Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes
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 α cells within rodent and human pancreatic islets are capable of secreting GLP-1, but littl...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-09-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300880 |
| _version_ | 1819070597841289216 |
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| author | Scott A. Campbell Dominic P. Golec Matt Hubert Janyne Johnson Nicole Salamon Amy Barr Patrick E. MacDonald Koenraad Philippaert Peter E. Light |
| author_facet | Scott A. Campbell Dominic P. Golec Matt Hubert Janyne Johnson Nicole Salamon Amy Barr Patrick E. MacDonald Koenraad Philippaert Peter E. Light |
| author_sort | Scott A. Campbell |
| collection | DOAJ |
| description | 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 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. 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 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. Conclusions: 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. |
| first_indexed | 2024-12-21T17:08:28Z |
| format | Article |
| id | doaj.art-321056be002342d08388d9b3fb834112 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-21T17:08:28Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-321056be002342d08388d9b3fb8341122022-12-21T18:56:27ZengElsevierMolecular Metabolism2212-87782020-09-0139Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetesScott A. Campbell0Dominic P. Golec1Matt Hubert2Janyne Johnson3Nicole Salamon4Amy Barr5Patrick E. MacDonald6Koenraad Philippaert7Peter E. Light8Alberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, CanadaAlberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Canada; Corresponding author. 1-005 LKS Centre, Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada. Tel.: +1 780 492 3077.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 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. 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 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. Conclusions: 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.http://www.sciencedirect.com/science/article/pii/S2212877820300880Human isletsGlucagon-like peptide-1GLP-1GlucagonAlpha-cellBeta-cell |
| spellingShingle | Scott A. Campbell Dominic P. Golec Matt Hubert Janyne Johnson Nicole Salamon Amy Barr Patrick E. MacDonald Koenraad Philippaert Peter E. Light Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes Molecular Metabolism Human islets Glucagon-like peptide-1 GLP-1 Glucagon Alpha-cell Beta-cell |
| title | Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes |
| title_full | Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes |
| title_fullStr | Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes |
| title_full_unstemmed | Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes |
| title_short | Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes |
| title_sort | human islets contain a subpopulation of glucagon like peptide 1 secreting α cells that is increased in type 2 diabetes |
| topic | Human islets Glucagon-like peptide-1 GLP-1 Glucagon Alpha-cell Beta-cell |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820300880 |
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