LKB1-Independent Metformin Response

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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.