Objectives Insulin resistance causes vascular complications of type 2 diabetes mellitus. Berberine (BBR), an isoquinoline alkaloid, widely used in Chinese herbs, has been demonstrated to lower blood glucose and regulate lipid metabolism disorders, but whether BBR can enhance insulin induced vascular function and the underlying mechanism remains unclear. We sought to study the effects of berberine on diabetes mesenteric artery endothelial dysfunction and the mechanisms.
Methods To develop type 2 diabetic models, male Sprague-Dawley rats were injected low dose streptozotocin and fed with a high-fat diet for 12 weeks. Rats were randomised to receiving saline or BBR treatments (200 mg/kg/d, orally gavaged) in the last 4 weeks. Mesenteric artery (100-150 mm) rings’ response was determined by isometric force measurement. Human mesenteric artery endothelial cell line Ealy 926 were cultured in high glucose (HG, 25 mM) DMEM and added palmitate (HF, 500 nM) additionally to induce the damage of insulin signalling pathway.
Results BBR (200 mg/kg/d) treatment dramatically restored the mesenteric arteries endothelium-dependent vasodilation (71.09 ± 12.77% vs. 19.10 ± 8.56% to 10-5 mol/L ACh, n = 12, p < 0.01) compared to diabetic rats. And BBR treatment improved the insulin mediated vasodilatation of mesentery artery (38.67 ± 4.46%% vs 7.54 ± 2.90%, n = 12, p < 0.01) compared with the diabetic rats. Furthermore, combined with insulin 1 nM, BBR (5 mM) significantly ameliorated the impairment of vascular relaxation preconstriced with PE in diabetic rats. Moreover, the BBR induced insulin-mediated vasodilatation could blunt by wortmannin (Wm, 15/kg/d, I. P), a PI3K/Akt inhibitor. We found HG/HF decreased Ealy 926 viability, treatment of BBR or insulin could not improve Ealy 926 viability, but the co-treatment of BBR (50 mM) + insulin (1 nM) showed obvious cell viability enhancement (100.6 ± 6.35%% vs 61.36 ± 5.21%, n = 4, p < 0.01) compared with insulin (1 nM) group. More importantly, Ealy 926 exposured to HF/HG 24h caused the pronounced reduction of the phosphorylation level of Akt at Ser473 and eNOS at Ser1177. Exposure of the cells to BBR (50 mM) + insulin (1 nM) resulted in significant increase of phosphorylated IR, IRS-1, Akt and eNOS.
Conclusions It suggested that BBR enhances insulin sensitivity and the mesenteric artery endothelium cells dependent vasodilatation partly through activation of IR-Akt-eNOS in type 2 diabetic rats.