The role of gastrin in human islet and type 1 diabetes animal model
Lynn Miao1, Hirotake H Komatsu1, Angel A Gu1, Mohamed M Husseiny1, Jeffrey J Rawson1, Nelson N Gonzalez1, Chris C Orr1, Jacob J Mares1, Sangeeta S Dhawan1, Hung-Ping H Shih1, Teresa T Ku 1, Fouad F Kandeel1.
1Department of Translational Research & Cell Therapeutics, City of Hope, Duarte, CA, United States
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.
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