morin and Hyperglycemia

Hyperglycemia associated ER stress has been found as a critical contributor in the pathogenesis of type 2 diabetes mellitus. However, reports regarding molecular mechanisms involved are limited. This study was aimed to identify the role of ER stress in regulating hepatic glucose metabolism and its link with oxidative stress. Further, this study explores the novel role of Morin, a flavonol, in modulating ER stress in STZ/nicotinamide induced type 2 diabetic male Wistar rats. Results demonstrate that hyperglycemia induced ER stress in rats and significantly lowered the expression of glucose transporter proteins resulting in impaired glucose metabolism during diabetes. Morin was found to downregulate PERK-eIF2α-ATF4 pathway by interacting with PERK protein as confirmed through pull-down assay. Additionally, Morin maintained the reducing environment in ER and enhanced PDI activity compared to diabetic rats. Morin prevented cell death by suppressing the expression of PERK dependent pro-apoptotic proteins including ATF4 and CHOP. Findings from this study affirm the role of ER stress in hyperglycemia induced gluco-metabolic aberrations and liver injury as confirmed by ISRIB, a standard chemical ER stress inhibitor. Notably, Morin promoted deactivation of UPR sensors and upregulated PDI activity endorsing its anti-ER stress potential which may allow the development of new therapeutic avenues to target hyperglycemic hepatotoxicity.

Topics: Activating Transcription Factor 4; Animals; Antioxidants; Apoptosis; Chronic Disease; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Down-Regulation; eIF-2 Kinase; Endoplasmic Reticulum Stress; Flavonoids; Hyperglycemia; Liver Diseases; Male; Rats; Rats, Wistar; Streptozocin

Morin is a natural bioflavonoid that exhibits antioxidant and anti-inflammatory properties. The present study was designed to evaluate the effect of morin on insulin resistance, oxidative stress, and inflammation in a high-fat-diet (HFD)-induced obese mice. Obesity was induced in ICR mice by feeding a HFD (60 % kcal from fat) for 12 weeks. After the first 6 weeks, obese mice were treated with morin (50 or 100 mg/kg/day) once daily for further 6 weeks. Blood glucose, lipid profile, insulin, leptin, adiponectin, and markers of oxidative stress and inflammation were then measured. Liver was excised, subjected to histopathology, glycogen determination, and gene and protein expression analysis. Morin administration reduced blood glucose, serum insulin, leptin, malondialdehyde, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) levels and increased serum adiponectin levels. Moreover, there was a reduction in serum lipid and liver triglyceride levels. Liver histology indicated that morin limited accumulation of lipid droplets. Interestingly, morin reduced expression of hepatic sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) and up-regulated hepatic carnitine palmitoyltransferase 1a (CPT1a) expression. Morin also stimulated glycogen storage and suppressed phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) protein expression. Furthermore, hepatic superoxide dismutase (SOD) and catalase (CAT) expression were increased after morin treatment. These findings indicate that morin has a positive effect in the HFD-induced obesity condition by suppressing lipogenesis, gluconeogenesis, inflammation, and oxidative stress activities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Antioxidants; Biomarkers; Diet, High-Fat; Dose-Response Relationship, Drug; Flavonoids; Gene Expression Regulation; Gluconeogenesis; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Insulin Resistance; Lipid Peroxidation; Lipogenesis; Liver; Male; Mice, Inbred ICR; Obesity; Oxidative Stress; Weight Gain

The present study was aimed to evaluate the effect of morin on blood glucose, insulin level, hepatic glucose regulating enzyme activities and glycogen level in experimental diabetes. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg b.w.). Five days after STZ injection, diabetic rats received morin (25 and 50 mg/kg b.w.) orally for 30 days. Glibenclamide was used as reference drug. Morin treatment significantly reduced the blood glucose and improved the serum insulin levels. Further, a dose-dependent reduction in glucose-6-phosphatase and fructose-1,6-bisphosphatase was observed along with the increase in liver hexokinase and glucose-6-phosphate dehydrogenase activities. Morin supplement were found to be effective in preserving the normal histological appearance of pancreatic islets as well as to preserve insulin-positive β-cells in STZ-rats. Therefore, these findings suggest that morin displays beneficial effects in the treatment of diabetes, mediated through the regulation of carbohydrate metabolic enzyme activities.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Flavonoids; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liver; Male; Pancreas; Rats; Rats, Wistar