A Novel Neural Mechanism that Mediates the Therapeutic Effects of Metformin

介导二甲双胍治疗效果的新型神经机制

• 批准号: 10352376
• 负责人: Makoto Fukuda
• 金额: $ 41.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352376
• 关键词: 5' -AMP-activated protein kinase; Accounting; Address; Affect; Anatomy; Antidiabetic Drugs; Area; Biochemical Pathway; Blood Glucose; Brain; Clinical Research; Closure by clamp; Cyclic AMP; Data; Diabetes Mellitus; Electrophysiology (science); Equilibrium; Extrahepatic; Future; GCG gene; Genetic; Glucose; Glucose Clamp; Glycerol-3-Phosphate Dehydrogenase; Guanosine Triphosphate Phosphohydrolases; Hepatic; Hyperglycemia; Hypoglycemic Agents; Hypothalamic structure; Insulin; Liver; Mass Spectrum Analysis; Mediating; Metabolic; Metformin; Methodology; Mitochondria; Modality; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Monomeric GTP-Binding Proteins; Mus; Neural Pathways; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phenocopy; Play; Process; Prosencephalon; Protein Kinase; Research; Resistance; Role; SF1; Signal Transduction; Site; Solid; Sulfonylurea Compounds; Techniques; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Time; Tissues; Tracer; Work; base; blood glucose regulation; clinical translation; energy balance; experimental study; gain of function; glucose metabolism; glucose output; glucose production; glucose uptake; glycemic control; improved; in vivo; inhibitor; insight; loss of function; neuromechanism; novel; novel therapeutics; patch clamp; postsynaptic; presynaptic; relating to nervous system; response; stable isotope; tool; ventromedial hypothalamic nucleus

Metformin is the most prescribed first-line anti-diabetic drug. It has been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver, and to a lesser extent by increasing peripheral glucose uptake. However, exactly how metformin can do so remains controversial and debated. The brain has (re)emerged as an important regulator of whole-body glucose metabolism. The central nervous system (CNS) is known to regulate glucose output and glucose uptake in the peripheral tissues, thereby changing whole-body glucose balance. We previously found that the small GTPase Rap1 in the brain or in the hypothalamus strongly influences glucose balance without affecting energy balance. Remarkably, we have further revealed that forebrain-specific Rap1 deficient mice are selectively resistant to metformin's glucose-lowering action, but retain sensitivity to other classes of anti-diabetic drugs. This preliminary discovery suggests a previously completely unrecognized CNS process potentially accounting for the anti- diabetic mechanism of metformin. To elucidate the neural mechanisms by which metformin lowers blood glucose, we will test the hypothesis that metformin acts centrally to lower hyperglycemia via inhibition of Rap1 in the ventromedial hypothalamic nucleus (VMH), a well-established site for glycemic control. This hypothesis is formulated on the basis of our exciting, solid preliminary data through genetic, anatomical, pharmacological and electrophysiology studies, which are for the first time presented here. The following three Specific Aims will be addressed to test our hypothesis: 1) using state-of-the-art in vivo methodologies such as euglycemic clamp and stable-isotope tracer techniques, we will investigate exactly how metformin in the brain regulates systemic glucose metabolism, 2) using in vivo GCaMP and chemogenetic tools, we will establish the importance of VMH SF1 neurons for the therapeutic action of metformin; and 3) experiments in Aim 3 will use loss-of-function and gain-of-function studies to conclusively determine the role of Rap1 in the VMH for metformin's anti-diabetic action. Together, these Aims will uncover an entirely novel site(s) and molecular mechanism(s) of action of metformin. This proposal will uncover a long-speculated mechanism explaining how metformin exerts its anti-diabetic actions by establishing a previously unknown connection between metformin, the brain (VMH) and the small GTPase Rap1. Lastly, the outcomes are thus likely to open a new area of pathophysiological and therapeutic discovery of type 2 diabetes.

二甲双胍是最常用的一线抗糖尿病药物。二甲双胍已被广泛接受 降低血糖主要是通过减少肝脏中的葡萄糖输出，并在较小程度上通过增加 外周葡萄糖摄取。然而，二甲双胍到底如何发挥作用仍然存在争议。 大脑已经（重新）成为全身葡萄糖代谢的重要调节器。中枢神经 众所周知，中枢神经系统（CNS）可以调节外周组织的葡萄糖输出和葡萄糖摄取，从而 改变全身葡萄糖平衡。我们之前发现，小GTPase Rap1在大脑或在 下丘脑强烈影响葡萄糖平衡而不影响能量平衡。值得注意的是，我们 进一步揭示前脑特异性 Rap1 缺陷小鼠对二甲双胍选择性耐药 具有降血糖作用，但保留对其他类别抗糖尿病药物的敏感性。此次初步 这一发现表明，一个以前完全未被认识的中枢神经系统过程可能解释了反- 二甲双胍的糖尿病机制。阐明二甲双胍降低血液的神经机制 葡萄糖，我们将测试二甲双胍通过抑制 Rap1 来集中降低高血糖的假设 位于下丘脑腹内侧核（VMH），这是一个公认的血糖控制部位。这个假设 是根据我们通过遗传、解剖学、药理学获得的令人兴奋、可靠的初步数据制定的 和电生理学研究，这些都是首次在这里提出。以下三个具体目标 将致力于检验我们的假设：1）使用最先进的体内方法，例如血糖正常 钳和稳定同位素示踪技术，我们将准确研究二甲双胍在大脑中的作用 调节全身葡萄糖代谢，2) 使用体内 GCaMP 和化学遗传学工具，我们将 确定 VMH SF1 神经元对于二甲双胍治疗作用的重要性；和 3) 目标 3 中的实验将使用功能丧失和功能获得研究来最终确定作用 VMH 中 Rap1 的二甲双胍抗糖尿病作用。这些目标共同将揭开一个全新的故事 二甲双胍的作用位点和分子机制。该提案将揭开人们长期猜测的一个谜团 通过建立先前未知的机制来解释二甲双胍如何发挥其抗糖尿病作用 二甲双胍、大脑 (VMH) 和小 GTPase Rap1 之间的联系。最后，结果是这样的 可能开辟 2 型糖尿病病理生理学和治疗发现的新领域。