes are given on p.450. Insulin dosage schedules make use of the varying durations of action, for example by incorporating a short-acting and intermediate-acting insulin into a daily schedule. Most patients with type 1 diabetes require two or three injections of insulin daily, or with intensive regimens even more. A once-daily regimen can be used if the patient is simply to be kept asymptomatic mis may also be successful in patients with type 2 diabetes not satisfactorily controlled by oral antidiabetics.
IMMUNOSUPPRESSION
Many patients with type 1 diabetes have a temporary improvement in pancreatic beta-cell function soon after initial treatment with insulin. This produces a period of partial remission known as the honeymoon period, during which a small dose of insulin (0.5 units/kg or less daily) is sufficient to maintain good control. Attempts to prolong the honeymoon period have included tight control immediately following diagnosis and also, given the probable auto-immune nature of the condition, use of an immunosuppressant. However, results have been at best ambiguous.
PANCREATIC TRANSPLANTATION
Transplantation of the whole pancreas in patients with type 1 diabetes poorly controlled by insulin therapy has led to insulin independence, and has usually been carried out with kidney transplantation (see also Pancreatic Transplantation). Transplantation of pancreatic islet cells has been investigated as an alternative. Since the introduction of the so-called ‘Edmonton Protocol’ and related regimens for immunosuppression, and improvements in techniques for harvesting and preparing islet cells, more experienced centres are now reporting some success in achieving insulin independence, and development of new immunosuppressive regimens continues. However, at present successful patients exchange lifelong insulin therapy for life-long immunosuppression. The induction of tolerance, less toxic immunosuppression, and enhanced islet engraftment remain the focus of investigation. Results in animals have suggested mat a reasonable degree of glycaemic control may be achievable long term without immunosuppression, using a vascularised ‘artificial pancreas’ containing allogeneic or even xenogeneic islet cells. The use of stem cells as potential sources of islet cells is also under investigation.
OTHER DRUG TREATMENTS
Other drugs have been tried for diabetes mellitus, particularly when conventional therapy has proved unsuccessful. Addition of the amy-lin analogue pramlintide to insulin therapy has improved glycaemic control in patients with type 1 and type 2 diabetes. Other approaches under investigation include inhibition of fatty acid oxidation or the use of β3-adrenoceptor agonists (selective agonists of β-receptors thought to be associated with lipolysis and thermogenesis) to stimulate energy expenditure.
Mecasermin (insulin-like growth factor I IGF-I) has been shown to improve metabolic control in patients with type 1 diabetes and insulin resistance (and in some type 2 patients). The incretin hormone glucagon-like peptide 1 (GLP-1 insulinotropin) plays a role in glucose homoeostasis, and when given therapeutically improves glycaemic control in type 2 patients. Incretin mimics such as exenatide (synthetic exendin-4) and liraglutide and inhibitors of the incretin-degrading enzyme dipeptidylpeptidase-4 (such as sitagliptin and vildagliptin) are also under investigation or have been licensed for use in type 2 diabetes. Improvements in insulin sensitivity have also been seen in insulin-resistant type 2 patients treated with a haemodialysate of calf blood, while in other studies improved insulin sensitivity was seen after treatment with the vanadium salt, vanadyl sulfate. Adjunctive chromium supplementation may reduce serum-glucose in type 2 diabetes, but high doses may be required and long-term safety and efficacy have not been established.
PROPHYLAXIS
Because overt diabetes is the culmination of a prolonged process, methods to delay or prevent its development are being investigated, either by modifying risk factors in populations or groups, or by targeting individuals thought to be at high risk. Strategies under consideration for the prevention of type 1 diabetes include avoidance of cows’ milk proteins (thought to be a possible environmental trigger) during infancy giving free radical scavengers such as nicotinamide prophylactic insulin (or possibly oral antidiabetics) to allow ‘beta cell rest’ encouraging the development of antigen tolerance, for example by taking oral antigens such as insulin, glutamic acid decarboxylase, or heat shock protein (a similar approach using subcutaneous antigen has apparently extended the honeymoon period in animal studies) or by immunosuppression (see above) or immunomodulation with agents such as BCG vaccine, although some have found the latter ineffective. Preventive strategies for insulin resistance and type 2 diabetes have tended to focus on weight loss, dietary modification, and exercise. However, prophylactic drug therapy may be possible. A systematic review concluded mat there was good evidence for a reduced incidence of diabetes in patients treated with metformin, acarbose, orlistat, and troglitazone, although the attrition rates were high with the latter 2 tings evidence of benefit from statins, oestrogen, and various antihyperten-sive tings (including ACE inhibitors) was more equivocal. It was considered likely mat some of the benefits were indirect, due to drug-induced weight loss, and in no case was the benefit definitive enough that the ting could be recommended for diabetes prevention. Studies are ongoing with drugs including ramipril, telmisartan, valsartan, nateglinide, rosiglitazone, and insulin glargine. Guidelines for the prevention of type 2 diabetes recommend mat individuals with pre-diabetes (impaired fasting glucose or impaired glucose tolerance) should be counselled on weight loss and exercise, and that ting therapy should not be routinely used until more information becomes available. Screening for diabetes has been encouraged, particularly for those patients with risk factors.
