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.

Duke Scholars

Author David A D'Alessio Medicine, Endocrinology, Metabolism, and Nutrition