Nat Metab
Rethinking metformin: new evidence points to a gut-driven mechanism
Clinical Takeaway: Metformin’s efficacy depends on repeated, meal-related inhibition of mitochondrial complex I in intestinal epithelial cells—supporting administration around mealtimes and reinforcing the gut as its primary site of action.
Metformin lowers blood glucose by inhibiting mitochondrial complex I in intestinal epithelial cells, effectively transforming the gut into a major site of glucose disposal, according to a new Nature Metabolism study. The findings reshape understanding of a cornerstone diabetes therapy and highlights the gut as a target for next-generation glucose-lowering strategies.
Human metabolomic analyses (n=33) identified citrulline—the top downregulated circulating metabolite—as a key marker of intestinal mitochondrial activity suppressed by metformin. In a separate cohort of patients with obesity and type 2 diabetes (n=26), chronic metformin therapy (1,500 mg/day) significantly reduced circulating citrulline levels compared with untreated controls.
Mechanistically, metformin accumulates in the intestine at concentrations up to ~300-fold higher than plasma, reaching levels capable of inhibiting mitochondrial complex I. This inhibition shifts gut epithelial cells toward glycolysis, increasing glucose uptake and conversion to lactate. In mouse models, metformin significantly increased intestinal FDG uptake and blood lactate, while raising downstream metabolites such as lactoyl-phenylalanine and the appetite-regulating hormone GDF15 (typical n≈5–12 per group).
Using a genetically engineered mouse model resistant to complex I inhibition in the intestine, investigators showed that blocking this pathway markedly blunted metformin’s glucose-lowering effects, including impaired glucose tolerance and reduced suppression of postprandial glucose excursions (n≈9–17 per group). These findings demonstrate that intestinal complex I inhibition is necessary for the drug’s antihyperglycemic action.
Importantly, the study found metformin’s benefit arises from repeated acute exposures rather than cumulative chronic effects; continuous low-dose administration failed to improve glycemic control, whereas bolus dosing produced robust glucose lowering.
The same gut-specific mechanism was observed with phenformin and berberine, suggesting a shared pathway among structurally distinct agents. As senior author Navdeep Chandel noted, metformin “helps the intestine suck the glucose out of the bloodstream,” highlighting the gut as a central regulator of systemic glucose homeostasis.
Together, these findings shift the therapeutic paradigm from a liver-centric to a gut-centric model of metformin action and suggest that targeting intestinal mitochondrial metabolism may offer a promising route for future diabetes therapies.
Source: Sebo ZL, et al. (2026, April). Nat Metab. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control