Circulating betatrophin is associated with insulin resistance in humans: cross-sectional and interventional studies in vivo and in vitro

Betatrophin has a closely relationship with metabolism. However, its effect on metabolism disorder remains unclear. This study was comprised of a series of cross-sectional and interventional studies in vivo and vitro. PCOS women with IR and healthy women were recruited from the general population and outpatients. Plasma betatrophin levels were measured with ELISA. Insulin sensitivity was assessed with EHC. Gene expressions at mRNA and protein levels were determined with RT-PCR and Western blotting. Influences of insulin, metformin, rosiglitazone and over- or knockdown-expression of betatrophin were analyzed ex vivo. Our results indicated that IR women had higher betatrophin levels compared with the controls. Circulating betatrophin was positively correlated with BMI, WHR, Fat%, triglyceride, total cholesterol, LDL-C, AUC(glucose) and AUC(insulin), luteinizing Hormone, FAI and HOMA-IR but negatively with M-value. Metformin treatment in PCOS women with IR led to a reduction of betatrophin levels. Insulin stimulation in hepatocytes increased betatrophin expression. Metformin or rosiglitazone led to a reduction of betatrophin expression in insulin-stimulated hepatocytes. In hepatocytes/macrophages co-culture systems, betatrophin expression was significantly increased, whereas this increase was eliminated by rosiglitazone. In hepatocytes, overexpression and knockdown of betatrophin decreased or increased insulin-stimulated insulin receptor, protein kinase B and insulin receptor substrate-1 phosphorylation respectively. Serum from metformin-treated women with IR decreased betatrophin expression and reinforced insulin signals. Thus, the present study provides the in vivo and in vitro evidence, suggesting that there is a cell cross-talking between hepatocytes with macrophages for the regulating betatrophin and it may be a useful marker for IR and metabolic disorders.