Insel Vaskularisierung in Typ 2 Diabetes Mellitus

Diabetes is a complex metabolic disorder characterized by the failure to maintain normoglycemia stemming from dysfunctional islet of Langerhans. It is caused by an autoimmune destruction of insulin secreting beta-cells in case of type 1 diabetes (T1D), or non-insulin dependent diabetes, caused by lack on insulin action and production in type 2 diabetes (T2D) and by insulin insufficiency during pregnancy as in gestational diabetes mellitus (GDM). T2D accounts for at least 90% of the cases of diabetes, although it may remain undetected or at a pre-diabetic stage for several years. Thus, therapeutic intervention to prevent the progression to T2D is a major goal to subside the incidence of the disease and thus prevent further metabolic complications. T2D is most commonly associated with obesity and thus peripheral insulin resistance. In the face of insulin resistance there occurs an array of molecular mechanisms, one of the major activator being inflammation. In serum, adipose tissue, liver and pancreatic islets from T2D patients, pro-inflammatory cytokines like IL-1beta, CXCL10, TNFalpha, IL-6 have been detected and clinical trials are initiated to prevent inflammatory action. In our study, we showed anti-mouse CXCL10 antibody prevented diabetes progression; it improved glucose tolerance, insulin sensitivity and restored glucose stimulated insulin secretion in the HFD fed mice. CXCL10 antagonism also prevented upregulation of pro-inflammatory cytokines, IL-1beta, IL-6 and CXCL10 mRNA in isolated islets, CXCL10 in adipose tissue and liver of high fat/high sucrose diet (HFD) fed mice. Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetics widely in use for T2D treatment. The first agent of its class sitagliptin was approved by the FDA in 2006 and since has been investigated for its direct effects on islet function. The gluco-incretin hormones GIP and GLP-1 secreted by the intestinal endocrine cells potentiate glucose stimulated insulin secretion but are rapidly inactivated by DPP-4. We treated cultured human islets with a diabetic milieu of high glucose, palmitate, cytokines and H2O2 in presence of the DPP-4 inhibitor linagliptin. Linagliptin restored beta-cell function and turnover, via mechanism involving stabilization of secreted GLP-1 in islet supernatants. Obesity induced insulin resistance requires expansion of beta-cell mass to maintain normoglycemia. There occurs a compensatory islet hyperplasia, progressing with altered islet vascularization and possibly angiogenesis, inflammation and eventually leading to reduced beta-cell mass, beta-cell failure and hyperglycemia. The molecular mechanisms involved in the concomitant pathophysiology of islet endothelial cells in T2D has focused on effects mediated by VEGF-A. In this study, we aimed to identify the regulation of and the changes driven by the Angiopoietin/Tie angiogenic factors in islet vascularization and function during the progression of T2D. Ang-1 expressed by perivascular cells and beta-cells and Ang-2 expressed by endothelial cells exert their autocrine and paracrine effects via the cognate receptor Tie-2, on the endothelial cells. Tie-2 signaling maintains quiescent vasculature via constitutive Ang-1 expression whereas Ang-2 is known to be in play in demand for angiogenesis or pathological stimuli involving inflammation. Ang/Tie regulation and thus its role in diabetes and islet vascularization is so far poorly understood. Islet vessel area was increased in autopsy pancreases from T2D subjects, compared to controls. 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 as well under gluco-lipotoxicity in vitro in human and mouse islets, in contrast to its downregulation with cytokine treatment. Ang-1 on the other hand was oppositely regulated, with reduction under glucolipotoxic conditions and upregulation by cytokine milieu. Modulation of such changes in Ang-2 expression by its overexpression or the inhibition of its receptor Tie-2 impaired beta-cell function at basal conditions but protected islets from cytokine induced apoptosis in vitro. In vivo, beta-cell-specific Ang-2 overexpression in mice induced vascularization under normal diet but contrastingly hypovascularized islets under HFD together with increased apoptosis and reduction of beta-cell mass. Our data show that increased islet hypervascularization is paralleled with T2D. Maintaining physiological Ang-2 levels is important for islet vascularization and beta-cell survival