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

[This corrects the article DOI: 10.1371/journal.pone.0161834.].

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

AIMS: Changes in the islet vasculature have been implicated in the regulation of ß-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the ß-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 ß-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-1ß, IFN-É£ 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 ß-cell function at basal conditions but protected islets from cytokine induced apoptosis. In vivo, ß-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 ß-cell mass. CONCLUSIONS: Islet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents ß-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis.

Manganese-mediated MRI signals correlate with functional ß-cell mass during diabetes progression.

Diabetes diagnostic therapy and research would strongly benefit from noninvasive accurate imaging of the functional ß-cells in the pancreas. Here, we developed an analysis of functional ß-cell mass (BCM) by measuring manganese (Mn(2+)) uptake kinetics into glucose-stimulated ß-cells by T1-weighted in vivo Mn(2+)-mediated MRI (MnMRI) in C57Bl/6J mice. Weekly MRI analysis during the diabetes progression in mice fed a high-fat/high-sucrose diet (HFD) showed increased Mn(2+)-signals in the pancreas of the HFD-fed mice during the compensation phase, when glucose tolerance and glucose-stimulated insulin secretion (GSIS) were improved and BCM was increased compared with normal diet-fed mice. The increased signal was only transient; from the 4th week on, MRI signals decreased significantly in the HFD group, and the reduced MRI signal in HFD mice persisted over the whole 12-week experimental period, which again correlated with both impaired glucose tolerance and GSIS, although BCM remained unchanged. Rapid and significantly decreased MRI signals were confirmed in diabetic mice after streptozotocin (STZ) injection. No long-term effects of Mn(2+) on glucose tolerance were observed. Our optimized MnMRI protocol fulfills the requirements of noninvasive MRI analysis and detects already small changes in the functional BCM.