Comparative anti-inflammatory and lipid-normalizing effects of metformin and omega-3 fatty acids through modulation of transcription factors in diabetic rats

Abstract

Background: Emerging evidence suggests beneficial effects of omega-3 fatty acids on diabetic complications. The present study compared the progressive effects of metformin and flax/fish oil on lipid metabolism, inflammatory markers, and liver and renal function test markers in streptozotocin-nicotinamide-induced diabetic rats.

Methods: Streptozotocin-induced diabetic rats were randomized into control and four diabetic groups: streptozotocin (STZ), metformin (200 mg/kg body weight (b.w)/day (D)), flax and fish oil (500 mg/kg b.w/D).

Results: Metformin and flax and fish oil exhibited increased expression of transcription factor peroxisome proliferator-activated receptor γ while the treatment downregulated sterol regulatory element-binding protein 1 and nuclear factor kβ as compared to those of the STZ group. Apart from modulation of transcription factor expression, the expression of fatty acid synthase, long chain acyl CoA synthase, and malonyl-CoA-acyl carrier protein transacylase was lowered by flax/fish oil treatment. Serum cholesterol, triglycerides, and VLDL were also significantly reduced in the treatment groups as compared to those in the STZ group. Although pathological abnormalities were seen in the liver and kidneys of rats on metformin, no significant changes in liver/renal function markers were observed at day 15 and day 30 of the treatment groups. Flax/fish oil had protective effects toward pathological abnormalities in the liver and kidney. Flax/fish oil improved lipid profile and alkaline phosphatase at day 30 as compared to that at day 15.

Conclusions: The present study demonstrates potential beneficial effects of metformin and flax/fish oil intervention in improving serum lipid profile by regulating the expression of transcription factors and genes involved in lipid metabolism in diabetic rats. In addition, these interventions also lowered the expression of atherogenic cytokines. The protective effects of flax/fish oil are worth investigating in human subjects on metformin monotherapy.

Keywords: Fish oil; Flax oil; Metformin; Omega-3 fatty acids; Streptozotocin.

Fig. 1

Study design

Fig. 2

a Expression of genes involved in lipid metabolism and inflammation. Data are presented as mean ± SE. *p < 0.05, **p < 0.01 for comparison between the control and STZ group and ^# p < 0.05, ^## p < 0.01 for comparison between the STZ group and treatment groups. GAPDH glyceraldehyde-3-phosphate dehydrogenase, PPARγ peroxisome proliferator-activated receptors γ, SREBP1 sterol regulatory element-binding protein, NFκβ nuclear factor kappa β, FAS fatty acid synthase, ACSL long chain acyl CoA synthetases, MCAT malonyl-CoA-acyl carrier protein transacylase, TNFα tumor necrosis factor α. b Diagrammatic representation of the possible mechanism of metformin and flax and fish oil on the lipid metabolism and inflammatory cytokines. PPARγ peroxisome proliferator-activated receptors γ, SREBP sterol regulatory element-binding protein, NFκβ nuclear factor kappa β, FAS fatty acid synthase, ACSL long chain acyl CoA synthetases, MCAT malonyl-CoA-acyl carrier protein transacylase, TNFα tumor necrosis factor α, up arrow up-regulation, down arrow down-regulation

Fig. 3

a Liver histology of control, STZ-induced diabetic, metformin-treated, and flax/fish oil-treated animals. Hematoxylin and eosin-stained cross sections of paraffin-embedded liver tissues of rats from the control and experimental groups (×40). Liver from the control group shows normal architecture. Sections of the liver from the STZ-induced diabetic group show severe destruction of hepatic cells, pathological calcification, hemorrhages, and mild mononuclear cells in the portal tracts. Liver from the metformin-treated group shows some destructive changes and congestion of some central vein. The liver histology of animals treated with flax oil and fish oil shows completely normal liver architecture without any anatomically detectable anomalies. b Kidney histology of healthy, STZ-induced diabetic, metformin-treated, and flax/fish oil-treated animals. Hematoxylin and eosin-stained cross sections of paraffin-embedded kidney tissues of rats from the control and experimental groups (×40). Kidney from the control group shows normal kidney architecture. Sections of kidney from the STZ diabetic group showed conjunction of glomerular capillary and blood vesicle. Some tubular epithelial cells show vacuolation and cloudy changes. Kidney from the metformin-treated group shows vacuolation of some tubular epithelial cells and conjunction of glomerular capillary. The liver histology of animals treated with flax and fish oil shows no considerable changes and show normal architecture