Abstract
Insulin secretory granules are β-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 β-cells and induction of apoptosis. It has also been described as modifying gene and protein expression in β-cells. Therefore, we hypothesized that a modulation of insulin secretory granule protein expression induced by chronic hyperglycemia may partially explain β-cell dysfunction. To identify the potential early molecular mechanisms underlying β-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 β-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 β-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 β-cell mediator in the AKT/GSK3 apoptotic pathway. In conclusion, the modification of specific β-cell pathways such as apoptosis and oxidative stress may partially explain the impairment of insulin secretion and β-cell failure, observed after prolonged exposure to high glucose concentrations.
Highlights
From the ‡Biomedical Proteomics Research Group, Department of Human Protein Sciences, University Medical Center, Geneva 1211, Switzerland and the **Department of Cell Physiology and Metabolism, University Medical Center, Geneva 1211, Switzerland
The present study demonstrates that its expression is modulated by chronic high glucose concentrations in insulin-secreting cells and that Neuronal pentraxin 1 (NP1) in INS-1E cells is linked to the AKT/GSK3 pathway
Insulin secretory granules (ISGs) Proteome—Because -cell failure is one of the major characteristics of type 2 diabetes mainly through a defect of insulin secretion, we focused our work on ISGs and analyzed their proteome changes under chronic high glucose exposure
Summary
Type 2 diabetes (T2D) is a multifactorial disease that results from insulin resistance of the target tissues (adipose tissue, skeletal muscle, and liver) and decreased insulin secretion by the pancreatic -cells. It is, still unclear which event is the primary defect in the development of T2D [1]. Insulin secretory granules (ISGs) are organelles specialized in insulin processing and storage in the pancreatic -cells. Their content is released by exocytosis in response to an acute increase of blood glucose, other nutrients, as well as hormonal and neuronal stimulation. The expression of -cell exocytotic proteins is modified after chronic hyperglycemia in vitro [3] and in isolated islets [22, 23] and from diabetic organ donors [24], the latter suggesting the consequence of altered gene expression after hyperglycemia in vivo
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