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

基本信息

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
项目类别：
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&apos -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

5&apos -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

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项目摘要

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.

二甲双胍是规定的一线抗糖尿病药物。二甲双胍已被广泛接受主要通过减少肝脏中的葡萄糖输出以及较小程度来降低血糖外围葡萄糖摄取。但是，二甲双胍可以如何做到这一点仍然存在争议和辩论。大脑（重新）成为全身葡萄糖代谢的重要调节剂。中央紧张已知系统（CNS）调节外周组织中的葡萄糖输出和葡萄糖摄取改变全身葡萄糖平衡。我们以前发现大脑或大脑中的小GTPase Rap1 下丘脑强烈影响葡萄糖平衡而不会影响能量平衡。值得注意的是，我们进一步揭示了前脑特异性的RAP1缺乏小鼠对二甲双胍有选择性抗性降低葡萄糖的作用，但保持对其他类别的抗糖尿病药物的敏感性。这个初步发现表明，以前完全无法识别的中枢神经系统过程可能考虑到反抗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，我们将检验以下假设：二甲双胍通过抑制Rap1的降低高血糖降低高血糖在腹侧下丘脑核（VMH）中，是一个公认的血糖控制部位。这个假设根据我们令人兴奋的，固体的初步数据，通过遗传，解剖学，药理学制定和电生理研究，这是这里首次提出的。以下三个特定目标将解决我们的假设：1）使用最先进的体内方法（例如尤利克斯特）夹具和稳定的异位示踪剂技术，我们将准确研究大脑中的二甲双胍调节系统性葡萄糖代谢，2）使用体内GCAMP和化学遗传学工具，我们将确定VMH SF1神经元对二甲双胍的治疗作用的重要性； 3） AIM 3中的实验将使用功能丧失和功能奖励研究来最终确定该作用 VMH中的Rap1用于二甲双胍的抗糖尿病作用。这些目标在一起将发现一个完全新颖的二甲双胍作用的位点和分子机制。该提议将揭示长期指定的机制解释了二甲双胍如何通过建立先前未知的抗糖尿病作用二甲双胍，大脑（VMH）和小GTPase RAP1之间的联系。最后，结果是可能打开2型糖尿病的病理生理和治疗发现的新领域。