Modulation of the Pancreatic Hormone, Glucagon by the Gut Peptide, GLP-1: Controversies, Challenges and Future Directions

Abstract

Type 2 diabetes (T2D) is a chronic disease characterised by a combination of insufficient insulin release and an excess of glucagon secretion. The gut hormone glucagon-like peptide-1 (GLP-1) is a successful therapy for the treatment of diabetes as it can both potentiate glucose-induced insulin secretion as well as inhibit glucagon secretion from the pancreatic alpha cells. Another major gut hormone called peptide tyrosine tyrosine (PYY) has recently been reported to restore impaired insulin and glucagon secretion in islets from severely diabetic rats and humans. Whilst the mechanism by which both PYY and GLP-1 normalise insulin secretion is well characterised, to date the regulation of glucagon release by the two gut hormones remains unclear. Given that the GLP-1 receptor is expressed at extremely low levels on alpha-cells, it has been argued that the effects of GLP-1 may be mediated by paracrine (indirect) mechanisms. In contrast, there is also evidence that GLP-1 directly regulates glucagon secretion in isolated alpha-cells, excluding the possibility of islet cross-talk. Likewise, no receptors for PYY have been demonstrated in the alpha-cells that can explain the robust effects of the hormone on glucagon release. Elucidation of the mechanism of GLP-1 (and PYY) action on alpha cells necessitates further work. Specifically it will be important to determine if GLP-1 can mediate its effects via another receptor on alpha-cells.