Arsenite reduces insulin secretion in rat pancreatic β-cells by decreasing the calcium-dependent calpain-10 proteolysis of SNAP-25

• Published in: Toxicology and applied pharmacology 2008-09, Vol.231 (3), p.291-299
• Main Authors: Díaz-Villaseñor, Andrea, Burns, Anna L., Salazar, Ana María, Sordo, Monserrat, Hiriart, Marcia, Cebrián, Mariano E., Ostrosky-Wegman, Patricia
• Format: Article
• Language: English
• Subjects: Animals; Arsenic; Arsenites - pharmacology; Biological and medical sciences; Calcium; Calcium - metabolism; Calpain - metabolism; Calpains; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Medical sciences; Metals and various inorganic compounds; Peptide Hydrolases - metabolism; Rats; SNAP-25; Synaptosomal-Associated Protein 25 - metabolism; Toxicology; Tumors; Type 2 diabetes
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2008.05.018

An increase in the prevalence of type 2 diabetes has been consistently observed among residents of high arsenic exposure areas. We have previously shown that in rat pancreatic β-cells, low arsenite doses impair the secretion of insulin without altering its synthesis. To further study the mechanism by which arsenite reduces insulin secretion, we evaluated the effects of arsenite on the calcium-calpain pathway that triggers insulin exocytosis in RINm5F cells. Cell cycle and proliferation analysis were also performed to complement the characterization. Free [Ca 2+] i oscillations needed for glucose-stimulated insulin secretion were abated in the presence of subchronic low arsenite doses (0.5–2 µM). The global activity of calpains increased with 2 µM arsenite. However, during the secretion of insulin stimulated with glucose (15.6 mM), 1 µM arsenite decreased the activity of calpain-10, measured as SNAP-25 proteolysis. Both proteins are needed to fuse insulin granules with the membrane to produce insulin exocytosis. Arsenite also induced a slowdown in the β cell line proliferation in a dose-dependent manner, reflected by a reduction of dividing cells and in their arrest in G2/M. Data obtained showed that one of the mechanisms by which arsenite impairs insulin secretion is by decreasing the oscillations of free [Ca 2+] i, thus reducing calcium-dependent calpain-10 partial proteolysis of SNAP-25. The effects in cell division and proliferation observed with arsenite exposure can be an indirect consequence of the decrease in insulin secretion.