118.6: The role of gastrin in human islet and type 1 diabetes animal model

Introduction: A major obstacle to the success of islet cell transplantation for type 1 diabetes (T1D) is the loss of beta-cells following transplantation. Gastrin, a peptide-hormone which is produced by intestinal cells and fetal islets can increase β-Cell mass and promote protection from T1D. In an ongoing clinical study in our center, gastrin (specifically gastrin-17) treatment enhanced outcomes of islet transplantation in individuals with T1D. Here, we investigated the effects of gastrin on human islets in vitro and in autoimmune non-obese diabetic (NOD) mice in vivo. Methods: In vitro culture: Isolated human islets were cultured (100 IEQ/per-well) in 6-well trans-well plates in a hyperoxia culture system under 50% oxygen for two weeks, and with or without 100 nM gastrin. Islet morphology, function and cell viability were assessed post-culture. Islet mRNA expression was determined by RT-PCR, and secretion of pro-inflammatory cytokines were detected using Luminex assay. Western blot was used to determine if reduction in NFkb pathway is involved in gastrin pro-survival effects on islets. In vivo animal study: 7-week-old NOD mice were injected i.p. with and without gastrin at 600 mg/kg daily for 14 weeks. Mice were monitored for blood glucose levels weekly. At the end of the 14-week injections, the intraperitoneal glucose tolerance test (IPGTT) was performed. The pancreas tissues were collected and sectioned for H&E staining to assess insulitis, and stained with anti-insulin, and anti-glucagon antibodies to assess beta-cell and alpha-cell mass. Results: Treatment with exogenous gastrin on human islets prolonged survival and function through downregulation of several pro-inflammatory related genes, such as IL-1β, IL-6, G-CSF, and GM-CSF expression. When stressed with pro-inflammatory cytokines (IL-1β, IFNr and TNFa), human islets treated with gastrin displayed better viability and function, and with down-regulated phosphor-NFkb/Ser536 at the protein level. In the in vivo NOD mice study, gastrin caused a significant delayed onset of diabetes, reduced insulitis, and maintained beta cell mass. Conclusion: Treatment of exogenous gastrin (Gastrin-17) enhances islet survival and function both in vitro and in vivo, likely through down-regulation of pro-inflammatory pathways. References: 1. Ilse Rooman, Gastrin Stimulates _-Cell Neogenesis and Increases Islet Mass From Transdifferentiated but Not From Normal Exocrine Pancreas Tissue. DIABETES, VOL. 51, MARCH 2002. 2. Suarez-Pinzon WL, Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet {beta}-cells from pancreatic duct cells and an increase in functional {beta}-cell mass. J Clin Endocrinol Metab. 2005;90(6):3401-9. doi: 10.1210/jc.2004-0761. PubMed PMID: 15769977. 3. Suarez-Pinzon WL, Lakey JR, Rabinovitch A. Combination therapy with glucagon-like peptide-1 and gastrin induces beta-cell neogenesis from pancreatic duct cells in human islets transplanted in immunodeficient diabetic mice. Cell Transplant. 2008;17(6):631-40. Epub 2008/09/30. doi: 10.3727/096368908786092775. PubMed PMID: 18819251. 4. Marie-Claude Gaudreau, Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes.Autoimmunity. 2022 March; 55(2): 95–108 5. Suissa Y, Magenheim J, Stolovich-Rain M, et al. Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas. PloS one. 2013;8(8):e70397. [PubMed: 23940571] 6. 5. Dahan T, Ziv O, Horwitz E, et al. Pancreatic beta-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes. Diabetes. 2017 Feb;66(2):426–436. [PubMed: 27864307] 7. Khan D, Vasu S, Moffett RC, et al. Expression of Gastrin Family Peptides in Pancreatic Islets and Their Role in beta-Cell Function and Survival. Pancreas. 2018 Feb;47(2):190–199. [PubMed: 29329158] 8. Tellez N, Joanny G, Escoriza J, et al. Gastrin treatment stimulates beta-cell regeneration and improves glucose tolerance in 95% pancreatectomized rats. Endocrinology. 2011 Jul;152(7):2580–8. [PubMed: 21558313] 69. Suarez-Pinzon WL, Lakey 9. Wang TC, Bonner-Weir S, Oates PS, et al. Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells. The Journal of clinical investigation. 1993 Sep;92(3):1349–56. [PubMed: 8376589] 10. Fosgerau K, Jessen L, Lind Tolborg J, et al. The novel GLP-1-gastrin dual agonist, ZP3022, increases beta-cell mass and prevents diabetes in db/db mice. Diabetes, obesity & metabolism. 2013 Jan;15(1):62–71. 11. Song I, Patel O, Himpe E, et al. Beta Cell Mass Restoration in Alloxan-Diabetic Mice Treated with EGF and Gastrin. PloS one. 2015;10(10):e0140148.