Convergence of IPMK and LKB1-AMPK Signaling Pathways on Metformin Action

Author:

Bang Sookhee1,Chen Yong1,Ahima Rexford S.2,Kim Sangwon F.1

Affiliation:

1. Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior (S.B., Y.C., S.F.K.); and Department of Medicine, Division of Endocrinology, Diabetes, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104

2. Metabolism and the Institute for Diabetes, Obesity, and Metabolism (R.S.A.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104

Abstract

Metformin is a biguanide drug that is widely prescribed for type 2 diabetes. Metformin suppresses hepatic gluconeogenesis and increases fatty acid oxidation. Although studies have suggested that metformin acts, at least in part, via activation of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, the specific molecular mechanisms underlying metformin's regulation of glucose and lipid metabolism have not been well delineated. Recently, we have shown that inositol polyphosphate multikinase (IPMK) plays an important role in cellular energy metabolism and glucose-mediated AMPK regulation. Here we investigated the role of IPMK in metformin-induced AMPK activation. We observed that metformin-mediated activation of AMPK was impaired in the absence of IPMK. Overexpression of wild-type IPMK was sufficient to restore LKB1-AMPK activation by either metformin or AICAR in IPMK−/− murine embryonic fibroblast cells, suggesting that IPMK may act as an upstream regulator of LKB1-AMPK signaling in response to metformin. Moreover, this regulation was mediated by protein-protein interaction between IPMK and LKB1 as a dominant-negative peptide, which abrogates this interaction, attenuated metformin's ability to activate AMPK. Our data demonstrate that IPMK plays an important role in LKB1/AMPK signaling and may be targeted for treatment of metabolic diseases.

Publisher

The Endocrine Society

Subject

Endocrinology,Molecular Biology,General Medicine

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