Metformin Lowers Fasting Hyperglycemia by Increasing Glucose Clearance in People with Moderately Controlled Type 2 Diabetes.

Authors

Sabine Kahl, Traci E LaMoia, Marc Jonuscheit, Geronimo Heilmann, Sophie Rohrer, Pavel Bobrov, Bedair Dewidar, Kalliopi Pafili, Theresia Sarabhai, Vera Schrauwen-Hinderling, Gerald I Shulman, Kitt Falk Petersen, Michael Roden

Published in

Drugs. Oct 15, 2026. Epub Oct 15, 2026.

Abstract

Metformin is the most frequently prescribed antidiabetic drug worldwide; however, the mechanism by which it lowers blood glucose remains incompletely understood. The objective of this study was to examine the effects of metformin on whole-body and specifically on hepatic glucose and energy metabolism in type 2 diabetes.
This open repeated-measures pilot study examined this question using Positional Isotopomer NMR Tracer Analysis (PINTA) to assess rates of endogenous glucose production (V_EGP), hepatic pyruvate carboxylase flux (V_PC), and citrate synthase (V_CS) flux in 16 men with moderately controlled type 2 diabetes (T2D; BMI 30 ± 3 kg/m², Hb_A1c 8.4 ± 1.4%) undergoing two examination days with (M+; 1 g twice daily) and without metformin (M-) treatment. Hepatic ATP and glycogen concentrations were quantified by ³¹P/¹³C magnetic resonance spectroscopy.
M+ reduced fasting glycemia by 18%, which could mostly be attributed to a 24% increase in rates of whole-body glucose clearance. Surprisingly, these changes were accompanied by a 58% increase in V_PC and a 34% increase in V_CS, due to a 26% increase in plasma glucagon concentrations. The increase in V_PC was offset by reductions in the contributions of glycerol conversion to glucose resulting in no change in V_EGP. Metformin decreased hepatic ATP content by 16% and increased plasma GDF-15 concentrations, but did not alter rates of net hepatic glycogenolysis.
Metformin treatment in male individuals of European ancestry with moderately controlled T2D decreases blood glucose concentrations by increasing rates of whole-body glucose clearance. Metformin further inhibits glycerol-derived gluconeogenesis, which is consistent with complex IV, not complex I, being the molecular target of metformin action.
ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT04088851.

PMID:
42875657
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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