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

• Published in: Molecular metabolism (Germany) Vol. 39; p. 101014
• Main Authors: Campbell, Scott A., Golec, Dominic P., Hubert, Matt, Johnson, Janyne, Salamon, Nicole, Barr, Amy, MacDonald, Patrick E., Philippaert, Koenraad, Light, Peter E.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01-09-2020; Elsevier
• Subjects: Alpha-cell; Beta-cell; GLP-1; Glucagon; Glucagon-like peptide-1; Human islets; Original; Human islets; Glucagon-like peptide-1; GLP-1; Beta-cell; Glucagon; Alpha-cell
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2020.101014

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 α 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.
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.
We have demonstrated that human islets secrete ∼50-fold more GLP-1 than murine islets and that ∼40% of the total human α cells contain GLP-1. Our results also confirm that dipeptidyl peptidase-4 (DPP4) is expressed in α 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 β 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+ α cells in T2D islets compared with ND islets obtained from cadaveric donors. Furthermore, GLP-1+ α cells were also identified in pancreatic islet sections obtained from living donors undergoing surgery.
In summary, we demonstrated that human islets secrete robust amounts of GLP-1 from an α cell subpopulation and that GLP-1R signalling may support GSIS to a greater extent in T2D islets.
•Here we show that glucagon-like peptide-1 (GLP-1) is secreted from a subpopulation of α cells within human islets.•Human islets secrete ∼50-fold more GLP-1 than murine islets and that ∼40% of the total human α cells contain GLP-1.•We observed significantly more GLP-1+ α cells in islets from donors with type 2 diabetes than in islets from donors with no diabetes.•GLP-1+ α cells can also be detected in pancreatic islet sections obtained from living donors undergoing surgery.•GLP-1 receptor signaling may support insulin secretion to a greater extent in type 2 diabetes.