Hepatic Rap1 in glucose homeostasis

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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.