Grant: Project Grant

Type 2 diabetes is characterized by impaired response of the body's tissues to insulin and impaired production of insulin from pancreatic beta cells. Obesity is associated with type 2 diabetes. In obesity, excess fat in tissues causes formation of damaging products that generate low-grade inflammation. Such inflammation in tissues that respond to insulin and tissues that produce insulin impairs their function, thus causing diabetes. However, anti-inflammatory treatment of diabetes has been only partially effective so far, we believe because it is not targeted towards the sensors of the fat-derived toxic products that initiate such low-grade inflammation. Our objective is to single out specific sensor(s) that participate in obesity-associated diabetes and are activated by fat-derived products. NOD1 is a sensor candidate because it is located inside cells and induces low-grade inflammation. Indeed, we have shown that NOD1 deficiency protects against high fat diet-induced diabetes in mice. However, we do not know whether NOD1 is activated by fat-derived products or by bacterial products, since high fat diet can increase intestinal absorption of bacterial products. Our preliminary data show that fat impairs the response to insulin and the secretion to insulin via NOD1, independently of gut bacteria, and thus implicate fat-derived products. We hypothesize that fat-derived products are recognized by NOD1 which brings about low-grade inflammation resulting in diabetes. In the present proposal we will feed a high fat diet to mice that have or do not have gut bacteria. We will also give fat directly into a vein, thus bypassing the gut. We will study mice that lack NOD1 in the whole body or in specific tissues that are responsible for the response to insulin and the production of insulin. Finally, we will explore the possibility of inhibiting NOD1 action as a treatment of type 2 diabetes.