Abstract
Aims/hypothesisThe 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.MethodsWe 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.ResultsIn 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/interpretationANGPTL8 does not stimulate beta cell replication in young or old mice.Electronic supplementary materialThe 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.
Highlights
Diabetes is associated with reduced beta cell mass leading to an absolute or relative insulin deficiency and hyperglycaemia [1, 2]
Total Angptl8 gene expression increased 4.6-fold compared with green fluorescent protein (GFP) controls by qPCR (Fig. 1b, ESM Table 2), equivalent to the threefold induction of Angptl8 expression induced by the insulin receptor antagonist S961 [10]
Melton and colleagues recently asserted that ANGP TL8 overexpression variably increases beta cell proliferation, we show here that angiopoietin-like protein 8 (ANGPTL8) overexpression in mice does not alter beta cell proliferation
Summary
Diabetes is associated with reduced beta cell mass leading to an absolute (type 1) or relative (type 2) insulin deficiency and hyperglycaemia [1, 2]. Therapeutic islet transplantation suffers from loss of glucose control over time and scarcity of cadaveric islets. Stem cell generation of beta cells, while progressing, has failed to phenocopy human beta cells [3]. The field of beta cell biology continues to focus on endogenous beta cell expansion. Normal beta cell growth occurs by self-duplication, without the contribution of specialised progenitor cells [4, 5]. Putative beta cell mitogens have been advanced, none has progressed as a diabetes therapy [6]
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