Hepatic Rap1 in glucose homeostasis

2型糖尿病(T2D)及其并发症构成了一个重大的全球公共卫生问题。患有T2D的个体更容易患上代谢和心血管疾病。大多数T2D患者都接受降胆固醇药物他汀类药物的治疗，以降低患心脏病的风险。矛盾的是，他汀类药物最近被认为与新发的T2D的发生有关；然而，其潜在的机制尚不清楚。这一建议是基于我们实验室的一项令人兴奋的新发现，该发现表明RAS超家族的小G蛋白Rap1a在葡萄糖稳态中发挥着重要作用。我们认为，肝脏RAP1a是一种新的肝脏葡萄糖产生(HGP)调节因子，抑制其活性有助于他汀类药物诱导的葡萄糖耐量减低和高血糖。在此基础上，我们将确定肝脏Rap1a在体内葡萄糖稳态中的作用(Aim 1)，阐明其在他汀类药物介导的葡萄糖耐量和高血糖(Aim 2)中的作用，并探索解释Rap1a如何调节HGP的分子假说(Aim 3)。我们将在体内和体外使用小鼠遗传、生理和生化方法的组合来测试这些新想法。这项拟议的研究将揭示一种新的血糖稳态机制，可用于未来减少T2D发生率的治疗策略。

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.