Effect And Mechanism Of Cajanonic Acid A On Regulating Blood Glucose And Serum Lipid

With the improvement of living standards, number of type2diabetic individuals with hyperlipidemia increases year by year, being a chronic disease that is seriously harmful to human health. The development of type2diabetes depends on a variety of disease causing genetic and environmental factors, in which insulin resistance (IR) is considered to be the originating factor. Insulin resistance, characterized by reduced responsiveness of target tissues to normal circulating insulin, is now considered as a fundamental aspect of etiology of type2daibetes and plays an important role in the impaired glucose tolerance, obesity, hypertension, dyslipidemia, atherosclerosis and other pathophysiological processes. Thus, mitigating IR becomes an important approach for the prevention and treatment of type2diabetes and its chronic complications. A lot of efforts have been paid for the development of antidiabetic drugs in the past decades. However, there is currently no medicine in clinical usage that is ideal for the treatment of type2diabetics T2DM with IR.ObjectiveOur previous studies showed that Cajanonic acid A (CAA), a new stilbene isolated from Pigeon pea [Cajanus cajan (L.) Millsp.], decreased fasting blood glucose (FBG) and improved glucose tolerance of obese and hyperglycemic ob/ob mice. In this study we intended to investigate the effect of CAA on glucose and lipid metabolism in T2DM SD rats, hyperlipidemic Zucker fatty rats and diabetic db/db mice and make an evaluation for CAA activity in antihyperglycemia and antihyperlipidemia, and further, to approach its acting mechanism, so as to provide more experimental evidences for the development of CAA as a clinical used treatment drug of T2DM with IR, hyperlipidemia and related diseases.Methods and Results This project covers two sides of content, one is document research which gives an overview for T2DM and its treatment, the other is experimental research which explores the activity and mechanism of CAA in antidiabetics and antihyperlipidemia.1. Document ResearchDocument research includes the following two aspects:(1) Recent advances on the T2DM, relationship between T2DM and IR, IR target, pathogenesis and modern theraphy;(2) Research progresses in insulin sensitizers.2. Experimental StudiesCAA was studied following the director of pharmacodynamic studies. By using Avandia as a drug positive control, CAA was tested in different animal models for its antidiabetic and antihyperlipidemic activity. Mechanism studies were performed by using3T3-L1preadipocytes. The studies include all of the follows.(1) In high-fat diet combined with streptozotocin-induced T2DM rats,10mg/kg/d of CAA significantly decreased the level of fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and homeostasis model assessment of insulin resistance (HOMA-IR) with obviously greater insulin sensitivity index (ISI) and Homa β-cell function index (HBCI). CAA also reversed damages in liver, kidney and islet of diabetic rats, showing potential in regulating disorder of glucose and lipid metabolism.(2) In obese and hyperlipidemic Zucker fa/fa rats, CAA significantly inhibited the increase of TG and reduced TC level dose-dependently without unexpected weight gain, was shown to be suitable for regulating lipid metabolism in Zucker fatty rats.(3) In diabetic and obese db/db mice,10mg/kg/d of CAA kept FBG at a relatively stable level and reduced postprandial blood glucose level, suggesting that CAA effectively regulated glucose metabolism disorders of db/db mice without side effect of accelerated weight gain.(4) In3T3-L1preadipocytes, the IC50of CAA was301.14μM and CAA exhibited inhibitory effect on drug-induced differentiation of cells into adipocytes in a dose-dependent manner, opposite to the stimulatory effect of rosiglitazone. Quantitative real time PCR analysis revealed that mRNA level of PPARy and C/EBPa in3T3-L1cells that were in the process of differention (on day5) was down-regulated by CAA dose-dependently, suggesting that CAA inhibited lipogenesis by acting not only as an inhibitor to PPARy activity, but also as suppressors of PPARy and C/EBPa gene expression.(5) In dexamethasone-induced IR3T3-L1adipocytes, CAA at25μM restored insulin sensitivity of cells without affecting the expression of cellular glucose transportor4(Glut4). In the presence of CAA, IR cells consumed nearly the same amount of glucose as insulin sensitive cells did.ConclusionIn our study, CAA significantly reduced blood glucose and blood lipid level, and reversed or partially reversed hyperglycemia-caused damages to liver, islet, and kidney in T2DM SD rats. CAA also reduced serum TG and TC in hyperlipidemic Zucker fatty rats, showing potential as a treatment drug for hyperglycemia and hyperlipidemia, or hyperglycemia accompanied with hyperlipidemia and/or damages to liver, kidney and islet. Our study also revealed that CAA was an insulin sensitizer with its working mechanism distinctly different from thiazolidinediones. It was not an agonist of PPARy but an antagonist of PPARy and C/EBPa, and therefore prevent individuals from weight gain and other side-effects caused by activating PPARy. Therefore, from safety considerations the CAA in the early and long-term applications were suitable for treatment with obesity and IR-related metabolic diseases. Our study provided a new idea for the prevention and treatment of type2diabetes and hyperlipidemia.