LKB1-Independent Metformin Response

LKB1 独立的二甲双胍反应

• 批准号: 7035309
• 负责人: Mark Lehrman
• 金额: $ 15.23万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035309
• 关键词: adenylate kinase; carbohydrate transport; cell line; enzyme structure; glucose metabolism; hypoglycemia; kinase inhibitor; mannose; membrane transport proteins; metformin; pharmacokinetics

DESCRIPTION (provided by applicant): This R21 application is submitted in response to the PA-02-008 Program Announcement, "Pilot and Feasibility Program in Diabetes Endocrinology and Metabolism", and meets the announcement's objective of "identification of novel signaling molecules and pathways " relevant to diabetes. The project's goal is to identify one of the proteins or genes involved in a novel pathway (discovered by the P.I.) that is responsive to metformin, a widely used drug for treatment of hyperglycemia in type 2 diabetes. Metformin decreases hepatic glucose output, and increases glucose transport by muscle. Currently, the most well accepted explanation for metformin's action is that it promotes phosphorylation (activation) of AMP-dependent protein kinase (AMPK, a master regulator of energy metabolism) by an upstream heterotrimeric kinase that includes an essential subunit designated LKB1. An inhibitor of AMPK blocks this response. A number of approaches show that LKB1 is absolutely required for activation of AMPK by metformin. However, it is not known whether the AMPK pathway accounts for all of metformin's beneficial effects and/or undesired side-effects. The P.I. has identified a novel hexose transport activity that is activated by metformin. Although the metformin time and concentration dependence are similar to the LKB1-AMPK response, this novel response is independent of both LKB1 expression and AMPK activation. Curiously, the novel response is blocked by the AMPK inhibitor at concentrations that block the LKB1-AMPK response. Thus, the novel metformin response is proposed to involve a kinase system analogous to, but distinct from, LKB1-AMPK. The proposed R21 experiments will identify proteins or genes involved in this LKB1-Independent Metformin Response (LIMR) by either biased (Aim 1) or unbiased (Aim 2) approaches. This will make possible a future R01 application to determine the role of LIMR in metformin's antihyperglycemic activity.

描述（由申请人提供）：此R21申请是为了响应 PA-02-008计划公告，“糖尿病内分泌学和代谢的试点和可行性计划”，并符合公告的目标，即“识别与糖尿病相关的新型信号分子和途径”。该项目的目标是确定一种新途径中涉及的蛋白质或基因（由P.I.发现）。其对二甲双胍（一种广泛用于治疗2型糖尿病高血糖症的药物）有反应。二甲双胍减少肝脏葡萄糖输出，并增加肌肉葡萄糖转运。目前，对二甲双胍作用的最广为接受的解释是，它通过上游异源三聚体激酶促进AMP依赖性蛋白激酶（AMPK，能量代谢的主要调节剂）的磷酸化（活化），该激酶包括命名为LKB 1的必需亚基。AMPK的抑制剂阻断这种反应。许多方法表明，LKB 1是二甲双胍激活AMPK所必需的。然而，目前尚不清楚AMPK途径是否解释了二甲双胍的所有有益作用和/或不良副作用。私家侦探已经确定了一种新的己糖转运活性，它被二甲双胍激活。尽管二甲双胍的时间和浓度依赖性与LKB 1-AMPK反应相似，但这种新反应不依赖于LKB 1表达和AMPK活化。奇怪的是，这种新的反应被AMPK抑制剂在阻断LKB 1-AMPK反应的浓度下阻断。因此，新的二甲双胍反应被认为涉及与LKB 1-AMPK类似但不同的激酶系统。拟议的R21实验将通过有偏（目标1）或无偏（目标2）方法鉴定参与这种LKB 1-独立代谢反应（LMR）的蛋白质或基因。这将使未来R 01应用于确定LIMR在二甲双胍抗高血糖活性中的作用成为可能。