Diabetes affects more than 8% of Americans and costs over $174 billion in 2007 in USA. Recently bariatric surgery, such as Roux-en-Y gastric bypass, has been proposed for treating diabetic patients with obesity due to its hypoglycemic effect on postprandial blood glucose and significant weight loss. In this proposal, we propose a novel method of automated intestinal electrical stimulation (IES) for the treatment of diabetes. Based on previous published studies in our group, we have discovered that IES alters gastrointestinal motility, physiology and hormones in a way similar to the gastric bypass procedure: it reduces food intake and nutrient absorption, inhibits gastric ghrelin and increases glucagon-like peptide (GLP-1) in the postprandial state. Based on these findings, we hypothesize that acute IES improves postprandial hyperglycemia and chronic IES results in improvement in long-term glycemic control. If proven effective, the proposed IES has advantages of being adjustable, reversible and less invasive, compared with bariatric surgery. The Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous Type 2 diabetes and most widely used in studying anti-diabetic mechanisms of bariatric surgeries will be used in this project to prove following hypotheses and accomplish following specific aims. 1) To optimize IES methodology such that the hypoglycemic effect of IES is maximized. Particularly, the stimulation parameters of IES will be systematically investigated and optimized. The effects of acute optimized IES on postprandial blood glucose and insulin sensitivity will be carefully examined. 2) To investigate possible mechanisms involved in the hypoglycemic effect of acute IES. Experiments are designed to test the hypothesis that IES-induced reduction in postprandial blood glucose is mediated mechanically by delayed gastric emptying and accelerated intestinal transit, and hormonally by reduced ghrelin and increased release of GLP-1. 3) To study effects and mechanisms of chronic IES on long-term glycemic control. Chronic experiments are designed to test the hypothesis that improvement in postprandial hyperglycemia prevents/reduces the detrimental effect of chronic hyperglycemia on beta-cell function and systemic insulin sensitivity, leading to improvement of long-term glucose control. An automatic food intake detection algorithm will be developed for the chronic experiments. A multi-disciplinary team has been assembled to undertake the task. The PI has extensive experience in gastrointestinal electrical stimulation on gastrointestinal motility, obesity and diabetes. The consultant Dr. Abate is an expert from in insulin resistance and diabetes. The small business has all required expertise and facilities to design and develop the proposed automatic feedback controlled IES system.
|Ouyang, X; Li, S; Foreman, R et al. (2015) Hyperglycemia-induced small intestinal dysrhythmias attributed to sympathovagal imbalance in normal and diabetic rats. Neurogastroenterol Motil 27:406-15|