Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state
| Autor: | Elham Zarrinpashneh, Benoit Viollet, Jocelyne Leclerc, Marc Foretz, Kei Sakamoto, Maud Soty, Sophie Hébrard, Gilles Mithieux, Fabrizio Andreelli |
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| Přispěvatelé: | Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MRC Protein Phosphorylation Unit, University of Dundee-College of Life Sciences, Nutrition et cerveau (U1213, U855), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie-Endocrinologie-Nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), This work was supported by the European Commission integrated project (LSHM-CT-2004-005272/ exgenesis), Association pour l'Etude des Diabètes et des Maladies Métaboliques (ALFEDIAM), Programme National de Recherche sur le Diabète (PNRD), Association de Recherche sur le Diabète (ARD), Institut Benjamin Delessert, Association pour la Recherche sur le Diabète, l'Insuffisance cérébrale et le Cancer (AREDIC) and Institut Appert. We thank Region Ile de France for contributing to the Cochin Institute animal care facility. KS was supported by Diabetes UK (07/0003529), Dundee and district of Diabetes UK Volunteer Group, the UK Medical Research Council, and the Swedish Foundation for International Cooperation in Research and Higher Education., ANR-06-PHYS-0026,MUSCLE BIOENERGETICS,'AMP-activated' et S6 kinases: roles opposés dans l'adaptation du muscle squelettique à l'état nutritionnel et à l'exercise(2006), European Project: 28783,EXGENESIS, Viollet, Benoit, Physiopathologie des maladies humaines (Physio) - 'AMP-activated' et S6 kinases: roles opposés dans l'adaptation du muscle squelettique à l'état nutritionnel et à l'exercise - - MUSCLE BIOENERGETICS2006 - ANR-06-PHYS-0026 - PHYSIO - VALID, Health benefits of exercise: identification of genes and signalling pathways involved in effects of exercise on insulin resistance, obesity and the metabolic syndrome - EXGENESIS - 28783 - OLD, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
endocrine system diseases Biology MESH: Metformin MESH: gluconeogenesis animal models MESH: Mice Knockout MESH: Protein-Serine-Threonine Kinases MESH: Hepatocytes 03 medical and health sciences 0302 clinical medicine AMP-activated protein kinase Downregulation and upregulation MESH: Mice Inbred C57BL Internal medicine MESH: Hypoglycemic Agents medicine MESH: Up-Regulation MESH: Animals MESH: AMP-Activated Protein Kinases Protein kinase A MESH: Mice 030304 developmental biology [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism 0303 health sciences MESH: AMPK MESH: Phosphoenolpyruvate Carboxykinase (ATP) MESH: Gluconeogenesis AMPK nutritional and metabolic diseases General Medicine [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism MESH: LKB1 MESH: Glucose-6-Phosphatase Metformin MESH: Glucose Endocrinology Gluconeogenesis 030220 oncology & carcinogenesis biology.protein Phosphoenolpyruvate carboxykinase MESH: Hyperglycemia Glucose 6-phosphatase medicine.drug MESH: Liver MESH: Diabetes Mellitus Type 2 |
| Zdroj: | Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2010, 120 (7), pp.2355-69. ⟨10.1172/JCI40671⟩ Journal of Clinical Investigation, 2010, 120 (7), pp.2355-69. ⟨10.1172/JCI40671⟩ |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/JCI40671⟩ |
| Popis: | pages 1-15; International audience; Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state. |
| Databáze: | OpenAIRE |
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