Metformin Acts Primarily Through Gut Mitochondrial Complex I Inhibition

Metformin is the most widely prescribed medication for type 2 diabetes. The research mapped multiple clinical effects of metformin, including reduced postprandial glucose excursions and elevated intestinal glucose uptake, to intestine-specific mitochondrial complex I inhibition.

Using publicly available human metabolomic data and genetic tools in mice, the authors showed that metformin suppresses citrulline synthesis, a process that occurs exclusively in small intestine mitochondria, and increases levels of GDF15. This inhibition causes the intestines to function as a glucose sink.

Excess glucose is taken up and converted to lactate and lactoyl-phenylalanine. The study found that glucose lowering depends on repeated bolus exposure to the drug rather than cumulative chronic effects.

Analysis of metabolomic data from patients without diabetes showed citrulline as the most significantly downregulated metabolite following metformin treatment. In a separate group of patients with obesity and type 2 diabetes receiving 1,500 mg of metformin daily for at least six months, circulating citrulline levels were also significantly reduced compared with those not taking the drug.

These findings align with prior reports of decreased citrulline in patients with type 2 diabetes on metformin. The enzymes responsible for citrulline synthesis, including ornithine transcarbamylase and carbamoyl phosphate synthetase I, are localized to mitochondria in the small intestine and liver.

The study notes that mitochondrial ATP is required for this process and cannot be replaced by glycolytic ATP.

The efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical used for type 2 diabetes, was also shown to depend on intestine-specific mitochondrial complex I inhibition. This indicates a shared therapeutic mechanism among the three compounds.

The study addresses earlier debates about metformin's site of action. While previous work had focused on suppression of hepatic gluconeogenesis, clinical imaging studies have consistently shown enhanced glucose utilization and lactate production in the intestines.

Metformin increases FDG accumulation in the small and large intestines, which has led to the standard practice of discontinuing the drug before FDG-PET scans to avoid interference with cancer detection. The authors conclude that mitochondrial complex I in the intestinal epithelium serves as an essential therapeutic target for metformin, phenformin and berberine.

This mechanism accounts for enhanced intestinal glucose utilization, blood glucose clearance, citrulline depletion, improved postprandial glycaemia, and elevated levels of lactoyl-phenylalanine and GDF15.