Sites of metformin-stimulated glucose metabolism

Metformin, the first line drug for treatment of type 2 diabetes, suppresses hepatic gluconeogenesis and reduces body weight in patients, the latter by an unknown mechanism.

Mice on a high fat diet were continuously fed metformin in a therapeutically relevant dose, mimicking a retarded formulation.

Feeding metformin in pharmacologically relevant doses to mice on a high fat diet normalized HbA1c levels and ameliorated glucose tolerance, as expected, but also considerably slowed down weight gain. This was due to increased energy expenditure, since food intake was unchanged and locomotor activity was even decreased. Metformin caused lactate accumulation in the intestinal wall and in portal venous blood but not in peripheral blood or the liver. Increased conversion of glucose-1-¹³C to glucose-1,6-¹³C under metformin strongly supports a futile cycle of lactic acid production in the intestinal wall, and usage of the produced lactate for gluconeogenesis in liver.

The reported glucose–lactate–glucose cycle is a highly energy consuming process, explaining the beneficial effects of metformin given continuously on the development of a type 2 diabetic-like state in our mice.

The use of metformin has been associated with diffusely increased colonic ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake. Interestingly, metformin use is associated with moderate weight loss. It could be hypothesized that increased colonic glucose disposal is related to this weight loss. It is unknown whether other factors influence ¹⁸F-FDG uptake in the colon. The aim of this study was to retrospectively assess independent determinants of colonic ¹⁸F-FDG uptake.

We retrospectively analysed 270 ¹⁸F-FDG PET–CTs which were made for diagnostic purposes. Colonic ¹⁸F-FDG uptake was assessed using a 4-point scale using the liver as a reference (1; lower, 2; similar, 3; moderately higher than hepatic activity, 4; intense diffuse increased uptake). Determinants of ¹⁸F-FDG uptake in the colon were assessed using forward logistic regression (i.e., grade 1&2 vs 3&4).

The patients had a mean age of 60.2 ± 14.8 years, a BMI of 25.8 ± 5.2 kg/m² and 52% were female. Most patients had a grade 2 (44%) or grade 3 (39%) ¹⁸F-FDG uptake in the colon. Diabetes mellitus type 2 was observed in 14% of the patients. In total, 5% of the patients used insulin, 12% used metformin and 5% used sulfonylurea derivatives (SU). While there seemed to be an effect of SU on ¹⁸F-FDG uptake in the ileum [OR 3.6 (95% CI: 1.3–33.1), p = 0.03], metformin was the only drug associated with ¹⁸F-FDG uptake for both the whole colon [OR 10.0 (95% CI: 2.9–34.7), p < 0.001] and all individual segments.

Metformin use is an independent determinant of increased colonic ¹⁸F-FDG uptake, suggesting a potential role for increasing colonic glucose disposal.