S100 calcium-binding protein A8 (S100A8), a member of damage-associated molecular pattern molecules (DAMPs), reportedly contribute to the islet inflammation by mediating interaction between β-cells and macrophages (J Biol Chem., 2018). However, the role of S100A8 in the regulation of β-cell function and mass remain unclear. To clarify the role of S100A8 in β-cell functionality, we generated β-cell-specific S100A8 knockout mice (KO) by crossing S100A8-floxed mice (control) and Ins1-cre mice. In the presence of high glucose (200 mg/dL) and palmitic acid, the expression of S100A8 in KO islets significantly reduced (0.025-fold, p<0.05) compared to control islets. Islets and peritoneal macrophage (Mφ) were isolated from control and KO, and cultured under the conditions of glucose concentration, presence or absence of palmitic acid, single culture or co-culture. When control Mφ co-cultured with KO islets in the presence of high glucose and palmitic acid, the expression of TNFα, IL-6, or CCL2 in Mφ was significantly reduced (0.17-fold, p<0.05; 0.69-fold, p<0.05; 0.22-fold, p<0.05) compared to that when co-cultured with control islets. KO fed normal chow showed comparable body weight, insulin sensitivity, and glucose tolerance with control. In contrast, high-fat diet-fed KO demonstrated improved glucose tolerance, increased β-cell mass (2.65-fold, p<0.05), and enhanced β-cell proliferation (1.91-fold, p<0.05) compared to control. Thus, β-cell-derived S100A8 mediates the islet inflammation induced by glucolipotoxicity through the interaction with infiltrated Mφ. Furthermore, S100A8 seemed to negatively regulate β cell proliferation in diet-induced obese mice, and could be a novel therapeutic target to reverse β-cell loss in subjects with diabetes.
D. Miyashita: None. J. Shirakawa: None. Y. Togashi: None. T. Okuyama: None. M. Kyohara: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk A/S, Sanofi. Consultant; Self; Astellas Pharma Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Medscape, Medtronic, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation.