esculetin and Hyperglycemia

Esculetin (6, 7- dihydroxycoumarin) was found to be protective against hepatic and renal damage associated with Streptozotocin (STZ) induced type 1 diabetes, because of its radical scavenging property. However, there are no reports regarding its effect on vascular dysfunction under hyperinsulinemic and hyperglycemic conditions. Hence, the present study aimed to investigate the effect of esculetin on vascular dysfunction under these conditions. Non-genetic model of hyperinsulinemia and hyperglycemia were developed by high fat diet (HFD) feeding and HFD + Streptozotocin (STZ, 35 mg/kg, I.P) treatment in Wistar rats, respectively. Esculetin was administered at 50 and 100 mg/kg/day (P.O, 2 weeks) doses and biochemical, vascular reactivity and immunohistochemical experiments were performed to assess the effect of esculetin on vascular dysfunctions. Esculetin treatment significantly attenuates metabolic perturbations, alleviates insulin levels in hyperinsulinemic condition. Thoracic aorta of hyperinsulinemic and hyperglycemic rats showed hyper-responsiveness to Ang II mediated contraction and impaired acetylcholine mediated relaxation, and esculetin attenuates alterations in vascular reactivity to Ang II and acetylcholine challenges. In addition, immunohistochemical evaluations revealed that esculetin prevents increase in AT1R, AT2R, Keap1, TGF-β, and decrease in ACE2 expression in aorta of hyperinsulinemic and hyperglycemic rats.

Topics: Acetylcholine; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Antioxidants; Aorta; Blood Pressure; Diabetes Mellitus, Experimental; Hyperglycemia; Hyperinsulinism; Hypertension; Male; Peptidyl-Dipeptidase A; Rats, Wistar; Transforming Growth Factor beta; Umbelliferones

Diabetes mellitus is the most common serious metabolic disorder and it is considered to be one of the five leading causes of death in the world. Hyperglycemia-mediated oxidative stress plays a crucial role in diabetic complications. Hence, this study was undertaken to evaluate the protective effect of esculetin on the plasma glucose, insulin levels, tissue antioxidant defense system and lipid peroxidative status in streptozotocin-induced diabetic rats. Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. Extent of oxidative stress was assessed by the elevation in the levels of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD); reduction in the enzymic antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST); nonenzymic antioxidants Vitamin C, E and reduced glutathione (GSH) were observed in the liver and kidney tissues of diabetic control rats as compared to control rats. Oral supplementation of esculetin to diabetic rats for 45 days significantly brought back lipid peroxidation markers, enzymic and nonenzymic antioxidants to near normalcy. Moreover, the histological observations evidenced that esculetin effectively rescues the hepatocytes and kidney from hyperglycemia mediated oxidative damage without affecting its cellular function and structural integrity. These findings suggest that esculetin (40 mg/kg BW) treatment exerts a protective effect in diabetes by attenuating hyperglycemia-mediated oxidative stress and antioxidant competence in hepatic and renal tissues. Further, detailed studies are in progress to elucidate the molecular mechanism by which esculetin elicits its modulatory effects in insulin signaling pathway.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Hyperglycemia; Insulin; Kidney; Lipid Peroxidation; Liver; Male; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Umbelliferones; Vitamin E

Bovine aortic endothelial and smooth-muscle cells down-regulate the rate of glucose transport in the face of hyperglycaemia, thus providing protection against deleterious effects of increased intracellular glucose levels. When exposed to high glucose concentrations these cells reduced the mRNA and protein content of their typical glucose transporter, GLUT-1, as well as its plasma-membrane abundance. Inhibition of the lipoxygenase (LO) pathway, and particularly 12-LO, reversed this glucose-induced down-regulatory process and restored the rate of hexose transport to the level seen in vascular cells exposed to normal glucose levels. This reversal was accompanied by increased levels of GLUT-1 mRNA and protein, as well as of its plasma-membrane content. Exposure of the vascular cells to elevated glucose concentrations increased by 2-3-fold the levels of cell-associated and secreted 12-hydroxyeicosatetraenoic acid (12-HETE), the product of 12-LO. Inhibition of 15- and 5-LO, cyclo-oxygenases 1 and 2, and eicosanoid-producing cytochrome P450 did not modify the hexose-transport system in vascular cells. These results suggest a role for HETEs in the autoregulation of hexose transport in vascular cells. 8-Iso prostaglandin F(2alpha), a non-enzymic oxidation product of arachidonic acid, had no effect on the hexose-transport system in vascular cells exposed to hyperglycaemic conditions. Taken together, these findings show that hyperglycaemia increases the production rate of 12-HETE, which in turn mediates the down-regulation of GLUT-1 expression and the glucose-transport system in vascular endothelial and smooth-muscle cells.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Antioxidants; Biological Transport; Cattle; Cell Membrane; Cells, Cultured; Endothelium, Vascular; Gene Expression Regulation; Glucose; Glucose Transporter Type 1; Hyperglycemia; Kinetics; Monosaccharide Transport Proteins; Muscle, Smooth, Vascular; Umbelliferones

Topics: Animals; Arachidonic Acid; Arteriosclerosis; Biological Transport, Active; Cattle; Cell Division; Cells, Cultured; Cyclooxygenase Inhibitors; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Endothelium, Vascular; Glucose; Humans; Hyperglycemia; Lipoxygenase; Lipoxygenase Inhibitors; Muscle, Smooth, Vascular; Umbelliferones