Abstract
Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin’s ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
| Original language | English (US) |
|---|---|
| Article number | eads5466 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 51 |
| DOIs | |
| State | Published - Dec 20 2024 |
Funding
We thank the following core facilities at Northwestern University: Pulmonary NextGen Sequencing Core, the Robert H. Lurie Comprehensive Cancer Center Metabolomics Core, and the Transgenic and Targeted Mutagenesis Laboratory. We also would like to thank the staff of Northwestern University\u2019s Center for Comparative Medicine. We are especially grateful to H. Abdala-Valencia (Northwestern University) for technical assistance with RNA-seq. This work was supported by National Institutes of Health grant R35CA197532 (N.S.C.); National Institutes of Health grant P01HL154998-03 (N.S.C.); National Institutes of Health grant P01AG049665 (N.S.C.); National Heart, Lung, and Blood Institute grant T32HL076139-11 (C.R.R.); Northwestern University Pulmonary and Critical Care Division Cugell Predoctoral Fellowship (R.P.C.); Cellular and Molecular Basis of Disease grant T32GM008061 (K.B.D.); NRSA Training Program in Signal Transduction and Cancer grant T32CA070085 (Z.L.S.); Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research (Z.L.S.); National Heart, Lung, and Blood Institute grant T32HL076139-21 (Z.L.S.); Schmidt Science Fellows, in partnership with the Rhodes Trust (R.A.G.); and the Simpson Querrey Fellowship in Data Science (R.A.G.).
ASJC Scopus subject areas
- General