Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

Research output: Contribution to journal › Journal article › Research › peer-review

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Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. / Madiraju, Anila K; Erion, Derek M; Rahimi, Yasmeen; Zhang, Xian-Man; Braddock, Demetrios T; Albright, Ronald A; Prigaro, Brett J; Wood, John L; Bhanot, Sanjay; MacDonald, Michael J; Jurczak, Michael J; Camporez, Joao-Paulo; Lee, Hui-Young; Cline, Gary W; Samuel, Varman T; Kibbey, Richard G; Shulman, Gerald I.

In: Nature, Vol. 510, No. 7506, 2014, p. 542-546.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Madiraju, AK, Erion, DM, Rahimi, Y, Zhang, X-M, Braddock, DT, Albright, RA, Prigaro, BJ, Wood, JL, Bhanot, S, MacDonald, MJ, Jurczak, MJ, Camporez, J-P, Lee, H-Y, Cline, GW, Samuel, VT, Kibbey, RG & Shulman, GI 2014, 'Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase', Nature, vol. 510, no. 7506, pp. 542-546. https://doi.org/10.1038/nature13270

APA

Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J., Jurczak, M. J., Camporez, J-P., Lee, H-Y., Cline, G. W., Samuel, V. T., Kibbey, R. G., & Shulman, G. I. (2014). Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature, 510(7506), 542-546. https://doi.org/10.1038/nature13270

Vancouver

Madiraju AK, Erion DM, Rahimi Y, Zhang X-M, Braddock DT, Albright RA et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542-546. https://doi.org/10.1038/nature13270

Author

Madiraju, Anila K ; Erion, Derek M ; Rahimi, Yasmeen ; Zhang, Xian-Man ; Braddock, Demetrios T ; Albright, Ronald A ; Prigaro, Brett J ; Wood, John L ; Bhanot, Sanjay ; MacDonald, Michael J ; Jurczak, Michael J ; Camporez, Joao-Paulo ; Lee, Hui-Young ; Cline, Gary W ; Samuel, Varman T ; Kibbey, Richard G ; Shulman, Gerald I. / Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. In: Nature. 2014 ; Vol. 510, No. 7506. pp. 542-546.

Bibtex

@article{e682276ff0954013a9840364a364717a,
title = "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase",
abstract = "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.",
keywords = "Animals, Blood Glucose, Cells, Cultured, Diabetes Mellitus, Type 2, Gluconeogenesis, Glycerolphosphate Dehydrogenase, Humans, Hypoglycemic Agents, Insulin, Lactic Acid, Liver, Male, Metformin, Mice, Knockout, Mitochondria, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",
author = "Madiraju, {Anila K} and Erion, {Derek M} and Yasmeen Rahimi and Xian-Man Zhang and Braddock, {Demetrios T} and Albright, {Ronald A} and Prigaro, {Brett J} and Wood, {John L} and Sanjay Bhanot and MacDonald, {Michael J} and Jurczak, {Michael J} and Joao-Paulo Camporez and Hui-Young Lee and Cline, {Gary W} and Samuel, {Varman T} and Kibbey, {Richard G} and Shulman, {Gerald I.}",
year = "2014",
doi = "10.1038/nature13270",
language = "English",
volume = "510",
pages = "542--546",
journal = "Nature",
issn = "0028-0836",
publisher = "nature publishing group",
number = "7506",

}

RIS

TY - JOUR

T1 - Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

AU - Madiraju, Anila K

AU - Erion, Derek M

AU - Rahimi, Yasmeen

AU - Zhang, Xian-Man

AU - Braddock, Demetrios T

AU - Albright, Ronald A

AU - Prigaro, Brett J

AU - Wood, John L

AU - Bhanot, Sanjay

AU - MacDonald, Michael J

AU - Jurczak, Michael J

AU - Camporez, Joao-Paulo

AU - Lee, Hui-Young

AU - Cline, Gary W

AU - Samuel, Varman T

AU - Kibbey, Richard G

AU - Shulman, Gerald I.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Glucose

KW - Cells, Cultured

KW - Diabetes Mellitus, Type 2

KW - Gluconeogenesis

KW - Glycerolphosphate Dehydrogenase

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin

KW - Lactic Acid

KW - Liver

KW - Male

KW - Metformin

KW - Mice, Knockout

KW - Mitochondria

KW - Oxidation-Reduction

KW - Rats

KW - Rats, Sprague-Dawley

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1038/nature13270

DO - 10.1038/nature13270

M3 - Journal article

C2 - 24847880

VL - 510

SP - 542

EP - 546

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7506

ER -

ID: 174466234