Is GLP‐1 a hormone: Whether and When?

Abstract

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.

Exenatide induces carcinoembryonic antigen‐related cell adhesion molecule 1 expression to prevent hepatic steatosis

“…The role of exenatide in suppressing appetite and inducing glucose‐stimulated insulin secretion is well documented . The current study identifies a novel positive effect of exenatide on insulin clearance in parallel with insulin secretion to prevent chronic hyperinsulinemia and the subsequent increase in hepatic de novo lipogenesis …”

“…(B) mRNA levels of (i) hGLP‐1R , (ii) hCEACAM1 ( hCC1 ), (iii) hPPAR α, and (iv) hPPAR γ were analyzed in HepG2 as above except for pre‐incubation with exendin 9‐39 (dark gray). * P < 0.05 versus S, † P < 0.05 Ex + exendin 9‐39 (Ex+ ) versus Ex alone. Abbreviations: Ex, exenatide; Ex , exendin fragment 9‐39; h, human; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; /GAPDH, normalized to GAPDH.…”

“…The role of exenatide in suppressing appetite and inducing glucose-stimulated insulin secretion is well documented. (8,9) The current study identifies a novel positive effect of exenatide on insulin clearance in parallel with insulin secretion to prevent chronic hyperinsulinemia and the subsequent increase in hepatic de novo lipogenesis. (30) Exenatide promotes insulin clearance by inducing the expression of CEACAM1, which increases the rate of receptor-mediated insulin uptake in a phosphorylation-dependent manner.…”

Integration of nano‐ and biotechnology for beta‐cell and islet transplantation in type‐1 diabetes treatment

“…Our principal target of the NPs is the glucagon‐like peptide 1 receptor (GLP‐1R) which is expressed on the membranes of beta cells and has an important role in the regulation of insulin secretion . The natural ligand, glucagon‐like peptide‐1 (GLP‐1) binds to the GLP1‐R with high affinity, but its half‐life in vivo is very short for the fine regulation of blood sugar level . Current therapeutic approaches have utilized mimetics of GLP‐1, most notably exenatide, the synthetic form of the naturally occurring peptide exendin‐4 (Ex4) …”

Gastrointestinal hormones and the gut connectome

“…Although this has been established for some GI hormones, this view has now been challenged for others. For example, GLP-1 which is synthesized in the distal small intestine and colon is potently inactivated by the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4) and further inactivated in the liver so that by the time it reaches the arterial circulation, its concentration is so low that it may not be sufficient to activate islet cell GLP-1 receptors [27, 28]. This observation has raised serious doubts about the endocrine model of GLP-1 and suggested that most of the physiological functions of GLP-1 secreted from enteroendocrine cells may be mediated through direct activation of enteric sensory nerve endings [29].…”