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

Abstract

AimsChanges 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.MethodsImmunohistochemical 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.ResultsIslet 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.ConclusionsIslet 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.

Islet Microvasculature Alterations With Loss of Beta-cells in Patients With Type 1 Diabetes

“…These data contrast with a recent study showing increased islet vessel area in donors with type 2 diabetes. 23 Islets with increased vessel numbers and smaller diameters could imply increased vessel tortuosity following beta-cell loss.…”

“…14 Recent studies show that the human islet microvasculature is ~5-fold less dense (number of vessels/islet area) than in mouse islets. 10,[20][21][22][23] Human islet vessels were reported to contain three-times higher α-smooth muscle actin (SMA) cells compared with islets from mice where SMA cells were found associated only with feeding arterioles found at the islet periphery. 21 Furthermore, patients with type 2 diabetes had increased islet vessel density or area compared with non-diabetic donors.…”

“…21 Furthermore, patients with type 2 diabetes had increased islet vessel density or area compared with non-diabetic donors. 20,23 The purpose of the current study was to conduct morphometric studies of the islet microvasculature in patients with type 1 diabetes in comparison to matched control donors. Both islet and exocrine microvascular networks were analyzed for vessel diameters, densities, and areas and SMA areas.…”

The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes

“…An increase in capillary density is observed, which is accompanied by thickening and fragmentation of islet capillaries (Fig. 3 and [7, 26]). Altered islet capillary morphology has also been described in a variety of rodent models of diabetes [20, 27–32].…”

“…Islet capillary density is increased by 36% in individuals with diabetes vs those without diabetes. Based, in part, on data from [7, 26]. …”