2110-P: Correlation between Ex Vivo Islet Proteomic Analysis and In Vivo Secretory Function in Humans

Insulin resistance and β-cell dysfunction are the main actors in the pathogenesis of type 2 diabetes mellitus, causing both quantitative and qualitative loss of insulin secretion and therefore hyperglycemia. The molecular mechanisms underlying progressive β-cell dysfunction, however, are still unknown. In order to correlate changes in the insular proteome to different metabolic conditions in vivo, a mass spectrometry analysis was performed on human islets, extracted by Laser Capture Microdissection, from surgical samples of 14 subjects who underwent duodeno-cephalopancreasectomy, and previously studied through OGTT and mixed meal test. The subjects were classified based on glucose tolerance into normal (n: 7 NGT), intolerant (n: 5 IGT) and diabetic (n: 2 DM2). A first quantitative analysis showed about 150 proteins differently expressed in the 3 groups. Among these, a protein, SEL1L, which regulates the differentiation of pancreatic precursors in the endocrine line was significantly increased in IGT rather than DM2 and NGT subjects and was inversely correlated with β-cell glucose sensitivity (r = -0.81, p = 0.01). The TCPD protein, involved in the folding and transport of neosynthesized proteins, which progressively decreases from NGT to DM2, was inversely correlated with the AUC of glycemia during OGTT (r = 0.5, p = 0.04). Finally, the expression of IQAG1 which was significantly reduced in DM2 compared to the other groups, and implicated in GLP-1 induced insulin production was inversely correlated with insulin resistance evaluated using the HOMA-IR index (r = -0.70, p = 0.004). The results suggest that both insulin resistance and/or β-cell dysfunction in vivo are closely linked to the intrainsular proteome in diabetic subjects.