Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes.
OBJECTIVE
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.
Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.
Payal
P
Shah
Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.
Navina
N
Lueschen
Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.
Amin
A
Ardestani
Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Jose
J
Oberholzer
Department of Immunology, Genetics and pathology, Uppsala University, Uppsala, Sweden.
Johan
J
Olerud
Department of Medical cell biology and Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Per-Ola
PO
Carlsson
Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.|German Center for Diabetes Research (DZD) project partner, University of Bremen, Bremen, Germany.
Kathrin
K
Maedler
D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007515:Islets of Langerhans / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015398:Signal Transduction
D042702:Angiopoietin-2