Human islets contain a subpopulation of glucagon-like peptide-1 secreting ? cells that is increased in type 2 diabetes.

ABSTRACT: OBJECTIVES:Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology and pathophysiology. It is known that ? cells within rodent and human pancreatic islets are capable of secreting GLP-1, but little is known about the functional role that islet-derived GLP-1 plays in human islets. METHODS:We used flow cytometry, immunohistochemistry, perifusions, and calcium imaging techniques to analyse GLP-1 expression and function in islets isolated from cadaveric human donors with or without type 2 diabetes. We also used immunohistochemistry to analyse GLP-1 expression within islets from pancreatic biopsies obtained from living donors. RESULTS:We have demonstrated that human islets secrete ?50-fold more GLP-1 than murine islets and that ?40% of the total human ? cells contain GLP-1. Our results also confirm that dipeptidyl peptidase-4 (DPP4) is expressed in ? cells. Sitagliptin increased GLP-1 secretion from cultured human islets but did not enhance glucose-stimulated insulin secretion (GSIS) in islets from non-diabetic (ND) or type 2 diabetic (T2D) donors, suggesting that ? cell GLP-1 receptors (GLP-1R) may already be maximally activated. Therefore, we tested the effects of exendin-9, a GLP-1R antagonist. Exendin-9 was shown to reduce GSIS by 39% and 61% in ND islets and T2D islets, respectively. We also observed significantly more GLP-1+ ? cells in T2D islets compared with ND islets obtained from cadaveric donors. Furthermore, GLP-1+ ? cells were also identified in pancreatic islet sections obtained from living donors undergoing surgery. CONCLUSIONS:In summary, we demonstrated that human islets secrete robust amounts of GLP-1 from an ? cell subpopulation and that GLP-1R signalling may support GSIS to a greater extent in T2D islets.

SUBMITTER: Campbell SA 

PROVIDER: S-EPMC7260680 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature