Cellular production of n-3 PUFAs and reduction of n-6--to--n-3 ratios in the pancreatic [beta]-cells and islets enhance insulin secretion and confer protection against cytokine-induced cell death

OBJECTIVE--To evaluate the direct impact of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the functions and viability of pancreatic [beta]-cells. RESEARCH DESIGN AND METHODS--We developed an mfat-1 transgenic mouse model in which endogenous production of n-3 PUFAs was achieved through overexpressing a C. elegans n-3 fatty acid desaturase gene, mfat-1. The islets and INS-1 cells expressing mfat-1 were analyzed for insulin secretion and viability in response to cytokine treatment. RESULTS--The transgenic islets contained much higher levels of n-3 PUFAs and lower levels of n-6 PUFAs than the wild type. Insulin secretion stimulated by glucose, amino acids, and glucagon-like peptide-1 (GLP-1) was significantly elevated in the transgenic islets. When challenged with tumor necrosis factor-[alpha] (TNF-[alpha]), interleukin-[beta] (IL-1[beta]), and [gamma]-interferon (IFN-[gamma]), the transgenic islets completely resisted cytokine-induced cell death. Adenoviral transduction of mfat-1 gene in wild-type islets and in INS-1 cells led to acute changes in the cellular levels of n-3- and n-6 PUFAs and recapitulated the results in the transgenic islets. The expression of mfat-1 led to decreased production of prostaglandin [E.sub.2] ([PGE.sub.2]), which in turn contributed to the elevation of insulin secretion. We further found that cytokine-induced activation of NF-[kappa]B and extracellular signal-related kinase 1/2 ([ERK.sub.1/2]) was significantly attenuated and that the expression of pancreatic duodenal hemeobox-1 (PDX-1), glucokinase, and insulin-1 was increased as a result of n-3 PUFA production. CONCLUSIONS--Stable cellular production of n-3 PUFAs via mfat-1 can enhance insulin secretion and confers strong resistance to cytokine-induced [beta]-cell destruction. The utility of mfat-1 gene in deterring type 1 diabetes should be further explored in vivo. Diabetes 59:471-478, 2010