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 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.

Titanium Nanoparticles Enhance Production and Suppress Stabilin-1-Mediated Clearance of GDF-15 in Human Primary Macrophages

“…It is worth mentioning that the TiNPs-induced pro-inflammatory reaction has been associated with increased production of reactive oxygen species (ROS) and mitochondrial damage ( 45 ). Interestingly, GDF-15 production is induced by mitochondrial uncoupling and by the treatment with mitochondrial inhibitors, including metformin ( 46 , 47 ). Likewise, TiNPs induce ER stress and disrupt the mitochondrial-associated ER membranes ( 48 ).…”

Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin

“…Slc5a1 gene encodes SGLT-1 in the intestine for absorption of glucose (Glc) and galactose (Gal) ( 28 ). Slc5a1 expression is reported to be reduced by the inhibitors of mitochondrial electron transport chain complexes (such as metformin, rotenone and antimycin A) in mouse ileal cultures mouse duodenal organoid derived 2D monolayer cultures ( 29 ). In human, Slc5a1 expression is increased in the duodenal of individuals with impaired glucose tolerance and T2DM ( 30 ).…”

Metformin and Glaucoma—Review of Anti-Fibrotic Processes and Bioenergetics

“…This apparent dose dependent response of metformin's effect on mitochondrial function may explain discrepancies in the literature between beneficial [172] and detrimental [173] effects on ATP levels, extracellular acidification and oxygen consumption rates. Wang et al demonstrated this on hepatocyte mitochondrial function with pharmacological metformin doses (75 µM) increasing mitochondrial respiration and fission [172].…”