Grant: Operating Grant

Diabetes and obesity are serious chronic diseases that lead to significantly reduced life expectancy and associated life-threatening complications such as heart disease, stroke, blindness, kidney failure and lower limb amputation. The incidence of diabetes is increasing rapidly and currently afflicts 6% of the population throughout the Western World (approximately 3 million Canadians), ranking it as the third most prevalent disease. Likewise, obesity is approaching epidemic proportions, with an estimated 25% of adults in Canada being obese. A major challenge in treating diabetes or obesity is reducing excessively high patient blood glucose levels. Human alpha-amylase is a particularly compelling target for the development of therapeutics for these diseases, being the first enzyme in the pathway of starch digestion, the principal source of dietary glucose. Unfortunately, previously identified inhibitors of human amylase exhibit limited specificity, and the effectiveness of those in medical use is severely limited by deleterious side effects (diarrhea, flatulence). To alleviate these problems we have pursued a targeted screening program of natural extracts and thereby developed a portfolio of novel human amylase inhibitors of exceptional affinity and exquisite specificity. We have further advanced the first of these uniquely active inhibitors, Montbretin A, through the proof of concept phase in a diabetic rat model system, demonstrating both the ability to significantly reduce blood glucose levels without adverse events and to delay the onset of diabetes in these animals. Future research will focus on two essential areas. Firstly, determining the modes of inhibition of Montbretin A and the other potent inhibitors that we have identified. Secondly, attaining a comprehensive mechanistic understanding of the catalytic function of human amylase, along with its mode of attack on polymeric starch and its relationship to alpha-glucosidases in the gut microbiome.