869-P: Gastrin Reduces Incidence of Type 1 Diabetes through Reducing Inflammation and Preserving ß-Cell Mass in Animal Model

Introduction: Progressive destruction of insulin-producing β-cells by autoimmunity is a primary feature of type 1 diabetes (T1D). Therapies that block immune attacks on islet cells and preserve or restore the functional β-cell mass are needed to halt or reverse disease progression. Here, we tested the therapeutic effects of GAST-17, an analogue of the natural gastric hormone that is produced by intestinal G cells and fetal islets, on preservation and restoration of β-cell mass in the NOD mice.

Methods: Normoglycemic female NOD mice were injected intraperitoneal with GAST-17 (300 or 600ug/kg/day) or saline (control) for 14-weeks. At end of the experiment, an intraperitoneal glucose tolerance test (IPGTT) was performed. Pancreatic tissues were examined for islets number, endocrine cell mass and inflammatory cell infiltration.

Results: GAST-17 treated animals had lower rates of diabetes incidents in a dose-dependent manner. Animals treated with 600 ug/kg/day of GAST-17, prevented diabetes in 70-80% compared to 20-57% in control, and area under the curve in IPGTT test was also lower compared to control (p<0.05). Islet morphology was not different among the diabetic mice, but GAST-17 treated nondiabetic mice had lower inflammatory cell infiltration (p<0.004), higher number of islets (p<0.01) and larger endocrine cell mass/islet than nondiabetic controls (p<0.01).Smaller (<10026uM²) but not larger islets showed higher ratios of insulin to glucagon and insulin per islet area when compared to controls(p<0.005). All normoglycemic animals had larger numbers of small islets, compared to larger islets that were closer to the ducts.

Conclusion: GAST-17 treatment protected NOD mice from the development of diabetes by reducing islet inflammatory cell invasion, preserving beta cell mass and likely augmenting islet neogenesis from a ductal origin. Lineage tracing experiments are ongoing.