Abstract 15122: Il18 Uses Both Il18 Receptor and Na-cl Co-transporter to Support Islet β Cell Proliferation and Insulin Secretion

Introduction: The regeneration of pancreatic β cells to restore insulin production is a promising therapeutic strategy for insulin-dependent type-1 (T1D) and type-2 diabetes (T2D). Plasma IL18 levels are increased in these patients. Prior studies suggest a role for IL18 in inducing islet insulin production. IL18 administration suppressed autoimmune diabetes in non-obese diabetic mice. We recently discovered that IL18 uses two receptors IL18r and NCC (Na-Cl co-transporter) with equal binding kinetics. Hypothesis: IL18r and NCC use different mechanisms to mediate IL18 activity in islet β cell insulin production. Methods and Results: Immunoblot and immunofluorescent staining localized IL18 on islet α cells, NCC on islet β cells, and IL18r on pancreas acinar cells. Development of T1D or T2D increased the α cell IL18 expression. From high fat diet (HFD)-induced T2D, deficiency of IL18r ( Il18r -/- ) or NCC ( Ncc -/- ), or combined deficiency of both receptors ( Il18r -/- Ncc -/- ) reduced insulin secretion, exacerbated β cell failure, decreased α cell content, reduced islet size, reduced β cell proliferation, and decreased the expression of islet proliferation markers. Deficiency of IL18r in Il18r -/- and Il18r -/- Ncc -/- mice aggravated β cell content and size reductions and glucose metabolism and increased β cell apoptosis after streptozotocin (STZ)-induced T1D. Il18r -/- Ncc -/- mice also showed increased macrophage accumulation in the islets from both T1D and T2D mice. Using α cell-selective IL18-deficient Gcg CreERT2 IL18 fl/fl mice, acinar cell-selective IL18r-deficient Mist1 CreERT2 Il18r fl/fl mice, and β cell NCC-deficient Ins1 Cre Ncc fl/fl mice, we demonstrated that these mice showed impaired insulin secretion and glucose metabolism, exacerbated β cell failure, and aggravated HFD-induced T2D. Mechanistic studies suggested that IL18 uses NCC on β cells to promote insulin secretion and uses IL18r on acinar cells to assist β cell development. Conclusions: Islet α cell IL18 uses NCC on β cells to promote β cell proliferation and uses IL18r on acinar cells to produce inflammatory molecules to assist β cell generation and insulin secretion. Both the IL18r and NCC signaling pathways are essential to β cell function in diabetic patients.