trans-sodium-crocetinate and Insulin-Resistance

The amelioration of insulin resistance by treatment with crocetin is closely related to the hypolipidaemic effect. The present study is designed to clarify the insulin-sensitizing mechanism of crocetin by elucidating the mechanism of regulation of lipid metabolism by crocetin.. Rats given a high-fat diet were treated with crocetin for 6 weeks before hyperinsulinaemic-euglycaemic clamp. 14C-palmitate was used as tracer to track the fate of non-esterified fatty acids or as substrate to measure beta-oxidation rate. Triglyceride clearance in plasma and lipoprotein lipase activity in tissues were tested. Content of lipids in plasma and tissues was determined. Real-time PCR was used to assay the level of mRNA from genes involved in non-esterified fatty acid and triglyceride uptake and oxidation.. Crocetin prevented high-fat-diet induced insulin resistance (increased clamp glucose infusion rate), raised hepatic non-esterified fatty acid uptake and oxidation, accelerated triglyceride clearance in plasma, enhanced lipoprotein lipase activity in liver, and reduced the accumulation of detrimental lipids (DAG and long-chain acyl CoA) in liver and muscle. Genes involved in hepatic lipid metabolism which are regulated by peroxisome proliferator-activated receptor-alpha, were modulated to accelerate lipid uptake and oxidation.. Through regulating genes involved in lipid metabolism, crocetin accelerated hepatic uptake and oxidation of non-esterified fatty acid and triglyceride, and reduced lipid availability to muscle, thus decreasing lipid accumulation in muscle and liver, and consequently improving sensitivity to insulin.

Topics: Adipose Tissue; Animals; Blood Glucose; Carnitine O-Palmitoyltransferase; Carotenoids; Dietary Fats; Disease Models, Animal; Dyslipidemias; Fatty Acids, Nonesterified; Glucose Clamp Technique; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipase; Lipoprotein Lipase; Lipoproteins; Liver; Male; Muscle, Skeletal; Oxidation-Reduction; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Triglycerides; Vitamin A

Crocetin, a unique carotenoid with potent antioxidative and anti-inflammatory activities, is a major ingredient of saffron which is used as an important spice and food colorant in various parts of the world. In the present study, the effect of crocetin on insulin resistance and its related abnormalities induced by high-fructose diet were investigated in male Wistar rats. Compared to the control rats fed on normal laboratory diet, fructose-fed rats developed a series of pathological changes including insulin resistance, hyperinsulinemia, dyslipidemia and hypertension. Although having no evident effect on the body weight, fructose feeding caused a marked increase in the weight of epididymal white adipose tissue. Furthermore, a significant reduction in the expression of both protein and mRNA of adiponectin (an insulin-sensitizing adipocytokine) was observed, whereas those of tumor necrosis factor (TNF)-alpha and leptin were enhanced in epididymal white adipose tissue in fructose-fed rats. These disorders were effectively normalized in crocetin-treated rats. Crocetin was also demonstrated here to alleviate free fatty acid (FFA)-induced insulin insensitivity and dysregulated mRNA expression of adiponectin, TNF-alpha and leptin in primary cultured rat adipocytes. These findings suggest the possibility of crocetin treatment as a preventive strategy of insulin resistance and related diseases. The favorable impact on adiponectin, TNF-alpha and leptin expression in white adipose tissue may be involved in the improvement of insulin sensitivity observed in crocetin-treated rats.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Antioxidants; Blood Pressure; Carotenoids; Cholesterol, LDL; Crocus; Dietary Carbohydrates; Energy Intake; Fructose; Insulin; Insulin Resistance; Leptin; Male; Organ Size; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Vitamin A

A number of studies have implicated adipocyte-derived factors in the development of insulin resistance. Intracellular redox status has been reported to play a significant role in the modulation of insulin action. This study was designed to investigate the potential of crocetin, a potent antioxidant, to protect adipocytes against the induction of insulin insensitivity and disordered expression of tumor necrosis factor (TNF)-alpha and adiponectin in vitro.. We used palmitate to induce insulin resistance in freshly isolated rat adipocytes, and observed the effect of crocetin, N-acetylcysteine, diphenyleneiodonium, rotenone and oxypurinol. Insulin sensitivity was measured using 2-deoxy-D-[1-(3)H]-glucose uptake assay. Levels of glucose transporter 4, TNF-alpha and adiponectin were evaluated by immunoblot analysis, and levels of mRNA for TNF-alpha and adiponectin by reverse transcription-polymerase chain reaction analysis. Intracellular production of reactive oxygen species (ROS) was determined spectrofluorometrically using 2',7'-dichlorofluorescin diacetate.. Palmitate induced a 45% decrease in insulin-stimulated glucose uptake in adipocytes. The mRNA and protein expression of TNF-alpha were enhanced by 64% and 59% respectively whereas the mRNA and protein expression of adiponectin were reduced by 43% and 36% respectively by palmitate treatment. These changes were accompanied by a 54% increase in intracellular ROS levels. Crocetin, N-acetylcysteine and diphenyleneiodonium were found to attenuate these abnormalities.. Crocetin blocked the impaired insulin-stimulated glucose uptake and disordered TNF-alpha and adiponectin expression induced by palmitate in rat adipocytes. Inactivation of NADPH oxidase may account for these observations.

Topics: Acetylcysteine; Adipocytes; Adiponectin; Animals; Antimetabolites; Antioxidants; Blotting, Western; Carotenoids; Deoxyglucose; Glucose; Glucose Transporter Type 4; Insulin Resistance; Male; Onium Compounds; Palmitates; Rats; Rats, Wistar; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Vitamin A

The main objective of the study was to examine whether crocetin, a natural product from Gardenia jaminoides Ellis, has beneficial effects on the state of insulin resistance induced by dexamethasone in a rat model. Measured using the oral glucose tolerance tests (OGTT), male Wistar rats treated with subcutaneous dexamethasone (0.08 mg/kg/d) for 6 weeks exhibited reduced insulin sensitivity at weeks 2 and 4 and impaired glucose tolerance at week 4. In the dexamethasone-treated group, serum insulin, free fatty acids (FFA), triglyceride (TG) and tumor necrosis factor (TNF)-alpha levels were significantly increased at the end of the study. In addition, the hepatic glycogen content was reduced as indicated by periodic acid-Schiff (PAS) staining, and pancreatic islet beta cells showed compensatory hyperactivity suggested by immunohistochemical (IHC) staining using an antibody against insulin. Treatment with crocetin (40 mg/kg/d) significantly attenuated all the described effects of dexamethasone. These results suggest that crocetin might prevent the development of dexamethasone-induced insulin resistance and related abnormalities in rats.

Topics: Administration, Oral; Animals; Blood Glucose; Carotenoids; Dexamethasone; Disease Models, Animal; Fruit; Gardenia; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Vitamin A