In T2D, chronic hyperglycemia causes beta cell dysfunction and failure. To systematically characterize the molecular alterations underlying this detrimental process, quantitative proteomic studies were carried out to compare global protein changes in INS-1 832/13 cells in normal (11mM) or high glucose (HG, 25mM) for 48 hours. In parallel, untargeted lipidomic studies were carried out to compare global lipid changes. In four experiments, a total of 4088 proteins were quantified, among which 184 proteins were significantly altered upon HG treatment. While we have confirmed some known hallmark changes (e.g., PDX1 and insulin) in beta cell glucotoxicity, most of these protein changes have not been reported previously. These proteins involve in key biological processes such as cell cycle regulation, calcium homeostasis, insulin biogenesis, protein folding, and ER export. Consistent with the significantly increased triglycerides in the lipidomic study, fatty acid synthase and acetyl-CoA carboxylase, two key enzymes in fatty acid synthesis, were significantly upregulated. In addition, for the first time in beta cells, MIG12 was found highly upregulated (4.50±1.50, n=4) in HG treated cells. This change was confirmed by Western blotting in mouse and human islets. MIG12 was previously reported in the liver to induce ACC1 polymerization and enhance its enzymatic activity. However, its role in beta cell is unknown. Our preliminary results showed that MIG12 knockdown inhibited HG-induced lipid droplet formation in beta cells. Among other novel findings, ether lipids and its regulating enzymes were significantly altered. This lipid change was confirmed by thin layer chromatography, and the enzyme change confirmed by Western blotting in beta cells and immunofluorescence in db islets. Functional consequences of several key protein changes are being investigated. Taken together, our study provides new targets for mechanistic studies of beta cell glucotoxicity.


J. Woods: None. B. Pan: None. X. Chen: None.


National Institutes of Health (R01DK110314)

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