Type 2 diabetes (T2D) and its complications constitute a significant public health problem worldwide. Individuals with T2D are more prone to developing metabolic and cardiovascular diseases. Majority of T2D patients are treated with the cholesterol-lowering drugs, statins, to decrease the risk of developing heart disease. Paradoxically, statins have recently been linked to development of new-onset T2D; however, the underlying mechanisms are not known. This proposal is based on an exciting new finding from our laboratory suggesting that the small G protein of the Ras superfamily, Rap1a, plays a major role in glucose homeostasis. We propose that hepatic Rap1a is a novel regulator of hepatic glucose production (HGP) and inhibition of its activity contributes to statin-induced glucose intolerance and hyperglycemia. Based on these, we will determine the in vivo role of hepatic Rap1a in glucose homeostasis (Aim 1), elucidate it?s in role statin- mediated glucose intolerance and hyperglycemia (Aim 2), and explore molecular hypotheses explaining how Rap1a regulates HGP (Aim 3). We will test these new ideas in vivo and ex vivo, using a combination of mouse genetic, physiological and biochemical approaches. The proposed studies will uncover a novel mechanism of glucose homeostasis, which can be exploited for future therapeutic strategies to reduce T2D incidence.
Type 2 diabetes (T2D) is reaching epidemic proportions throughout the world and is a major burden to healthcare systems and societies worldwide. The objective of this proposal is to explore the novel hypothesis that Rap1a regulates hepatic glucose production and contributes to development of T2D. Successful completion of these studies will reveal a new mechanism involved in the regulation of glucose homeostasis and may offer therapeutic targets for the growing T2D epidemic.