Yongqiang Liu, Xiaoli Wang, Bingdi Wang, Guofeng Sun, Francine Gregoire, Keefe Chng, Jinhu Wang, Yixin (Jim) Wang and Yong-Fu Xiao
Effects of betatrophin on β-cell proliferation and insulin secretion have been reported controversially in rodent studies. This study was to investigate the dynamic changes of betatrophin and its potential effect on β-cell function in non-human primates (NHPs). Blood betatrophin levels in naturally developed diabetes cynomolgus monkeys (n=65) significantly correlated with their body weights and blood glucose levels in the females (n=20) and with insulin and C-peptide levels in the males (n=45). Liver expression of betatrophin mRNA was markedly higher in spontaneously developed diabetes monkeys than in normoglycemic ones. Its liver expression correlated well with islet size and insulin content in normoglycemic cynomolgus monkeys and also well in spontaneously hyperglycemic (>200 mg/ dL) cynomolgus monkeys with high blood insulin level, but not well in those with very low blood insulin content. Both blood glucose and betatrophin increased dramatically in normoglycemic rhesus monkeys (n=7) after streptozocin (STZ) administration. Blood insulin initially increased on day 1 after STZ dosing and then decreased dramatically. Two NHPs with blood glucose back to ~80 mg/mL on day 14 after STZ injection showed recovery of insulin secretion. In another two STZ-treated NHPs with blood glucose >250 mg/dL, apparent proliferation of both β-cells and non-β- cells was observed in their islets. The rest NHPs with more completed β-cell destruction after STZ dosing showed much higher blood glucose (>300 mg/dL) with very low insulin and no obvious β-cell proliferation. Our results indicate that NHP liver expresses abundant betatrophin mRNA. As its levels correlated well with islet size and insulin content in some diabetic NHPs, it might play a role in β-cell proliferation. Our data are consistent with the clinical finding of the elevation of circulating betatrophin in patients with type 2 diabetes. In addition, betatrophin-enhanced β-cell proliferation seems requiring a minimal base level of pancreatic β-cells and islets.
