Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L-cell

The incretin hormone glucagon-like peptide-1 enhances glucose-dependent insulin secretion and is therefore a most attractive therapeutic approach for the treatment of Type 2 Diabetes Mellitus. The anti-diabetic drug, metformin, has previously been shown to increase circulating levels of GLP-1, although its mechanism of action is currently unknown. Neither metformin nor AICAR (activators of AMPK) directly stimulated GLP-1 secretion from the L-cell in vitro. However, oral treatment of rats with metformin enhanced plasma levels of active and total GLP-1, independent of GLP-1 degradation. Furthermore, pre-treatment with the general muscarinic antagonist, atropine, or the M3 antagonist, 4-DAMP, decreased metformin–induced GLP-1 secretion, while M1 and M2 antagonists did not. Chronic bilateral subdiaphragmatic vagotomy had no effect, while the GRP antagonist, RC-3095, reduced metformin-induced GLP-1secretion. Therefore, I conclude that metformin-induced GLP-1 secretion occurs in part through the parasympathetic nervous system, the M3 and GRP receptors, but is independent of the vagus nerve.