Monitoring of therapy
Monitoring of therapy is an integral part of the management of the diabetic patient. Detection of urinary glucose has generally been superseded by the monitoring of blood glucose (see Glucose Tests). For adequate diabetic control, the aim is to reduce fasting blood-glucose concentrations to within the range 3.3 to 5.6 mmol/litre of venous whole blood, and postprandial concentrations to below 10 mmol/litre. Many patients monitor their blood-glucose concentrations regularly at home and mis is essential for intensified insulin regimens when tight control is required. Although the value of self-monitoring of blood-glucose concentrations in type 2 patients is less clear, the results of a large cohort study suggest that such monitoring can improve glycaemic control in these patients. Detection of urinary ketones is useful in diabetics prone to ketosis mis is usually done in clinics. Diabetic clinics also measure the degree of haemoglobin glycosylation (HbA1 or HbA1C) as an indicator of longer term blood-glucose control and hence the risk of complications (see Diabetic Complications, below). UK guidelines recommend mat a general target of 6.5 to 7.5% should be set for HbA1C in individuals with type 2 diabetes. In the USA, a target of HbA1C below 7.0% has been recommended for diabetes patients in general. The advanced glycation end-product (AGE) of haemoglobin has also been found to be a useful indicator of long-term blood glucose control. Measurement of glycated serum proteins, particularly albumin, is also used to give an indication of glucose control, but for a shorter period than haemoglobin. Other techniques that have been developed for monitoring blood-glucose concentrations include continuous monitoring by a subcutaneous system, and a minimally invasive device that uses reverse iontophoresis through the skin.
Pregnancy
Adverse pregnancy outcomes, including spontaneous abortion and congenital malformation, are more common in diabetic than in nondiabetic women. Improved management of the pregnant diabetic patient, particularly in early pregnancy, lessens the incidence of such events, but an increased risk still exists. Diabetic women are advised to plan their pregnancies so mat glycaemic control can be improved before conception.Some may need to avoid pregnancy (most commonly because of renal disease), but management has improved sufficiently for mis to be rare.
Insulin is the preferred treatment in pregnancy, even in women with type 2 diabetes patients taking oral antidiabetics should therefore be switched to insulin. However, there is increasing evidence to suggest that metformin might be used safely during pregnancy, and NICE has suggested that it may be used either as an adjunct or alternative to insulin if the likely benefits from improved glycaemic control outweigh the potential for harm. Insulin regimens are similar to those in nonpregnant patients, the dose being adjusted according to regular blood-glucose measurements. Insulin requirements may decrease during the first trimester but they increase during the latter two, reaching about twice pre-pregnancy requirements at term they men fall once labour has begun and fall again after delivery.
Pregnant diabetic patients are at risk of nocturnal hypoglycaemia owing to continued fetal glucose consumption while the mother is in a relatively fasting state. They are also prone to diabetic ketoacidosis which must be treated with great urgency because of the high risk of fetal loss. Gestational diabetes mellitus is defined as glucose intolerance with onset or first recognition during pregnancy.Many women with gestational diabetes can be managed by diet alone or, if necessary, also with insulin. Some suggest giving prophylactic insulin even to women who could be managed by diet alone, in view of the metabolic effects of insulin. Insulin analogues such as insulin lispro and insulin aspart have been investigated. Dietary management of gestational diabetes can improve maternal and fetal outcomes, and insulin therapy reduces fetal macro-somia and perinatal morbidity. NICE also considers that metformin or glibenclamide may be considered as an adjunct or alternative to insulin. There has been much debate about the benefits of screening for gestational diabetes, and both universal and selective screening based on risk factors have been promoted.
Surgery
Insulin-dependent diabetics who require surgery may be managed with a continuous intravenous insulin infusion. Insulin is given as normal the night before operation, and switched to either a variable rate infusion via a syringe pump, with a 5 or 10% glucose drip (with potassium chloride, provided the patient is not hyperkalaemic), or to a combined insulin-glucose infusion, on the day of operation. (Many anaesthetists prefer insulin and a sodium chloride infusion if blood glucose is already high.) Subsequent conversion back to subcutaneous insulin should be undertaken before breakfast, giving the first subcutaneous dose 30 minutes before stopping continuous infusion. Non-insulin-dependent patients should have any oral treatment omitted on the day of operation, and may be given insulin by a similar regimen if control is poor or deteriorates as can happen with major surgery.