Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice

AIMS/HYPOTHESIS: The identification of novel targets that stimulate endogenous regeneration of beta cells would represent a significant advance in the treatment of patients with diabetes. The betatrophin hypothesis suggests that increased expression of angiopoietin-like protein 8 (ANGPTL8) induces dramatic and specific beta cell proliferation and subsequent beta cell mass expansion with improved glucose tolerance. In light of recent controversy, we further investigated the effects of ANGPTL8 overexpression on beta cell proliferation. METHODS: We performed hydrodynamic tail vein injections of green fluorescent protein (GFP) or Angptl8 (also known as Gm6484) DNA in multiple cohorts of mice of different ages. We employed state-of-the-art methods to comprehensively quantify beta cell mass and proliferation, controlling for mouse age, genetic strain, source of DNA injected, Angptl8 gene expression and proliferation markers. RESULTS: In two young and two aged cohorts of B6.129 mice, no substantial change in beta cell replication, mass or glucose homeostasis was observed following ANGPTL8 overexpression. Even in mice with extremely elevated Angptl8 expression (26-fold increase), beta cell replication was not significantly altered. Finally, we considered mice on the ICR background exactly as studied by Melton and colleagues, and still no beta cell mitogenic effect was detected following ANGPTL8 overexpression. CONCLUSION/INTERPRETATION: ANGPTL8 does not stimulate beta cell replication in young or old mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3590-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.