Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells

Abstract Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of...

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Autores principales:	Ming Yang, Tamana Darwish, Pierre Larraufie, Debra Rimmington, Irene Cimino, Deborah A. Goldspink, Benjamin Jenkins, Albert Koulman, Cheryl A. Brighton, Marcella Ma, Brian Y. H. Lam, Anthony P. Coll, Stephen O’Rahilly, Frank Reimann, Fiona M. Gribble
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3277fbedd1ef4a0488a75dc21d27c7a7
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spelling	oai:doaj.org-article:3277fbedd1ef4a0488a75dc21d27c7a72021-12-02T14:16:34ZInhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells10.1038/s41598-021-81349-72045-2322https://doaj.org/article/3277fbedd1ef4a0488a75dc21d27c7a72021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81349-7https://doaj.org/toc/2045-2322Abstract Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin’s effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance.Ming YangTamana DarwishPierre LarraufieDebra RimmingtonIrene CiminoDeborah A. GoldspinkBenjamin JenkinsAlbert KoulmanCheryl A. BrightonMarcella MaBrian Y. H. LamAnthony P. CollStephen O’RahillyFrank ReimannFiona M. GribbleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ming Yang Tamana Darwish Pierre Larraufie Debra Rimmington Irene Cimino Deborah A. Goldspink Benjamin Jenkins Albert Koulman Cheryl A. Brighton Marcella Ma Brian Y. H. Lam Anthony P. Coll Stephen O’Rahilly Frank Reimann Fiona M. Gribble Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells
description	Abstract Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin’s effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance.
format	article
author	Ming Yang Tamana Darwish Pierre Larraufie Debra Rimmington Irene Cimino Deborah A. Goldspink Benjamin Jenkins Albert Koulman Cheryl A. Brighton Marcella Ma Brian Y. H. Lam Anthony P. Coll Stephen O’Rahilly Frank Reimann Fiona M. Gribble
author_facet	Ming Yang Tamana Darwish Pierre Larraufie Debra Rimmington Irene Cimino Deborah A. Goldspink Benjamin Jenkins Albert Koulman Cheryl A. Brighton Marcella Ma Brian Y. H. Lam Anthony P. Coll Stephen O’Rahilly Frank Reimann Fiona M. Gribble
author_sort	Ming Yang
title	Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells
title_short	Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells
title_full	Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells
title_fullStr	Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells
title_full_unstemmed	Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells
title_sort	inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and gdf-15 release from intestinal cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3277fbedd1ef4a0488a75dc21d27c7a7
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Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells

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