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Biphasic effect of metformin on human cardiac energetics. Transl Res 2021 Mar;229:5-23



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Scopus ID

2-s2.0-85095776755 (requires institutional sign-in at Scopus site)   20 Citations


Metformin is the first-line medication for treatment of type 2 diabetes and has been shown to reduce heart damage and death. However, mechanisms by which metformin protects human heart remain debated. The aim of the study was to evaluate the cardioprotective effect of metformin on cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) and mitochondria isolated from human cardiac tissue. At concentrations ≤2.5 mM, metformin significantly increased oxygen consumption rate (OCR) in the hiPSC-CMs by activating adenosine monophosphate activated protein kinase (AMPK)-dependent signaling and enhancing mitochondrial biogenesis. This effect was abrogated by compound C, an inhibitor of AMPK. At concentrations >5 mM, metformin inhibited the cellular OCR and triggered metabolic reprogramming by enhancing glycolysis and glutaminolysis in the cardiomyocytes. In isolated cardiac mitochondria, metformin did not increase the OCR at any concentrations but inhibited the OCR starting at 1 mM through direct inhibition of electron-transport chain complex I. This was associated with reduction of superoxide production and attenuation of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in the mitochondria. Thus, in human heart, metformin might improve cardioprotection due to its biphasic effect on mitochondria: at low concentrations, it activates mitochondrial biogenesis via AMPK signaling and increases the OCR; at high concentrations, it inhibits the respiration by directly affecting the activity of complex I, reduces oxidative stress and delays mPTP formation. Moreover, metformin at high concentrations causes metabolic reprogramming by enhancing glycolysis and glutaminolysis. These effects can be a beneficial adjunct to patients with impaired endogenous cardioprotective responses.

Author List

Emelyanova L, Bai X, Yan Y, Bosnjak ZJ, Kress D, Warner C, Kroboth S, Rudic T, Kaushik S, Stoeckl E, Ross GR, Rizvi F, Tajik AJ, Jahangir A


Xiaowen Bai PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Gracious R. Ross Research Scientist II in the Cardiovascular Center department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

AMP-Activated Protein Kinases
Cardiotonic Agents
Cells, Cultured
Dose-Response Relationship, Drug
Energy Metabolism
Gene Expression Regulation
Induced Pluripotent Stem Cells
Middle Aged
Mitochondria, Heart
Oxygen Consumption