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

• 批准号: 9186543
• 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
• 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/9186543
• 关键词: 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; Impairment; 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; glucose production; hyperglucagonemia; improved; in vivo; mouse model; mutant; novel therapeutics; public health relevance; reconstitution; response; targeted treatment; upstream kinase

 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.

 描述（由适用提供）糖尿病影响美国的2580万个人和全球至少3.87亿个人。 2型糖尿病（T2D）占糖尿病病例的90％以上。自1950年代以来，二甲双胍一直被用来治疗T2D，现在全球有超过1.5亿人服用这种药物。 2012年，在治疗T2D的指南中，美国糖尿病协会和欧洲糖尿病研究协会共同建议将二甲双胍作为准备T2D的初始药物。然而，二甲双胍的作用如何仍然被部分理解和有争议。我们发现，在门静脉中通常发现的低二甲双胍浓度通过AMPK的激活在原发性肝细胞中抑制葡萄糖的产生。然而，尚不清楚AMPKα亚基的哪种同工型对于通过二甲双胍抑制肝细胞中的葡萄糖产生至关重要，而AMPK亚基上的二甲双胍结合位点尚未表征。使用实时特异性AMPKα1，AMPKα2和AMPKα1/2敲除小鼠和AMPK亚基的突变，我们将在AIM 1中解决这些问题。超过三分之一的糖尿病患者表现出各种程度的二甲双胍抵抗。我们发现，CAMP-PKA途径的激活是糖尿病患者的标志，它通过在S485处磷酸化AMPKα直接拮抗AMPK激活，从而降低了AMPK酶活性。这可能导致二甲双胍耐药性。我们建议研究导致AIM 2中二甲双胍耐药性的机制，这对糖尿病患者的二甲双胍使用具有重要的临床意义。众所周知，水杨酸盐是一种常用的药物，可以激活AMPK。我们将测试水杨酸酯对AIM 3中二甲双胍效率提高葡萄糖产生的影响。我们认为，这项工作将为理解二甲双胍作用的机制和新的治疗指南提供新的证据，以使用二甲双胍治疗T2D。