Glucagon signaling in metabolic homeostasis

双激素疾病糖尿病的一个标志是血糖和胰岛素之间的平衡失调。 调节激素胰岛素和胰高血糖素。肝脏是胰岛素和胰高血糖素代谢作用的主要器官。胰岛素是合成代谢（进食）状态期间协调和信号传导的主要激素，而胰高血糖素协调分解代谢（禁食）代谢状态，确保代谢稳态和存活。 从禁食状态到用餐期间快速供应营养的转变（喂养）对肝脏提出了特别的挑战-胰岛素作用调节从分解代谢到合成代谢状态的快速转变，包括从肝脏葡萄糖产生到糖原储存，脂质和蛋白质合成的转变。 虽然对胰岛素通过其受体作用于肝细胞的代谢效应和信号传导途径有了很大了解，但肝脏中胰高血糖素信号传导的分子组分才刚刚开始被了解。胰高血糖素与其在肝脏中的受体结合后激活的主要信号传导途径是 磷脂酶C（PLC）-肌醇-3-磷酸（IP 3）途径和环AMP（cAMP）途径。后者分为cAMP -蛋白激酶A（PKA）途径和cAMP-EPAC（cAMP激活的交换蛋白）途径。EPAC 2C（一种鸟嘌呤核苷酸交换因子）是EPAC 2的一种亚型，仅在肝脏中表达。重要的是，EPAC 2C信号及其下游效应子Rap 1（Ras-近端-1或Ras-相关蛋白1）在肝脏中的稳态和代谢作用知之甚少。 令人惊讶的是，肝脏EPAC 2C敲低导致从禁食到进食的紊乱过渡，伴随葡萄糖耐受不良、胰岛素抵抗、高胰岛素血症和轻度高胰高血糖素血症-使人联想到2型糖尿病的变化。 基于这些观察结果，我们假设在禁食期间，胰高血糖素激素-通过EPAC 2C-Rap 1信号传导-启动肝脏对随后的胰岛素作用以响应进食，并且EPAC 2C-Rap 1是 一个重要的信号成分，以确保肝脏代谢的灵活性和代谢稳态。 基于这些观察结果，我们还发现肝脏中组成型活性EPAC 2C同种型的病毒转导的过表达改善了饮食诱导的肥胖小鼠中的葡萄糖稳态。 目前的建议旨在扩展我们令人兴奋的发现，以进一步阐明肝脏EPAC 2C-Rap 1信号在代谢稳态。我们提出的研究将扩大我们对胰高血糖素在肝脏中作用的理解，并确定治疗糖尿病的新治疗靶点。

A hallmark of the bi-hormonal disease diabetes mellitus is a disturbed balance between the gluco- regulatory hormones insulin and glucagon. The liver is the principal organ where the metabolic actions of insulin and glucagon action are borne out. Insulin is the main hormone orchestrating and signaling during the anabolic (fed) state, while glucagon orchestrates a catabolic (fasting) metabolic state ensuring metabolic homeostasis and survival. The transition from the fasting state to the rapid supply of nutrients during a meal (feeding) poses a particular challenge to the liver - whereby insulin action regulates the rapid shift from a catabolic to an anabolic state including a switch from hepatic glucose production to glycogen storage, lipid and protein synthesis. While much is understood about the metabolic effects and signaling pathways of insulin acting via its receptor on hepatocytes, the molecular components of glucagon signaling in the liver are only beginning to be understood. The main signaling pathways activated upon glucagon binding to its receptor in the liver are the phospholipase C (PLC) -inositol-3-phosphate (IP3) pathway and the cyclic AMP (cAMP) pathway. The latter bifurcates into the cAMP – protein kinase A (PKA) pathway and the cAMP-EPAC (exchange protein activated by cAMP) pathway. EPAC2C (a guanine nucleotide exchange factor) is an isoform of EPAC2 that is uniquely expressed only in the liver. Importantly, homeostatic and metabolic role of EPAC2C signaling and its downstream effector Rap1 (Ras-proximate-1 or Ras-related protein 1) in the liver are poorly understood. Surprisingly, liver EPAC2C knockdown results in a disturbed transition from fasting to feeding accompanied by glucose intolerance, insulin resistance, hyperinsulinemia and mild hyperglucagonemia – changes reminiscent of type 2 diabetes mellitus. Based on these observations, we hypothesize that during fasting the hormone glucagon - via EPAC2C-Rap1 signaling - primes the liver for subsequent insulin action in response to feeding and that EPAC2C-Rap1 is an important signaling component to secure liver metabolic flexibility and metabolic homeostasis. Building on these observations, we also find virus transduced over-expression of a constitutively active EPAC2C isoform in the liver ameliorates glucose homeostasis in diet-induced obese mice. The present proposal aims to extend our exciting findings to further elucidate liver EPAC2C-Rap1 signaling in metabolic homeostasis. Our proposed studies will expand our understanding of glucagon action in the liver and also identify a novel therapeutic target for treating diabetes mellitus.