2186-P: Circulating Exosomes from Simple Obese Humans Inhibited Islet ß-Cell Proliferation through Increasing Cellular Inflammation

Abstract

The progressive decline of the β cell function is one major pathogenesis of type 2 diabetes mellitus. The obese people with normal glucose have already had β cell dysfunction. We aim to investigate whether the circulating exosome vesicles (EVs) could be a new mechanism linking obesity to β cell dysfunction. A total of 43 healthy lean and 44 simple obese volunteers were recruited from June 2017 to February 2018. Compared to lean subjects, obese subjects had lower glucose disposition index (DI) and Secretion-sensitivity index (ISSI-2). Compared to EVs isolated from circulations of lean subjects (L-EVs), EVs from obese subjects (O-EVs) inhibited β cell proliferation while did not affect its apoptosis. Moreover, the O-EVs induced β cell inflammation via activating the NF-kB and increasing the gene expression of chemokine CCL-2. By Quantitative Proteomic Analysis, we further explored that 29 proteins were differentially regulated in O-EVs compared to L-EVs. Among them, the Rapamycin-insensitive companion of mTOR (Rictor) and the Omentin-1 were downregulated by 65% (P<0.01) and by 27% (P=0.03) respectively. The existences and downregulations of both the total and phosphorylated forms of the Rictor, as well as the omentin-1, were verified by Western blot and ELISA (total Rictor: 0.21±0.04 vs. 0.15±0.05, P<0.01; phosphorylated Rictor: 0.33±0.09 vs. 0.25±0.08, P=0.02; Omentin-1: 33.5±5.2 vs.16.3±2.5, P<0.01). Both the phosphorylated Rictor and the Omentin-1 in EVs correlated negatively with the visceral fat mass, the HOMA insulin resistance index, and the fasting insulin secretion. Additionally, the Omentin-1 correlated positively with the DI and the ISSI-2. Thus, circulating EVs from simple obese humans inhibited β cell proliferation through increasing cellular inflammation. This effect may result from the changed protein cargos of EVs during obesity. The two newly identified exosomal proteins may be new therapeutic targets for improvingβcell function. Disclosure X. Xie: None. Q. Ge: None. R. Huang: None. X. Xiao: None. X. Li: None.