Differential impact of acute and chronic lipotoxicity on gene expression in INS-1 cells.

Fatty acids induce abnormal insulin secretion, so-called lipotoxicity, which may develop over a period that can span from a few hours to several years. The relationship between insulin secretion patterns and the pace of lipotoxicity development is, however, sparse. In this study acute lipotoxicity was defined as the functional changes in clonal pancreatic beta cells, INS-1 cells, cultured with 400 and 1,000 micromol/L palmitate for 2 days. Chronic lipotoxicity was demonstrated by exposure of INS-1 cells to 50 and 200 micromol/L palmitate for up to 10 weeks. During acute lipotoxicity, basal insulin secretion (BIS), as well as glucose- and fatty acid-stimulated insulin secretion, were reduced after 1,000 micromol/L palmitate exposure. Concomitantly, total cell protein and (3)H-thymidine incorporation were significantly reduced. In chronic lipotoxicity, BIS increased, whereas a decrease in insulin responsiveness to glucose and fatty acid (defined as fold increase in insulin compared with BIS) was observed after 5 weeks in cells cultured with 200 micromol/L palmitate. Carnitine palmitoyltransferase I gene expression was induced by palmitate upon acute, as well as chronic, exposure. Genes involved in the insulin signal pathway may play an important role in the pathogenesis of lipotoxicity in beta cells. Thus, insulin receptor substrate-1 and 2 gene expressions were downregulated during acute lipotoxicity, while insulin receptor gene expression was suppressed in chronic lipotoxicity. In conclusion, insulin secretion and gene expression in INS-1 cells depends on palminate exposure time and concentration. Copyright 2002 by W.B. Saunders Company