High Pancreatic n-3 Fatty Acids Prevent STZ-Induced Diabetes in Fat-1 Mice: Inflammatory Pathway Inhibition

Abstract

OBJECTIVEBecause of confounding factors, the effects of dietary n-3 polyunsaturated fatty acids (PUFA) on type 1 diabetes remain to be clarified. We therefore evaluated whether fat-1 transgenic mice, a well-controlled experimental model endogenously synthesizing n-3 PUFA, were protected against streptozotocin (STZ)-induced diabetes. We then aimed to elucidate the in vivo response at the pancreatic level.RESEARCH DESIGN AND METHODSβ-Cell destruction was produced by multiple low-doses STZ (MLD-STZ). Blood glucose level, plasma insulin level, and plasma lipid analysis were then performed. Pancreatic mRNA expression of cytokines, the monocyte chemoattractant protein, and GLUT2 were evaluated as well as pancreas nuclear factor (NF)-κB p65 and inhibitor of κB (IκB) protein expression. Insulin and cleaved caspase-3 immunostaining and lipidomic analysis were performed in the pancreas.RESULTSSTZ-induced fat-1 mice did not develop hyperglycemia compared with wild-type mice, and β-cell destruction was prevented as evidenced by lack of histological pancreatic damage or reduced insulin level. The prevention of β-cell destruction was associated with no proinflammatory cytokine induction (tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase) in the pancreas, a decreased NF-κB, and increased IκB pancreatic protein expression. In the fat-1–treated mice, proinflammatory arachidonic-derived mediators as prostaglandin E2 and 12-hydroxyeicosatetraenoic acid were decreased and the anti-inflammatory lipoxin A4 was detected. Moreover, the 18-hydroxyeicosapentaenoic acid, precursor of the anti-inflammatory resolvin E1, was highly increased.CONCLUSIONSCollectively, these findings indicate that fat-1 mice were protected against MLD-STZ–induced diabetes and pointed out for the first time in vivo the beneficial effects of n-3 PUFA at the pancreatic level, on each step of the development of the pathology—inflammation, β-cell damage—through cytokine response and lipid mediator production.

Early Low-Fat Diet Enriched With Linolenic Acid Reduces Liver Endocannabinoid Tone and Improves Late Glycemic Control After a High-Fat Diet Challenge in Mice

“…After 10 weeks, half of the population of each series was used for analyses, and the rest was challenged with an HFD (30% w/w total lipids from lard) for an additional period of 10 weeks. C57BL/6J transgenic fat-1 mice were generated and housed as described previously (29).…”

Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic β-Cells

“…Results were normalized to 18 S ribosomal RNA as an endogenous reference gene, and the relative amount of each mRNA was calculated by the comparative Ct (threshold cycle) method. iNOS mRNA content in the islets was evaluated by RT-PCR, as described previously (46,47), using specific primers for mouse and human iNOS (mouse, 5Ј-ACAGCCTCAGAGT-CCTTCAT-3Ј and 5ЈTTGTCACCACCAGCAGTAGT-3Ј; human, 5Ј-CAGTACGTTTGGCAATGGAGACTGC-3Ј and 5Ј-GGTCACATTGGAGGTGTAGA GCTTG-3Ј). RT-PCR products were quantified using a densitometer and image analyzer (Bio-Rad) (46).…”

n-3 polyunsaturated fatty acids and insulin secretion

“…Fat-1 mice treated with the b-cell toxin streptozotocin are protected from developing hyperglycemia, b-cell destruction, and hypoinsulinemia (Bellenger et al 2011). Conversely, provision of an EPA/DHA-enriched diet for 7 months did not influence plasma glucose, insulin, or C-peptide during an oral glucose tolerance test in pigs (Castellano et al 2010).…”