Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans

Background Metformin lowers glucose by acting on the liver and the gastrointestinal tract and may reduce body weight by increasing circulating levels of the stress-induced cytokine GDF15. The tissue responsible for the release of GDF15 and whether this is paralleled by the induction of another, mainly liver derived, stress-responsive cytokine, FGF21, remains unclear. Objective We examined the effect of metformin on GDF15 and FGF21 in humans and in intestinal cells in vitro . Methods In a randomized, cross-over trial, 34 healthy individuals completed a 42-h fast twice, either with or without prior treatment with metformin for a week. Glucose metabolism was assessed using [3- 3 H]-glucose and indirect calorimetry and blood samples were drawn for the analysis of plasma metformin and serum GDF15 and FGF21. The effects of metformin on the expression and secretion of GDF15 and FGF21, and on mitochondrial respiration and glycolysis were examined in human intestinal epithelial cells (Caco-2). Results Metformin increased glucose utilization (p=8.9x10 -13 ) due to increased glycolysis (p=7.6x10 -13 ) in vivo . This was accompanied by increased serum GDF15 (1004±61 vs 607±89 ng/ml; p<0.001), whereas serum FGF21 (146±30 vs 156±29 ng/ml; p=0.65) was unaltered. The change in serum GDF15 did not correlate with plasma metformin levels. In vitro , metformin markedly increased mRNA levels and secretion of GDF15, whereas FGF21 levels were not detectable in Caco-2 cells or media. Moreover, metformin dose-dependently inhibited mitochondrial respiration and increased glycolysis in vitro . Conclusions The metformin-induced increase in serum GDF15, but not the liver-derived FGF21, in humans is consistent with the actions of metformin in human intestinal cells in vitro . These findings corroborate with recent studies demonstrating the gastrointestinal tract is an important site of metformin action. Clinical Trial Registration ClinicalTrials.gov , Identifier NCT01400191.