Glucagon signaling in metabolic homeostasis

双激素疾病糖尿病的一个特点是血糖和血糖之间的平衡失调。 调节荷尔蒙胰岛素和胰升糖素。肝脏是胰岛素和胰升糖素代谢作用得以证实的主要器官。胰岛素是合成代谢(FED)状态下协调和传递信号的主要激素，而胰高血糖素则协调分解代谢(空腹)代谢状态，确保代谢平衡和生存。从禁食状态到进餐期间营养的快速供应的转变对肝脏构成了特别的挑战--胰岛素的作用调节着从分解代谢状态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、脂肪和蛋白质合成的转变。虽然胰岛素通过其受体作用于肝细胞的代谢效应和信号通路已经被了解很多，但对肝脏中胰高血糖素信号的分子成分的了解才刚刚开始。肝脏中胰高血糖素与其受体结合后激活的主要信号通路是 磷脂酶C(PLC)-3-磷酸肌醇(IP3)途径和环磷酸腺苷(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。EPAC2C(一种鸟嘌呤核苷酸交换因子)是Epac2的一种亚型，仅在肝脏中唯一表达。重要的是，EPAC2C信号及其下游效应因子RAP1(RAS近似物1或RAS相关蛋白1)在肝脏中的稳态和代谢作用还知之甚少。令人惊讶的是，肝脏EPAC2C基因敲除会导致从禁食到进食的紊乱转变，并伴有葡萄糖耐量异常、胰岛素抵抗、高胰岛素血症和轻微的高血糖素血症--这些变化使人想起2型糖尿病。基于这些观察，我们推测，在禁食期间，通过EPAC2C-RAP1信号，肝脏为随后的胰岛素反应做好准备，EPAC2C-RAP1是 确保肝脏代谢灵活性和代谢动态平衡的重要信号成分。 在这些观察的基础上，我们还发现病毒转导的具有结构性活性的EPAC2C亚型在肝脏过度表达可以改善饮食诱导的肥胖小鼠的葡萄糖稳态。 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EPAC2C-Rap1信号在代谢稳态中的作用。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了解，并确定治疗糖尿病的新靶点。

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.