Docosahexaenoic acid is comparable to vildagliptin in improving hyperglycemia and pancreatic insulin signaling of diabetic rats via SIRT1/Akt/PI3K pathway

Abstract

Sirtuin1 (SIRT1) is a histone deacetylase that plays a critical role in insulin sensitivity. Vildagliptin (Vilda) is dipeptidyl peptidase-4 inhibitor approved as oral antidiabetic agent. Docosahexaenoic (DHA) could attenuate hyperglycemia and insulin resistance. The current study was conducted to evaluate the effect of DHA versus Vilda on insulin resistance and hyperglycemia in type 2 diabetes (T2D) rat model via SIRT1/Akt/PI3K. Eighty male Wistar rats were divided into five groups: normal control, diabetes control (the diabetic rats fed high carbohydrate-high fat diet for four weeks, followed by a single intraperitoneal injection of 35 mg/kg streptozotocin, Vilda + diabetic (diabetic rats received 6 mg/kg vildagliptin), DHA + diabetic (diabetic rats received 300 mg/kg DHA), and DHA only group (normal non-diabetic rats received 300 mg/kg DHA). All treatments were given orally for 4 weeks. Each of Vilda and DHA significantly (p < 0.001) decreased blood glucose (131.40. ± 6.10 mg/L and 137.10 ± 7.37, respectively vs. 449.9 ±46.28 1.84 mg/L), increased insulin levels (7.77 ±0.26 µIU/mL and 7.56 ± 0.42, respectively vs. 3.86 ± 0.37 ), decreased HOMA-IR (2.52 ± 0.09 and 2.55 ± 0.091, respectively vs. 4.26 ± 0.34), decreased pancreatic malondialdehyde (MDA) (3.84 ± 0.29 nmol/mg protein and 3.18 ± 0.21, respectively vs. 6.65 ± 0.71), increased gluthathione (2.18±0.11μmol/mg protein and 2.51±0.09, respectively vs. 1.00±0.29), catalase (104.50±6.74 nmol/mg protein and 122.30±6.20, respectively vs. 70.30±13.98), increased glutathione peroxidase activity (GPx) (0.76±0.19 U/mg protein and 0.99±0.16, respectively vs. 0.47± 0.14) and increased superoxide dismutase activity (SOD) (6.43±1.15 U/mg protein and 8.13±1.16, respectively vs. 3.98±1.4) compared with diabetic group. DHA & Vilda significantly (p < 0.001) improved lipid profile (total cholesterol, triglycerides, LDL-C & HDL-C). DHA was superior to Vilda in increasing levels of glutathione (2.51 ± 0.09 µmol/mg protein vs. 2.18 ± 0.11), catalase activity (122.30 ± 6.20 nmol/mg protein vs. 104.50 ± 6.74 ), SOD activity (8.13±1.16 U/mg vs. 6.43±1.15) and GPx activity (0.99±0.16 U/mg protein vs. 0.76±0.19). Moreover, both Vilda and DHA significantly increase gene expression of SIRT1, Akt, and PI3K and markedly restored normal pancreatic tissue architecture compared with diabetic control group. DHA was comparable to Vilda as insulinotropic and anti-hyperglycemic agent in T2D rats via activation of SIRT1/Akt/PI3K pathway & reducing oxidative stress.