Clinical Evaluation of Glucosidase Inhibitors
Glucosidase inhibitors act by reducing activity of the digestive enzymes of the small intestinal brush border. Most of those which have shown any clinical promise are reversible, competitive inhibitors of these enzymes with reasonably high specificity.
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Clinical Evaluation of Glucosidase Inhibitors R.H. TAYLOR and E.M. BARDOLPH
A. Introduction Glucosidase inhibitors act by reducing activity of the digestive enzymes of the small intestinal brush border. Most of those which have shown any cIinical promise are reversible, competitive inhibitors of these enzymes with reasonably high specificity.
I. Carbohydrate Digestion Dietary carbohydrate is digested in the gut in aseries of stages of enzymatic hydrolysis prior to absorption through the surface of the enterocyte, mainly in the form of monosaccharides and much smaller amounts of oligosaccharides. In most Western diets and in diabetic diets as currently recommended, the staple carbohydrate source is starch, which may provide up to 55% of dietary energy intake. It occurs naturally in two forms which are present in variable proportions in natural foods. Amylose consists of long chains of glucose residues joined by a 1,4-linkages, whereas amylopectin has similar a l,4-linkages in addition to a 1,6-linkages, which give it a multiply branched structure. Cellulose and related complex polysaccharides are joined by ß-linkages, which cannot be digested by human digestive enzymes specific for the a-configuration, though other animal species and also bacteria can digest them. Starch is digested by a-amylase from the salivary glands and the pancreas and is broken down to maltose, maltotriose and a-limit dextrins within the lumen of the upper gastrointestinal tract. The rate of digestion is dependent on pH, particIe size, presence of protein, fat and fibre and the complexity of the natural matrix structure of foods. These products of digestion join the dietary disaccharides, sucrose, lactose, maltose and trehalose, for the final stage of digestion at the brush border of the small intestinal enterocytc. There are four a-glucosidases and one ß-galactosidase in the brush border which complete the digestion of oligosaccharides to the monosaccharides, glucose, fructose and galactose, which are then absorbed by the cellular transport mechanisms. Glucoamylase hydrolyses a 1,4-linkages, releasing glucose residues. Sucrase-a-dextrinase is a hybrid enzyme with J. Kuhlmann et al. (eds.), Oral Antidiabetics © Springer-Verlag Berlin Heidelberg 1996
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R.H.
TAYLOR
and E.M.
BARDOLPH
two independent active sites, sucrase, which splits sucrose to glucose, and fructose and a-dextrinase, which hydrolyses the a I ,6-linkages of the a-Iimit dextrins. TrehaIase digests the disaccharide trehaIose, which occurs only in mushrooms. The ß-galactosidase is lactase, which hydrolyses lactose to glucose and galactose. Its activity decIines in many people after infancy. The monosaccharide products of intraluminal and brush border digestion of carbohydrate and any dietary monosaccharides are absorbed rapidly through the enterocyte and into the circulation. Glucose and galactose enter by a sodium-dependent carrier, a second non-sodium-dependent carrier and hy passive diffusion, and fructose has aseparate active carrier.
11. Diet and Glucosidase Inhibit
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