Question

Effect of inhibitors on maltase glucoamylase for treatment of diabetes type 2

Answer 1

An approach to controlling blood glucose levels in individuals with type 2 diabetes is to target α-amylases and intestinal glucosidases using α-glucosidase inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucoamylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose. Here we present the X-ray crystallographic studies of ntMGAM in complex with a new class of α-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used traditionally in Ayuverdic medicine for the treatment of type 2 diabetes. Included in these extracts are the active compounds salacinol, kotalanol, and de-O-sulfonated kotalanol. This study reveals that de-O-sulfonated kotalanol is the most potent ntMGAM inhibitor reported to date (Ki= 0.03 μM), some 2000-fold better than the compounds currently used in the clinic, and highlights the potential of the salacinol class of inhibitors as future drug candidates.

Answer 2

Enzymes secreted in the small intestine specific to carbohydrate hydrolysis include α-amylase, α-glucosidases (sucrase, glucoamylase, maltase), and β-galactosidase (lactase). Relatively little α-amylase is present in equine saliva, so limited hydrolysis occurs prior to arrival of carbohydrates in the stomach. In the stomach, gastric acid hydrolyzes carbohydrates to an extent, independent of enzymes. Limited microbial fermentation occurs in the stomach (see below), which may help initiate carbohydrate digestion but may also contribute to gastric distress, such as spasmodic colic, gas colic or ulcers (Murray & Grodinsky 1989, de Fombelle et al 2003).
Key Points
Hydrolyzable carbohydrates include simple sugars, disaccharides and starch. Hydrolysis of disaccharides and starch yields simple sugars for absorption.
In the small intestine, hydrolysis of carbohydrates is initiated primarily by pancreatic α-amylase. In the luminal phase, α-amylase cleaves α-1,4 linkages but not α-1,6 or terminal α-1,4 linkages of starch molecules. Amylopectinase cleaves α-1,6 linkages. The end products of the luminal phase are disaccharides and oligosaccharides such as maltotriose – no free sugars are yielded. Sucrase, lactase and maltase are expressed along the length of the equine small intestine at the brush border mucosal cells (Dyer et al 2002). Sucrase activity was higher in the duodenum and jejunum than the ileum, while maltase activity was similar in duodenum, jejunum, and ileum (Dyer et al 2002). Functional lactase was present in all portions of the small intestine of mature horses, higher in the duodenum and jejunum than the ileum. Although its activity was lower in mature than weaned horses, the presence of functional lactase suggests that mature horses can digest lactose (Dyer et al 2002). The action of these disaccharidases at the brush border mucosal cells completes hydrolysis to yield free sugars, glucose, galactose and fructose, providing relatively high energy yield. The activity of disaccharidases was shown to be unaffected by a diet rich in NSC compared to pasture alone (Dyer et al 2009).
Starch may be resistant to hydrolysis by physical entrapment, chemical structure, or by heating and retrogradation. Corn contains physically resistant starch, so its digestibility is improved with processing. Potato and manioc contain chemically resistant starch, with preileal digestibility of less than 10% (Meyer et al 1995).