Linoleic and alpha linolenic acids ameliorate streptozotocin induced diabetes in mice

Streptozotocin (STZ) induced diabetes in mice progresses with decreased desaturase
activities and alterations in the metabolism of essential fatty acids (EFA). Objectives Based on our previous studies with soybean oil that ameliorated the STZ damage in mice, we tested here the accountability of its main EFA components, i.e. linoleic acid (LA) and alpha linolenic acid (ALA), in the prevention of pancreas damage and D6 desaturase decrease. Materials and methods Seven days after injection with STZ and EFA gavage, ICR mice were sacrificed. Plasma glucose and insulin levels, pancreas histology and liver fatty acid desaturases were analysed. Results: EFA reduced pancreas damage, insulin and glucose plasma levels and restored D6 desaturase activity and mRNA expression levels. Discussion By reducing pancreas damage, EFA ameliorated insulin levels, D6 desaturase and fatty acid metabolism. LA further enhanced Fads2 promoter activity. Conclusion EFA ameliorate STZ induced diabetes in mice. (Authors abstract)

The role of nutritional fatty acids in the amelioration of type 1 diabetes remains an important but, nevertheless, controversial subject of research. The involvement of essential fatty acids (EFA) in type 1 diabetes was suggested by the observation that alloxan induced diabetes accelerated and intensified in symptoms due to EFA deficiency. No definitive recommendations exist regarding the use of EFA, namely linoleic (LA) or alpha linolenic acids (ALA), for the prevention or improvement of type 1 diabetes in humans. It is known, however, that EFA, as well as other fatty acids, stimulate insulin secretion through GPR 40.  The aim of this study was to test the ability of LA and ALA to ameliorate pancreas damage and to repair the low D6 desaturase in STZ induced type 1 diabetes in mice. Taken together, the results presented here show that EFA, both LA and ALA, were able to partially reduce the STZ induced pancreas necrosis and to increase insulin plasma levels. Basal plasma glucose levels were normalized by the administration of LA, ALA and LA ALA. STZ is a known pancreas tissue toxin transported into beta islet cells via the glucose transporter Glut2. STZ causes DNA damage as well as metabolic defects in the insulin-secreting cells. In our model, in pancreata of animals receiving EFA treatment a mild increase in the number of beta cells was observed, in particular for ALA and LA ALA, than in those of animals receiving only STZ, although less than in Control animals.  Similarly, a more significant increase in the number of islets was observed in animals receiving ALA and LA ALA, compared with STZ alone. The surviving islets seemed to be functional and thus glucose levels and plasma insulin were normalized. EFA incorporation into membranes may influence the endocytosis process involved in the degradation of insulin, both in liver and kidney, in such a way that higher insulin plasma levels would be maintained in EFA treated animals compared with STZ alone.  These results indicate that D6 desaturase activity was enhanced by the exogenously provided EFA, in comparison to STZ treated mice. Moreover, D5 desaturase activity seems to have also been enhanced.
Fads2 mRNA expression levels were 50 per cent lower in STZ injected animals compared with controls. LA treatment alone, or in combination with ALA, restored and even significantly increased the low mRNA expression levels in diabetic mouse compared to Control. ALA mildly increased by 50 per cent  the values in STZ. EFA supplementation could affect pancreatic cell membranes’ phospholipid fatty acid composition as well as GPR 40 receptor activity and insulin secretion. For the pancreatic beta cell, while the presence of some fatty acids is essential for glucose stimulated insulin secretion, they have enormous capacity to amplify glucose stimulated insulin secretion.  It has been proposed that fatty acids do this via three interdependent processes, assigned to a model of beta cell lipid signalling.  This is one of the first report that gavage of LA or ALA to mice reversed the STZ induced diabetic phenotype and restored D6 desaturase activity and fatty acid metabolism. EFA supplementation improved insulin and glucose levels in plasma. Coincidentally, fatty acid metabolism was improved.  Low desaturase activities and metabolic products, as well as mRNA expression levels were normalized. Furthermore, LA enhanced Fads2 promoter activity. The differential mechanisms of action of EFA in type 1 diabetes mellitus, as well as the correlation between fatty acid metabolic homeostasis and the immunologic and inflammatory pancreas alterations should be further addressed in animal studies, together with molecular genetics and cell culture models. The outcomes may contribute to the understanding of EFA role in the dietary prevention or amelioration of diabetes with potential application in nutritional guidelines for humans. (Editors comments)