Glucagon Mediated Potentiation of Insulin Sensitivity in Glucose Metabolism

摘要 在过去几十年中发展起来的久坐和饮食生活方式与 高血压、血脂异常、肥胖等代谢紊乱的发生率空前增加 和2型糖尿病。胰高血糖素是对抗胰岛素作用的关键逆调节荷尔蒙，在 胰腺α细胞的低血糖周期刺激肝脏葡萄糖的产生和恢复 正常血糖。因此，过多的胰高血糖素信号是糖尿病的重要病理生理成分。 这些作用在1型和2型糖尿病患者中都得到了广泛的研究。 新出现的证据表明，高血糖素调节一系列可能是非常可取的行动。 患有代谢综合征的患者。事实上，含有胰高血糖素激动素的潜在药物靶点 成为治疗肥胖症和糖尿病的有希望的候选药物。然而，目标组织和分子 造成这些有益影响的机制尚不清楚。指导这一点的科学假说 有观点认为，胰高血糖素通过其肝脏受体(GCGR)，增强TORC2依赖的成分 胰岛素信号级联，它被下丘脑GCGR信号进一步增强，为个体做好准备 用于增强全身葡萄糖的处理。在我们的假设下，胰高血糖素的反调节作用 在禁食期间保持正常血糖，也参与了增强后续胰岛素作用的机制。我们的 假说是在我们的初步和已发表的数据上提出的，这些数据表明血糖水平升高 高胰岛素-正常血糖钳夹小鼠的耐受性和改善胰岛素敏感性的实验研究 或一种有效的胰升糖素受体激动剂。然而，胰升糖素如何调节胰岛素的作用，以及 负责这些胰岛素/胰高血糖素联合作用的组织仍未解决。

Abstract The sedentary and dietary life style that evolved during the last decades has been paralleled by an unprecedented increase in the incidence of metabolic disturbances such as hypertension, dyslipidemia, obesity and type-2 diabetes. Glucagon, the key counter-regulatory hormone opposing insulin action, is released during periods of hypoglycemia by pancreatic alpha-cells to stimulate hepatic glucose production and restore euglycemia. Accordingly, excessive glucagon signaling is a crucial pathophysiological component of diabetes mellitus and these actions have been widely studied in both type 1 and 2 diabetic patients. Emerging evidence suggests that glucagon regulates a range of actions that may be quite desirable in patients with the metabolic syndrome. Indeed, potential drug targets that contain glucagon agonism have emerged as promising therapeutic candidates for obesity and diabetes. Yet, the targeted tissues and molecular mechanisms responsible for these beneficial effects are yet unknown. The scientific hypothesis that guides this proposal is that glucagon, via its hepatic receptors (GcgR), potentiates TORC2-dependent components of insulin-signaling cascade, which is further potentiated by hypothalamic GcgR signaling, to prime an individual for enhanced whole-body glucose disposal. Under our hypothesis, the counterregulatory actions of glucagon that maintain euglycemia during fasting, also engage mechanisms to potentiate subsequent insulin action. Our hypothesis is formulated both on our preliminary and published data demonstrating enhanced glucose tolerance and improved insulin sensitivity during hyperinsulinemic-euglycemic clamp in mice pretreated with glucagon, or a potent glucagon-receptor agonist. However, how glucagon regulates insulin action, and the tissues responsible for these combined insulin/glucagon-effects remain unresolved.