Effects of methimazole on Drosophila glucolipid metabolism in vitro and in vivo.

Methimazole (MMI) is an antithyroid agent widely used in the treatment of hyperthyroidism, and metabolized by cytochrome P450 enzymes and flavin-containing monooxygenases in mammals. However, drug overdose and the inadequate detoxification of the metabolite(s) are responsible for hepatocellular damage and organ dysfunction. Depending on the desired properties, Drosophila melanogaster has recently emerged as an ideal model organism for the study of human diseases. Here we investigated the changes in metabolic profiles and mRNA expressions related to glucolipid metabolism in response to treatment with MMI in Drosophila. Remarkable loss of lifespan occurred in fruit flies fed on the diets containing 10 or 30mM MMI compared to unsupplemented controls. To examine whether MMI affects glucolipid metabolism in vitro and in vivo, fruit flies were fed diets containing 30mM MMI for two weeks and Drosophila S2 cells were incubated with 300µM MMI for 48h. Measurements of metabolites showed that triglyceride content dramatically decreased (30.56% in vivo and 18.13% in vitro), and glycogen content significantly increased (10.7% in vivo and 126.8% in vitro). Quantitative analyses indicated that mRNA expression levels of Dmfmo1, s6k, dilp2, acc and dilp5 genes involved in metabolic homeostasis were remarkably down-regulated in vivo and in vitro. Meanwhile, the addition of MMI could significantly reduce the lipid droplet content in S2 cells by approximately 25% compared to control subjects. These data may provide a biological basis for the study of MMI on disease symptoms and complications, and discovery of therapeutic treatments.

Investigation of antidiabetic action of Antidesma bunius extract in type 1 diabetes.

CONTEXT: Antidesma bunius L (Phyllanthaceae) is commonly known to local people in North-east Thailand as a medicinal plant. OBJECTIVES: To investigate hypoglycaemic activities of methanolic extract of A. bunius in type 1 diabetes. MATERIALS AND METHODS: A daily dose of A. bunius extract (250 mg/kg body weight) was given orally to alloxan-induced diabetic rats for 28 days. Blood glucose, insulin, TC, TG, amylase, lipase, liver glycogen were analysed. RESULTS: Extract revealed a significant reduction in blood glucose level (80.5%) along with an increase in serum insulin (134%), lipase (90.7%) and liver glycogen level (160%). Also amylase (28.2%) activity, TC (40.2%), and TG (28.8%) levels were significantly decreased when compared with diabetic control rats. A. bunius extract improved the histo-architectural of the ß-cells. DISCUSSION AND CONCLUSION: The results suggested that A. bunius extract possess anti-diabetic activity, through the enhancement of hepatic glycogen storage and regeneration of the islet of Langerhans.

Angelica sinensis polysaccharide regulates glucose and lipid metabolism disorder in prediabetic and streptozotocin-induced diabetic mice through the elevation of glycogen levels and reduction of inflammatory factors.

The present study was designed to evaluate the potential hypoglycemic and hypolipidemic effects of Angelica sinensis polysaccharide (ASP), purified from the fresh roots of Angelica sinensis (AS), in prediabetic and streptozotocin (STZ)-induced diabetic BALB/c mice. It was observed that fasting blood glucose (FBG) levels in both models were reduced after a 4-week oral administration of ASP or metformin, and abnormal fasting serum insulin (FINS) concentrations were ameliorated as well. Moreover, the homeostasis model assessment-insulin resistance (HOMA-IR) index was decreased strikingly and body weight (BW) was reduced significantly in prediabetic mice after treatment with ASP. In addition, ASP also contributed to improving the dyslipidemia conditions. Elevated serum total cholesterol (TC) or triglyceride (TG) concentrations were reduced after treatment with ASP in prediabetic mice or STZ-induced diabetic mice. Meanwhile, hepatic glycogen (HG) and muscle glycogen (MG) concentrations were increased while insulin resistance (IR)-related inflammatory factors IL-6 and TNF-α in serum were reduced in STZ-induced diabetic mice. Histopathological examination indicated that the impaired pancreatic/hepatic tissues or adipose tissues were effectively restored in STZ-induced diabetic mice or prediabetic mice after the ASP treatment. Taken together, these results revealed that ASP efficiently exerted hypoglycemic and hypolipidemic benefits, and its potential effect was associated with the amelioration of IR. ASP can be applied in the prevention and treatment of diabetes.

Apelin ameliorates TNF-α-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ.

Apelin, a novel adipokine, is the specific endogenous ligand of G protein-coupled receptor APJ. Consistent with its putative role as an adipokine, apelin has been linked to states of insulin resistance. However, the function of apelin in hepatic insulin resistance, a vital part of insulin resistance, and its underlying mechanisms still remains unclear. Here we define the impacts of apelin on TNF-α-induced reduction of glycogen synthesis in the hepatocytes. Our studies indicate that apelin reversed TNF-α-induced reduction of glycogen synthesis in HepG2 cells, mouse primary hepatocytes and liver tissues of C57BL/6J mice by improving JNK-IRS1-AKT-GSK pathway. Moreover, Western blot revealed that APJ, but not apelin, expressed in the hepatocytes and liver tissues of mice. We found that F13A, a competitive antagonist for G protein-coupled receptor APJ, suppressed the effects of apelin on TNF-α-induced reduction of glycogen synthesis in the hepatocytes, suggesting APJ is involved in the function of apelin. In conclusion, we show novel evidence suggesting that apelin ameliorates TNF-α-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ. Apelin appears as a beneficial adipokine with anti-insulin resistance properties, and thus as a promising therapeutic target in metabolic disorders.