To what extent GLP-1 has any capacity to enhance oxidative glucose metabolism in the cell is a topic of considerable interest. intracellular Ca2+ release channels, and Ca2+-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM. insulin secretagogue actions of sulfonylureas such as tolbutamide. Sulfonylureas do not exert a self-terminating action to stimulate insulin secretion, and for this reason their use involves a risk for hypoglycemia (Knop et al., 2008). Studies of mice demonstrate that in addition to its insulin secretagogue action, GLP-1 acts as a cell growth factor to stimulate insulin gene expression and insulin biosynthesis (Holz and Chepurny, 2003). These studies also demonstrate that GLP-1 stimulates cell proliferation (mitosis) while slowing cell death (apoptosis) (Holz and Chepurny, 2005). Although it remains to be demonstrated that such actions of GLP-1 occur in humans, these findings suggest that long-term administration of a GLP-1R agonist might result in a beneficial increase of cell mass and islet insulin content. The expected outcome would be an increased pancreatic insulin secretory capacity in T2DM patients administered GLP-1R agonists. Such beneficial antidiabetogenic properties are not characteristic of sulfonylureas. It is also important to recognize that glucoregulation under the control of GLP-1 results not simply from its direct action at pancreatic cells. Administered GLP-1R analogs act at pancreatic cells to inhibit glucagon secretion, and this effect is accompanied by a suppression of hepatic glucose production (Hare et al., 2010). Extra-pancreatic actions of GLP-1 lead to a slowing of gastric emptying, a suppression of appetite, and improved cardiovascular performance (Asmar and Holst, Tectorigenin 2010). Such actions of GLP-1 are likely to be mediated not only by its Class II GPCR, but also by a nonconventional pathway activated by metabolites of GLP-1 designated as GLP-1(9C36-amide) (Tomas and Habener, 2010) or GLP-1(28C36-amide) (Tomas et al., 2011). Indeed, speculation has Tectorigenin centered on whether this as-yet-to-be identified nonconventional pathway allows GLP-1 to exert an insulin mimetic action at the liver. It is presently unclear which GLP-1R analogs now in use for the treatment of T2DM have the capacity to exert effects mediated by this non-conventional pathway, and furthermore, it is uncertain whether inhibitors of GLP-1 metabolism exert undesirable side effects as a consequence of their ability to prevent the formation of GLP-1(9C36-amide) and GLP-1(28C36-amide). Therefore, opportunity exists to expand on our present understanding of GLP-1 pharmacology and physiology. 2. GLP-1 based therapies for the treatment of type 2 diabetes One GLP-1-based strategy for the treatment of T2DM involves the subcutaneous administration of GLP-1R agonists such as Byetta (exenatide; a synthetic form of exendin-4) or Victoza (liraglutide), a modified form of GLP-1. Unlike GLP-1, both Byetta and Victoza are resistant to metabolic degradation catalyzed by dipeptidyl peptidase-IV (DPP-IV), and for this reason these compounds exert prolonged insulin secretagogue actions when they are administered subcutaneously. This is significant because the hydrolytic activity of DPP-IV quickly renders endogenous GLP-1 inactive, thereby making it an unsuitable treatment for T2DM (Holst, 2004; Israili, CLEC4M 2009). A second GLP-1-based strategy for the treatment of T2DM involves the administration of DPP-IV inhibitors, compounds that Tectorigenin have an ability to raise levels of circulating GLP-1, while having no direct stimulatory effect on L-cell GLP-1 secretion. Mechanistically, DPP-IV inhibitors prevent the conversion of GLP-1(7C36-amide) to GLP-1(9C36-amide). Such compounds include Januvia (sitagliptin) and Galvus (vildagliptin), both of which are now in use for the treatment of T2DM. As alluded to above, GLP-1(9C36-amide) may have important actions mediated by a non-conventional pathway, and for this reason it could be that that the actions of GLP-1(9C36-amide) would be absent in T2DM patients administered DPP-IV inhibitors. Despite this uncertainty, DPP-IV inhibitors are an attractive therapeutic option due to the fact that these small molecule compounds can be.