Glucose homeostasis and regulation of food intake are both promoted by the secretion of gut hormones following nutrient stimulation of enteroendocrine cells (L-cells) in the lower gut. This process is impaired in diabetes but is restored when delivery of dietary compounds such as amino acids and fatty acids to the lower gut is facilitated. This effect of delivery of nutrients to the lower gut is observed after gastric bypass surgery and during fermentation of carbohydrates in the colon, both of which can result in resolution of diabetes. These approaches to deliver nutrients to the lower gut are not without complications, although their resulting efficacy is often superior to existing drugs. Currently marketed anti-diabetes drugs have deficiencies in efficacy, durability of effect, and safety, and the pharmaceutical industry has, therefore, been looking for novel approaches to restore impaired gut-hormone secretion. BioKier has identified a simple, direct, safe method to deliver one of the key nutrients to the colon in a way that can be developed for the treatment of diabetes and other conditions characterized by impaired L-cell stimulation. BioKier's concept involves the approach of delivering nutrients as gut hormone secretagogues to the colon via a colon-targeting formulation for the treatment of diabetes and other disorders. Acute studies conducted by BioKier showed that direct delivery via catheter of specific nutrients to the colon of diabetic animals and humans restored the oral glucose-induced gut hormone response. Chronic treatment with an oral formulation of a representative nutrient completely prevented the development of diabetes in a diabetes-prone rat model and supported the concept that the approach could lead to development of a marketable therapeutic. Based on lead-selection data from the acute clinical studies, L-glutamine was formulated in an oral, sustained-release, colon-targeted capsule for testing in type 2 diabetes patients. In order to conduct human testing, the glutamine formulation needs to be tested in animals for safety; as is proposed in Phase I of the SBIR application in a local toxicity and toxicokinetic study of BKR 013 capsules in dogs. Phase II involves conduct of a Phase 1 clinical trial to evaluate pharmacokinetics, plasma GLP-1 and insulin biomarker responses, and safety of BKR-013 in diabetes drug-nave type 2 diabetes patients. Endpoints are to assess the bioavailability of L-glutamine and measure biomarkers to confirm colon- specific delivery. Progress thus far has attracted the interest of several potential pharmaceutical partners who have indicated the results of the clinical study to be funded by this application are crucial to discussions of a licensing agreement.
Insulin resistance and type 2 diabetes are major health risks increasing in all parts of the world. Bariatric surgeries in which sections of the upper small intestine are bypassed, such as RYGB, are widely documented to resolve diabetes within days in a very high percentage of obese type 2 diabetes patients. We propose an orally deliverable therapeutic designed to mimic the anti-diabetic effects of the intestinal-shortening surgery.