Is GLP‐1 a hormone: Whether and When?

Glucagon‐like peptide‐1 (GLP‐1) is a product of proglucagon cleavage synthesized in L cells in the intestinal mucosa, α‐cells in the pancreatic islet, and neurons in the nucleus of the solitary tract. GLP‐1 is essential for normal glucose tolerance and acts through a specific GLP‐1 receptor that is expressed by islet β‐cells as well as other cell types. Because plasma concentrations of GLP‐1 increase following meal ingestion it has been generally presumed that GLP‐1 acts as a hormone, communicating information from the intestine to the endocrine pancreas through the circulation. However, there are a number of problems with this model including low circulating concentrations of GLP‐1 in plasma, limited changes after meal ingestion and rapid metabolism in the plasma. Moreover, antagonism of systemic GLP‐1 action impairs insulin secretion in the fasting state, suggesting that the GLP‐1r is active even when plasma GLP‐1 levels are low and unchanging. Consistent with these observations, deletion of the GLP‐1r from islet β‐cells causes intolerance after IP or IV glucose, challenges that do not induce GLP‐1 secretion. Taken together, these data support a model whereby GLP‐1 acts through neural or paracrine mechanisms to regulate physiologic insulin secretion. In contrast, bariatric surgery seems to be a condition in which circulating GLP‐1 could have an endocrine effect. Both gastric bypass and sleeve gastrectomy are associated with substantial increases in postprandial GLP‐1 release and in these conditions interference with GLP‐1r signaling has a significant impact on glucose regulation after eating. Thus, with either bariatric surgery or treatment with long‐acting GLP‐1r agonists, circulating peptide mediates insulinotropic activity. Overall, a case can be made that physiologic actions of GLP‐1 are not hormonal, but that an endocrine mechanism of GLP‐1r activation can be co‐opted for therapeutics.