Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.

pages 1-15International audienceMetformin 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

Mécanismes de régulation post-traductionnelle de la glucose-6-phosphatase par l'AMPc (importance de la glucose-6-phosphate translocase)

LYON1-BU.Sciences (692662101) / SudocSudocFranceF

L'inhibition de l'absorption intestinale de di/tripeptides induit le développement d'un état prédiabétique

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Intestinal glucose production activates the leptin signal cascade to promote its metabolic benefits

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La néoglucogenèse intestinale exerce ses effets métaboliques bénéfiques en activant la voie de signalisation de la leptine et les neurones à CGRP

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La glucogenèse intestinal périnatale contrôle le développement hypothalamique du nouveau-né permettant une amélioration du métabolisme de l'individu adulte.

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Gut-Brain Glucose Signaling in Energy Homeostasis

International audienceIntestinal gluconeogenesis is a recently identified function influencing energy homeostasis. Intestinal gluconeogenesis induced by specific nutrients releases glucose, which is sensed by the nervous system surrounding the portal vein. This initiates a signal positively influencing parameters involved in glucose control and energy management controlled by the brain. This knowledge has extended our vision of the gut-brain axis, classically ascribed to gastrointestinal hormones. Our work raises several questions relating to the conditions under which intestinal gluconeogenesis proceeds and may provide its metabolic benefits. It also leads to questions on the advantage conferred by its conservation through a process of natural selection

La néoglucogenèse intestinale contrôle une interaction humorale entre le tissu adipeux blanc et les cellules beta-pancréatiques

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La néoglucogenèse intestinale contrôle le développement néonatal de l'hypothalamus.

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Intestinal gluconeogenesis controls the neonatal development of the hypothalamus.

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