New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Abstract

The two major deficits in type 2 diabetes, insulin resistance and impaired beta cell function, are often treated with metformin and incretin-based drugs, respectively. However, there may be unappreciated benefits of this combination of therapies. In this issue of Diabetologia, Maida et al. (doi:10.1007Maida et al. (doi:10. /s00125-010-1937 report that metformin acutely increases plasma levels of glucagon-like peptide 1 (GLP-1) in mice. Moreover, they show that metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells. Interestingly, these incretin-sensitising effects of metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of metformin action involving AMP-activated protein kinase. These provocative findings by Maida et al. extend our understanding of the mechanism of action of metformin and provide further insights into the benefits of combining metformin with incretin-based drugs to combat diabetes.

Metformin: A Hopeful Promise in Aging Research

“…Additionally, metformin improves glucose homeostasis by promoting an increase in insulin-independent phosphorylation of insulin receptor and insulin receptor substrates (IRS)-1 and (IRS)-2, and subsequent translocation of glucose transporters GLUT4 to the plasma membrane (Gunton et al 2003;Yuan et al 2003). The regulation of the incretin hormone (e.g., glucagon-like peptide 1) and insulin secretory responses with metformin treatment has been reported (Cho and Kieffer 2011;Maida et al 2011;Kim et al 2014).…”

Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

“…Subsequently, OGIS and glucagon responses were added to the model as potential explanatory variables of the relationship between incretins and triglycerides or ALT. Although no medication was used on the test day, metformin may have impacted on the GLP-1 response as it has been suggested to act as a GLP-1 enhancer (31). Therefore, we performed a sensitivity analysis by excluding patients who were on metformin.…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…The major advantage of new compounds in this field is the glucose dependence of insulin release (one major advantage over sulfonylureas), which may depend on the K ATP channels of the ␤-cell that close when activated by a rise in the intracellular ATP concentration, making them sensitive to the intracellular glucose metabolism and therefore the plasma glucose concentration. It is noteworthy that metformin has been shown to influence GLP-1 secretion (Cho and Kieffer, 2011;Maida et al, 2011), which previously was not a known action.…”