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.


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-1beta (IL-1beta), 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(2) (PGE(2)), which in turn contributed to the elevation of insulin secretion. We further found that cytokine-induced activation of NF-kappaB and extracellular signal-related kinase 1/2 (ERK(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.
Wei
Dong
D
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Li
Jie
J
Shen
Miaoda
M
Jia
Wei
W
Chen
Nuoqi
N
Chen
Tao
T
Su
Dongming
D
Tian
Haoming
H
Zheng
Shusen
S
Dai
Yifan
Y
Zhao
Allan
A
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers; D015342:DNA Probes; D018076:DNA, Complementary / Q000235:genetics; D044943:Fatty Acid Desaturases / Q000235:genetics; D015525:Fatty Acids, Omega-3 / Q000096:biosynthesis / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D005822:Genetic Vectors; D005973:Glutamine / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007930:Leucine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D016207:Cytokines; D017931:DNA Primers; D015342:DNA Probes; D018076:DNA, Complementary; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D007328:Insulin; D016328:NF-kappa B; C466741:fat-1 protein, C elegans; D005973:Glutamine; D044943:Fatty Acid Desaturases; D048052:Mitogen-Activated Protein Kinase 3; D007930:Leucine