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Toffoli B.,University of Ferrara | Toffoli B.,Institute for Maternal and Child Health | Bernardi S.,University of Trieste | Candido R.,Diabetic Center | And 6 more authors.
Molecular and Cellular Endocrinology | Year: 2011

Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin-angiotensin system (RAS).OPG-treated mice showed increased islet monocyte/macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (transforming growth factor β and connective tissue growth factor) and inflammatory molecules (monocyte chemotactic protein-1 and vascular adhesion molecule type 1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and that the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction. © 2010 Elsevier Ireland Ltd. Source

Candido R.,Diabetic Center | Toffoli B.,University of Ferrara | Bernardi S.,University of Trieste | Zella D.,University of Maryland, Baltimore | And 2 more authors.
Journal of Vascular Research | Year: 2010

Background/Aims: Since elevated plasma levels of osteoprotegerin (OPG) represent a risk factor for death and heart failure in patients affected by diabetes mellitus and coronary artery disease, this study aimed to elucidate potential roles of OPG in the pathogenesis of atherosclerosis. Methods and Results: Recombinant human full-length OPG, used at concentrations comparable to the elevated levels found in the serum of diabetic patients, significantly increased the proliferation rate of rodent vascular smooth muscle cells (VSMC). To mimic the moderate chronic elevation of OPG observed in diabetic patients, low doses (1 μg\mouse) of full-length human OPG were injected intraperitoneally every 3 weeks in diabetic apolipoprotein E (apoE)-null mice. The group of animals treated for 12 weeks with recombinant OPG showed a small increase in the total aortic plaque area at necropsy in comparison to vehicle-treated animals. Importantly, while no differences in the amount of interstitial collagen or the degree of macrophage infiltration were observed between OPG-treated and vehicle-treated apoE-null diabetic animals, a significant increase in the number of α-actin-positive smooth muscle cells was observed in the plaques of OPG-treated mice. Conclusions: Our data suggest that OPG promotes VSMC proliferation and might be directly involved in pathogenetic aspects of atherosclerosis. Copyright © 2009 S. Karger AG, Basel. Source

Toffoli B.,Institute for Maternal and Child Health | Bernardi S.,Baker IDI Heart and Diabetes Institute | Candido R.,Diabetic Center | Zacchigna S.,International Center for Genetic Engineering and Biotechnology | And 2 more authors.
Investigational New Drugs | Year: 2012

Recent clinical trials carried out in patients with advanced cancer have shown that recombinant TRAIL administration is usually safe and well tolerated when used either alone or in association with chemotherapeutic drugs. Notably, anticancer chemotherapy can be associated to cardiomiopathy. We have here demonstrated that TRAIL (administrated as either recombinant soluble TRAIL or as AAV-TRAIL expression viral vector) reduced the development of cardiomyopathy in the ApoE-/- diabetic mouse model. These data suggest, for the first time, that therapeutically administration of TRAIL might have a cardioprotective effect. © 2012 Springer Science+Business Media, LLC. Source

Shibasaki S.,Osaka Medical College | Imagawa A.,Osaka Medical College | Imagawa A.,Osaka University | Tauriainen S.,University of Tampere | And 15 more authors.
Endocrine Journal | Year: 2010

Fulminant type 1 diabetes, established in 2000, is defined as a novel subtype of diabetes mellitus that results from remarkably acute and almost complete destruction of pancreatic beta cells at the disease onset. In this study, we aimed to clarify the pathogenesis of fulminant type 1 diabetes with special reference to insulitis and viral infection. We examined pancreatic autopsy samples from three patients who had died soon after the onset of disease and analyzed these by immunohistochemistry and in situ hybridization. The results were that both beta and alpha cell areas were significantly decreased in comparison with those of normal controls. Mean beta cell area of the patients just after the onset was only 0.00256 % while that of normal control was 1.745 %. Macrophages and T cells-but no natural killer cells-had infiltrated the islets and the exocrine pancreas. Although both of them had massively infiltrated, macrophages dominated islet infiltration and were detected in 92.6 % of the patients' islets. Toll-like receptor (TLR) 3, a sensor of viral components, was detected in 84.7±7.0 % of macrophages and 62.7±32.3 % of T cells (mean±SD) in all three patients. TLR7 and TLR9 were also detected in the pancreas of all three patients. Enterovirus RNA was detected in beta-cell positive islets in one of the three patients by in situ hybridization. In conclusion, our results suggest that macrophage-dominated insulitis rather than T cell autoimmunity contributes to beta cell destruction in fulminant type 1 diabetes. Source

Nanda Kumar L.G.,MNR Medical College | Kaveri N.K.,MNR Medical College | Anmol M.N.Y.,Diabetic Center
Diabetes and Metabolic Syndrome: Clinical Research and Reviews | Year: 2011

Background: Reports of urban based studies suggest an increase in the prevalence of MS worldwide along with diabetes, hypertension and atherogenic dyslipidemia. The supporting rural based studies on MS are few and prevalence of MS among women is underestimated. In this prospective study we have evaluated the clinic prevalence of metabolic syndrome among rural Indian population with special emphasis on prevalence in women. Research design and method: 2329 patients attending to diabetic centre were evaluated for the markers of MS. Anthropometric measurements, clinical assessment, capillary blood glucose and lipid profile (TC, HDL-C, TG, LDL-C, VLDL-C) were done and classified as per NCEP ATP III and NCEP ATP III modified for Asian guidelines. We compared the prevalence of MS between males and females for statistical significance by SPSS 16.0 statistical software. The level of significance was kept at <0.05. Results: The Clinic prevalence of metabolic syndrome was 61.74% with 57.59% males and 69.66% females as per NCEP ATP III guidelines. 73.85% of the study population had MS, with 68.85% males and 83.39% females had MS as per modified Asian criteria. We could get a statistically significant variation between males and females in FBS, PPBS, SBP, DBP, TC, HDL-C, TG, LDL-C, VLDL-C, TC/HDL, LDL/HDL, BMI, W/H ratio and W/S ratio. Conclusion: Prevalence MS is increasing at an epidemic proportion bringing with it micro and macro vascular complications. Women are more prone to develop MS in rural population than the men and there is a statistically significant variation in the biochemical and anthropometric parameters. This is an era of 'gender equality'; here we see women over taking men in metabolic syndrome and its complications. © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved. Source

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