New horizons in diabetes therapy--alpha glucosidase inhibitors (original) (raw)

A normal life despite diabetes is only possible when intervention therapy aims at achieving a physiological level of blood glucose and HbA 1c, maintenance of a desirable body weight and serum lipids to avoid hyperinsulinaemia and late diabetes complications and to retard the development of atherosclerosis 1. The first revolution in the treatment of diabetes came with the discovery of insulin in 1921, before which nearly 64% diabetic subjects died prematurely in diabetic coma 2. This was followed by the introduction of oral anti-diabetic suiphonylureas and biguanides about 3 decades ago. The suiphonylureas increase endogenous insulin secretion from the beta cells of the pancreas thus lowering the elevated blood sugar levels through a physiological action of insulin. The basic requirement for suiphonylureas to be effective are functioningbeta cells 3. Biguanides act through a different pathway to produce their hypoglycaemic effect. Several mechanisms have been implicated of which reduction in gastrointestinal glucose obsorption, increased anaerobic glycolysis, inhibition of gluconeogenesis, stimulation of peripheral glucose uptake and increased binding of insulin to its receptor are the most accepted 3. A new concept introduced in the treatment of diabetes mellitus was the postponement of intestinal glucose absorption. This was achieved by the introduction of a-glucosidase inhibitors in the form of acarbose 4,5. Delaying glucose absorption in the gut was attempted first by dietary modification. The nutrient load was spread out into frequent small servings throughout the day. This provided a stable blood glucose and prevented steep rises. This holds good for both insulin dependent and non-insulin dependent diabetics. Complex carbohydrates from starchy foods do not raise blood sugar levels as much as simple ones. Fibre in the food slows down carbohydrate absorption and reduces fasting blood glucose, glycosylated haemoglobin and serum lipid levels. Dietary modification does delay glucose absorption but it does not solve the problem of postprandial hyperglycaemia. This leads to the new pharmacological approach through alteration of the activity of intestinal a-glucosidase by using specific inhibitors 6. Acarbose, isolated from fermentation of actinoptanes strains, is a pseudotetrasaccharide of microbial origin 7. It is a competitive and reversible inhibitor of intestinal aglucosidase activity 8. a-glucosidases are located in the luminal brush border formed by enterocytes of the small gut. Since carbohydrates are taken up in the form of monosaccharides only in the intestine, the disaccharides and polysaccharides are broken down by glucosidases before they can be absorbed 9. In this process cc-glucosidase inhibitors delay carbohydrate digestion leading to delayed glucose absorption. Glucose, fructose and sorbitol which are directly absorbed and un digestable carbohydrates as cellulose, are not affected by the drug. Thus the efficacy of a-glucosidase inhibitors depends on the carbohydrate composition of the meals. Studies conducted with acarbose on non-insulin-dependent diabetic patients demonstrated an improved metabolic control regardless of whether being administered in addition to oral hypoglycaemic agents or to a diet alone 10,11. The most significant finding was a reduction in the post-prandial blood glucose concentration. Evidence was also had for a reduction in serum insulin levels 12. Acarbose does not lead to malabsorption of carbohydrates. A diet rich in poorly digestable complex carbohydrates causing an intestinal load will result in bacterial fermentation which can cause flatulence, distension and diarrhoea. Due to an effective assimilation in the large bowel no faecal loss of calories takes place 9. Studies have been conducted on IDDM patients by adding acarbose to their insulin regime. Post-prandial blood glucose concentrations are reduced, smoother diurnal blood glucose profiles were achieved and in some cases the daily insulin requirement was reduced 13. The