科研之友
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摘要
Insulin secretory granules are beta-cell vesicles dedicated to insulin processing, storage, and release. The secretion of insulin secretory granule content in response to an acute increase of glucose concentration is a highly regulated process allowing normal glycemic homeostasis. Type 2 diabetes is a metabolic disease characterized by chronic hyperglycemia. The consequent prolonged glucose exposure is known to exert deleterious effects on the function of various organs, notably impairment of insulin secretion by pancreatic beta-cells and induction of apoptosis. It has also been described as modifying gene and protein expression in beta-cells. Therefore, we hypothesized that a modulation of insulin secretory granule protein expression induced by chronic hyperglycemia may partially explain beta-cell dysfunction. To identify the potential early molecular mechanisms underlying beta-cell dysfunction during chronic hyperglycemia, we performed SILAC and mass spectrometry experiments to monitor changes in the insulin secretory granule proteome from INS-1E rat insulinoma beta-cells cultivated either with 11 or 30 mM of glucose for 24 h. Fourteen proteins were found to be differentially expressed between these two conditions, and several of these proteins were not described before to be present in beta-cells. Among them, neuronal pentraxin 1 was only described in neurons so far. Here we investigated its expression and intracellular localization in INS-1E cells. Furthermore, its overexpression in glucotoxic conditions was confirmed at the mRNA and protein levels. According to its role in hypoxia-ischemia-induced apoptosis described in neurons, this suggests that neuronal pentraxin 1 might be a new beta-cell mediator in the AKT/GSK3 apoptotic pathway. In conclusion, the modification of specific beta-cell pathways such as apoptosis and oxidative stress may partially explain the impairment of insulin secretion and beta-cell failure, observed after prolonged exposure to high glucose concentrations. Molecular & Cellular Proteomics 11: 10.1074/mcp.M112.018051, 244-254, 2012.
- 出版日期2012-8
