2126-P: Physiological Concentrations of IL-1 Beta Promote Islet Amyloid Deposition by Increasing Beta-Cell Secretion of Human Islet Amyloid Polypeptide

Abstract

Aggregation of the β-cell secretory product human islet amyloid polypeptide (hIAPP) results in islet amyloid deposition as observed in type 2 diabetes (T2D). Formation of islet amyloid is associated with increased expression of proinflammatory cytokines and contributes to β-cell dysfunction and death. We previously showed that physiological levels of IL-1β increase inflammatory marker expression and islet amyloid deposition in isolated hIAPP transgenic mouse islets, a model of islet amyloidosis in T2D. To confirm these findings, we cotreated hIAPP transgenic islets with a physiological dose of IL-1β (4 pg/ml) and an IL-1β neutralizing antibody (1 μg/ml) for 48 h. Cotreatment reduced amyloid deposition by 55% compared to IL-1β alone (1.64±0.36 vs. 3.64±0.68% amyloid area per islet area, n=4, p=0.04), indicating this effect is dependent on IL-1β. Given that physiological levels of IL-1β have been shown to increase insulin secretion, we hypothesized they also stimulate IAPP secretion and thereby provide a mechanism for increased islet amyloid formation and inflammation. Islets treated with 4 pg/ml IL-1β secreted increased amounts of both insulin and IAPP over 48 h compared to vehicle treated islets (insulin: 87.5±8.9 vs. 48.3±17.3 nM/5 islets, n=4, p=0.04; IAPP: 409 ± 82 vs. 165 ± 51 pM/5 islets, n=4, p=0.02). Although IL-1β treated islets exhibited significant reductions in Ins2 (0.47 ± 0.03 vs. 1.01 ± 0.08, n=9, p<0.01) and Iapp (0.75 ± 0.06 vs. 1.01 ± 0.10, n=9, p=0.03) mRNA expression, content of insulin and IAPP was unchanged after 48 h (insulin: 167.9±14.2 vs. 144.3± 24.6 nM/5 islets, n=4, p=0.44; IAPP: 2272 ± 296 vs. 2340 ± 419 pM/5 islets, n=4, p=0.9). In summary, physiological levels of IL-1β promote islet amyloid deposition, likely by increasing β-cell secretion of IAPP. Neutralization of this effect of IL-1β may therefore decrease the deleterious effects of amyloid formation on β-cell function and survival. Disclosure A.T. Templin: None. M. Mellati: None. D. Zeman-Meier: None. M.F. Hogan: None. N. Esser: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Funding U.S. Department of Veterans Affairs (BX001060); National Institutes of Health (F32DK107022)