Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

By A. Madiraju, D. Erion, Y. Rahimi, Xian‐Man Zhang, D. Braddock, R. Albright, Brett J. Prigaro, J. Wood, S. Bhanot, M. MacDonald and 7 more. Nature, 2014

1,208 citations recorded by the source corpus.

Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin’s blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.

Subfields: Molecular Biology, Rheumatology, Surgery

View Paper: https://www.semanticscholar.org/paper/376d0c085b265304fdece8e959a8ecc33682e59d

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Citations in the corpus

Metformin and the gastrointestinal tract (2016, background): “phosphate dehydrogenase, reducing the conversion of cytosolic lactate into pyruvate [42].”
Cellular and Molecular Mechanisms of Metformin Action (2020, methodology): “Acute intravenous metformin administration of 50, 100, and 250 mg/kg resulted in peak plasma concentrations of 74, 345, and 1300 µ M, respectively, and liver metformin concentrations reached ~100 µ M following intravenous 50 mg/kg metformin administration in awake rats (50).”
The mechanisms of action of metformin (2017, background): “Note that the possible effect of metformin on mitochondrial glycerophosphate dehydrogenase [7] has not been included.”
Metformin: from mechanisms of action to therapies. (2014, background): “In agreement with this hypothesis, it has been recently shown that AMPK activation by A-769662, the metformin analog phenformin, or the new antidiabetic drug GLP-1 limited glucotoxicity in adult cardiomyocytes (Balteau et al., 2014).”
Metformin-associated lactic acidosis: Current perspectives on causes and risk. (2016, background): “[95] Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DR, Albright RA, et al.”
Benefits of Metformin in Attenuating the Hallmarks of Aging (2020, background): “Decreased hepatic gluconeogenesis is also demonstrated to be associated with metformin’s direct inhibition of mitochondrial glycerophosphate dehydrogenase (mGPDH)- a flavin-linked respiratory chain-linked dehydrogenase, which in turn modulates cytosolic redox state (Madiraju et al. 2014).”
Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status (2016, positive): “More recently, mitochondrial glycerophosphate dehydrogenase has been suggested as an alternative target.(12) Mitochondrial inhibition activates AMPactivated protein kinase (AMPK),(13) and recent work suggests that duodenal AMPK contributes toward effects of the drug on hepatic glucose production.”
A Comprehensive Review of Drug–Drug Interactions with Metformin (2015, background): “N A [3 7 ]”