Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.
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.
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Anila K
AK
Madiraju
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Derek M
DM
Erion
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Yasmeen
Y
Rahimi
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Xian-Man
XM
Zhang
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Demetrios T
DT
Braddock
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Ronald A
RA
Albright
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA.
Brett J
BJ
Prigaro
Cancer Prevention Research Institute of Texas Scholar, Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, USA.
John L
JL
Wood
Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA.
Sanjay
S
Bhanot
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA, 53706.
Michael J
MJ
MacDonald
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Michael J
MJ
Jurczak
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Joao-Paulo
JP
Camporez
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Hui-Young
HY
Lee
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Gary W
GW
Cline
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Varman T
VT
Samuel
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Richard G
RG
Kibbey
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark, DK-2200.
Gerald I
GI
Shulman
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000096:biosynthesis; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D005993:Glycerolphosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D019344:Lactic Acid; D008687:Metformin; D005993:Glycerolphosphate Dehydrogenase