Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes

PLoS One. 2016 Sep 12;11(9):e0161834. doi: 10.1371/journal.pone.0161834. eCollection 2016.

Abstract

Aims: Changes in the islet vasculature have been implicated in the regulation of β-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the β-cell to compensate for the increased insulin demand in obesity eventually leads to diabetes; as a result of the complex interplay of genetic and environmental factors (e.g. ongoing inflammation within the islets) and impaired vascular function. The Angiopoietin/Tie (Ang/Tie) angiogenic system maintains vasculature and is closely related to organ inflammation and angiogenesis. In this study we aimed to identify whether the vessel area within the islets changes in diabetes and whether such changes would be triggered by the Tie-antagonist Ang-2.

Methods: Immunohistochemical and qPCR analyses to follow islet vascularization and Ang/Tie levels were performed in human pancreatic autopsies and isolated human and mouse islets. The effect of Ang-2 was assessed in β-cell-specific Ang-2 overexpressing mice during high fat diet (HFD) feeding.

Results: Islet vessel area was increased in autopsy pancreases from patients with T2D. The vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD and under glucolipotoxic conditions (22.2 mM glucose/ 0.5 mM palmitate) in vitro in human and mouse islets, in contrast to its downregulation by cytokines (IL-1β, IFN-ɣ and TNF-α). Ang-1 on the other hand was oppositely regulated, with a significant loss under glucolipotoxic condition, a trend to reduce in islets from patients with T2D and an upregulation by cytokines. Modulation of such changes in Ang-2 by its overexpression or the inhibition of its receptor Tie-2 impaired β-cell function at basal conditions but protected islets from cytokine induced apoptosis. In vivo, β-cell-specific Ang-2 overexpression in mice induced hypervascularization under normal diet but contrastingly led to hypovascularized islets in response to HFD together with increased apoptosis and reduced β-cell mass.

Conclusions: Islet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents β-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis.

MeSH terms

  • Angiopoietin-2 / metabolism*
  • Animals
  • Apoptosis
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diet, High-Fat
  • Disease Models, Animal*
  • Islets of Langerhans / blood supply*
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / metabolism*
  • Signal Transduction

Substances

  • Angiopoietin-2

Grant support

This work was supported by the European Research Council (ERC), the German Research Foundation (DFG), by the German Diabetes Center grant (DZD) from the BMBF (to KM) and by an Albert Renold travel grant from the EFSD (to PS). Human islets were provided through the JDRF award 31-2008-413 (ECIT Islet for Basic Research program) and by the integrated islet distribution program (IIDP). Autopsy pancreases were provided by the National Disease Research Interchange NDRI, supported from the NIDDK.