Glycosidases and diabetes: metabolic changes, mode of action and therapeutic perspectives
The use of α‐glucosidase inhibitors (AGIs) for the treatment of type‐2 diabetes (TD2) delays the absorption of carbohydrates, which allows the beta cells time to increase insulin secretion, reducing then glucose levels in the circulation, especially in the postprandial period. Based on the benefits of AGIs, this chapter will disclose the involvement of glycosidase enzymes in metabolic disorders found in diabetes, besides displaying glycosidases mode of action and addressing new potential AGIs against diabetes.
The mechanism by which α‐glucosidases cleave the glycosidic bond of carbohydrates involves the participation of two carboxylic acid‐containing amino acids in the catalytic site, acting either as an acid or a base, with generation of a positively charged oxonium‐carbenium ion transition state. This charge buildup is accompanied by pseudo‐axial orientation of the CO bond to be broken and concomitant distortion of the pyranose ring out of its chair conformation. Hence, synthetic AGIs are in general envisioned to mimic this distorted conformation of the transition state, as observed for natural glucosidase substrates.
The potency and specificity of glucosidase inhibitors are directly associated to their capacity to mimic the supracited enzyme transition state, being their inherent conformational (shape, structural) and electrostatic (charge) properties of great relevance for binding into the enzyme active site. Accordingly, besides the currently therapeutically used antidiabetics miglitol