ANGPTL8/Betatrophin Does Not Control Pancreatic Beta Cell Expansion

Abstract

SUMMARY Yi et al. (2013) recently reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought “betatrophin” that could control pancreatic beta cell proliferation. However, studies of Angptl8−/− mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis (Wang et al. 2013). We now report that Angptl8−/− mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from either a high fat diet, or from the administration of the insulin receptor antagonist S961. Furthermore, overexpression of ANGPTL8 in livers of mice doubles plasma triglyceride levels, but does not alter beta cell expansion nor glucose metabolism. These data indicate ANGPTL8 does not play a role in controlling beta cell growth, nor can it be given to induce such expansion. The findings that plasma triglyceride levels are reduced by Angptl8 deletion and increased following ANGPTL8 overexpression support the possibility that inhibition of ANGPTL8 represents a therapeutic strategy for hypertriglyceridemia.

Aumento del nivel de betatrofina en suero en sujetos con síndrome metabólico: estudio de casos y controles

“…Furthermore, Zhang et al (10) identified betatrophin as a hepatokine that increases serum TG content, via reducing TG clearance. Finally, Gusarova et al (11) confirmed again that overexpression of betatrophin in mice liver doubled plasma TG levels.…”

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes

“…All analyses were performed by SPSS Statistics 17.0. P < 0.05 was consid-phin in the liver, and in mice administered S961, an insulin receptor antagonist [8]. These controversial results show that betatrophin may not be an essential hormone for beta cells proliferation in mice.…”

Dynamic Changes of Betatrophin and Its Potential Effect on β-cells in Spontaneously Developed or Streptozocin-induced Diabetes Monkeys

“…In rodents, an increase in hepatic betatrophin gene expression stimulated mouse β-cell replication [42]. However, Gusarova et al reported that β-cell proliferation was not affected by the lack of ANGPTL8 in response to diet induced insulin resistance or the S961 insulin receptor antagonist treatment in ANGPTL8 knockout mice [18]. The results from two recent studies also demonstrate that ANGPTL8 does not stimulate significant β-cell proliferation [16,17].…”

“…Betatrophin, a polypeptide, primarily produced in the liver showed the enhancement effect on β-cell regeneration/proliferation and insulin secretion in in early rodent study [12,36], but such effect was not disapproved in late studies [16][17][18]. The islets between rodents and primates exists obvious differences in the structure and signaling pathway.…”

“…However, the late studies in rodents found ANGPTL8 does not stimulate beta cell replication [16][17][18]. Human study showed that betatrophin concentrations were approximately 40% higher or doubled in patients with type Ι and type II diabetes compared with controls [19][20][21][22][23].…”