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Activation of the cAMP-PKA pathway antagonizes metformin action

cAMP-PKA 通路的激活会拮抗二甲双胍的作用

基本信息

批准号：
9008164
负责人：
Ling He
金额：
$ 36.45万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9008164
关键词：
Accounting Address Adverse effects Affect American Animals Antidiabetic Drugs Binding Sites Catalytic Domain Clinical Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Diabetes Mellitus Dose European Evaluation Exhibits Glycerol-3-Phosphate Dehydrogenase Guidelines Hepatic Hepatocyte High Fat Diet Human Hyperglycemia Individual Knock-out Knockout Mice Lactic Acidosis Liver Measures Mediating Metabolic Diseases Metformin Mitochondria Monitor Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Obese Mice Oral Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Portal vein structure Protein Isoforms Reporting Resistance Role STK11 gene Salicylic Acids Serum Signal Transduction Testing Therapeutic Intervention Time Work Yeasts analog diabetic patient feeding glucose production hyperglucagonemia improved in vivo mouse model mutant novel therapeutics public health relevance reconstitution response targeted treatment upstream kinase

项目摘要

DESCRIPTION (provided by applicant) Diabetes affects 25.8 million individuals in the USA and at least 387 million individuals worldwide. Type 2 diabetes (T2D) accounts for more than 90% of diabetes cases. Metformin has been used to treat T2D since the 1950s, and now over 150 million people worldwide take this medication. In 2012, in guidelines for the treatment of T2D, the American Diabetes Association and the European Association for the Study of Diabetes jointly recommended metformin as the initial drug to prescribe to T2D. Yet how metformin acts remains only partially understood and controversial. We find that low metformin concentrations typically found in the portal vein suppress glucose production in primary hepatocytes through the activation of AMPK. However, it remains unclear which isoform of the AMPKα subunits is critical for the suppression of glucose production in hepatocytes by metformin, and metformin binding sites on AMPK subunits have not been characterized yet. Using liver-specific AMPKα1, AMPKα2, and combined AMPKα1/2 knockout mice and mutations of AMPK subunits, we will address these questions in Aim 1. Over one-third of diabetic patients exhibit various degrees of metformin resistance. We find that activation of the cAMP-PKA pathway, a hallmark of patients with diabetes mellitus, directly antagonizes AMPK activation by phosphorylating AMPKα at S485, which in turn reduces AMPK enzymatic activity. This could result in metformin resistance. We propose to study the mechanism leading to metformin resistance in Aim 2, which has important clinical implications for metformin usage in diabetic patients. Salicylate, a commonly used agent, is known to activate AMPK. We will test salicylate's effect on the improvement of metformin efficacy in the suppression of glucose production in Aim 3. We believe this work will provide new evidence for understanding the mechanism of metformin's action and new therapeutic guidelines for the use of metformin to treat T2D.