LKB1-Independent Metformin Response

描述(由申请人提供)：本R21申请是为回应 PA-02-008计划宣布，“糖尿病内分泌学和代谢的试点和可行性计划”，并符合宣布的“识别与糖尿病相关的新信号分子和途径”的目标。该项目的目标是识别参与一条新途径的蛋白质或基因之一(由P.I.发现)。二甲双胍是一种广泛用于治疗2型糖尿病高血糖的药物，对此有反应。二甲双胍可减少肝脏葡萄糖输出，增加葡萄糖在肌肉中的转运。目前，对二甲双胍作用的最广泛接受的解释是，它通过上游的异三聚体激酶促进AMP依赖的蛋白激酶(AMPK，能量代谢的主要调节因子)的磷酸化(激活)，该激酶包括一个称为LKB1的必要亚基。AMPK的抑制剂可阻断这一反应。许多方法表明，LKB1是二甲双胍激活AMPK所绝对需要的。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。P.I.已经发现了一种新的己糖转运活性，它是由二甲双胍激活的。尽管二甲双胍的时间和浓度依赖关系类似于LKB1-AMPK反应，但这种新的反应不依赖于LKB1的表达和AMPK的激活。奇怪的是，AMPK抑制剂在阻断LKB1-AMPK反应的浓度下就能阻断这种新的反应。因此，新的二甲双胍反应被认为涉及一个类似于LKB1-AMPK但不同于LKB1-AMPK的激酶系统。拟议的R21实验将通过有偏(Aim 1)或无偏(Aim 2)的方法识别参与这种LKB1非依赖性二甲双胍反应(LIMR)的蛋白质或基因。这将使未来的R01应用成为可能，以确定LIMR在二甲双胍的降血糖活性中的作用。

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.