LKB1-Independent Metformin Response

LKB1 独立的二甲双胍反应

• 批准号: 6909513
• 负责人: Mark Lehrman
• 金额: $ 15.6万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909513
• 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申请是针对 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“识别与糖尿病有关的新型信号分子和途径”。该项目的目标是识别一种对二甲双胍响应的新型途径（发现）的蛋白质或基因，该蛋白质是一种响应于二甲双胍的蛋白质，这是一种用于治疗2型糖尿病中高血糖的药物。二甲双胍可降低肝葡萄糖输出，并增加肌肉的葡萄糖转运。当前，对二甲双胍作用的最公认的解释是，它促进了上游杂点酶激酶的磷酸化（激活）（AMPK，AMPK，一种能量代谢的主要调节剂），其中包括包括必不可少的亚基指定的LKB1。 AMPK的抑制剂阻止了此反应。许多方法表明，二甲双胍激活AMPK绝对需要LKB1。但是，尚不知道AMPK途径是否解释了二甲双胍的所有有益作用和/或不希望的副作用。 P.I.已经确定了一种新型的己糖转运活性，该活性被二甲双胍激活。尽管二甲双胍的时间和浓度依赖性与LKB1-AMPK响应相似，但这种新颖的反应与LKB1表达和AMPK激活无关。奇怪的是，新的反应被AMPK抑制剂阻止，以阻止LKB1-AMPK响应的浓度。因此，提出了新型的二甲双胍反应涉及类似于LKB1-AMPK的激酶系统。提出的R21实验将通过偏置（AIM 1）或无偏（AIM 2）方法来鉴定与该LKB1无关的二甲双胍反应（LIMR）涉及的蛋白质或基因。这将使未来的R01应用成为可能，以确定LIMR在二甲双胍的抗血糖活性中的作用。