Abstract

Objective: To evaluate the direct impact of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) on the functions and viability of pancreatic β-cells.

Research design and methods: We developed an mfat-1 transgenic mouse model in which endogenous production of ω-3 PUFAs was achieved through overexpressing a C. elegans ω-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 contain much higher levels of ω-3 PUFAs, lower levels of ω-6 PUFAs, than those of the wild type. Insulin secretion stimulated by glucose-, amino acids, and GLP-1 was significantly elevated in the transgenic islets. When challenged with TNF-α, IL-1β, and IFN-γ, 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 ω-3- and ω-6 PUFAs, and recapitulated the results in the transgenic islets. The expression of mfat-1 led to decreased production of PGE₂, which in turn contributed to the elevation of insulin secretion. We further found that cytokine-induced activation of NF-κB and ERK_1/2 was significantly attenuated, and that the expression of PDX-1, glucokinase, and insulin-1 was increased as a result of ω-3 PUFA production.

Conclusion: Stable cellular production of ω-3 PUFAs via mfat-1 can enhance insulin secretion and confers strong resistance to cytokine-induced β-cell destruction. The utility of mfat-1 gene in deterring type-1 diabetes should be further explored in vivo.