The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Allan Flyvbjerg - One of the best experts on this subject based on the ideXlab platform.
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Diabetic Angiopathy the complement system and the tumor necrosis factor superfamily
Nature Reviews Endocrinology, 2010Co-Authors: Allan FlyvbjergAbstract:Diabetic Angiopathy is among the most serious consequences of diabetes mellitus owing to its impact on quality of life, morbidity, mortality and burden to health-care systems. This Review discusses data that support a role of dysregulation of components of the complement system and the tumor necrosis factor superfamily in the development of Diabetic Angiopathy.
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Diabetic Angiopathy, the complement system and the tumor necrosis factor superfamily.
Nature reviews. Endocrinology, 2010Co-Authors: Allan FlyvbjergAbstract:Among the most serious consequences of diabetes mellitus is the development of Diabetic Angiopathy, of which the clinical features are cardiovascular disease, retinopathy, nephropathy and neuropathy. Diabetic kidney problems affect up to one third of all patients with diabetes mellitus and are a major cause of end-stage renal failure. Although a huge number of pharmaceutical interventions are available today, Diabetic Angiopathy remains a leading cause of mortality and morbidity in diabetes mellitus, therefore, an urgent need exists to develop new therapeutic strategies. Recent data support the hypothesis that dysregulation of the complement system and of members of the tumor necrosis factor (TNF) superfamily may be involved in the development of Diabetic vascular complications. The mannose-binding lectin pathway-an overall regulatory component of the complement system-is a particularly promising biomarker as it is directly involved in the development of Diabetic Angiopathy. In addition, two components of the TNF superfamily, namely TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and osteoprotegerin, may be involved in the pathogenesis of Diabetic Angiopathy. Several ways of specifically manipulating the complement and TNF superfamily systems already exist, but whether or not these drugs provide new targets for intervention for late Diabetic complications is still to be revealed.
John E. Tooke - One of the best experts on this subject based on the ideXlab platform.
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Possible pathophysiological mechanisms for Diabetic Angiopathy in type 2 diabetes.
Journal of diabetes and its complications, 2000Co-Authors: John E. TookeAbstract:The expression of large and small vessel disease in type 2 diabetes differs from that observed in type 1, with a higher prevalence of atherosclerosis and hypertension, maculopathy rather than proliferative retinopathy, and nephropathy of a more complex nature. Such differences are mirrored by differences in vascular pathophysiology with an early impairment of microvascular vasodilatory reserve being a prominent feature. The defect appears to be endothelium dependent and in conjunction with evidence of endothelium activation suggests that the endothelium plays a crucial role in the pathogenesis of vascular disease in type 2 diabetes and may even be an intrinsic feature or common antecedent of the insulin resistance syndrome. Several cellular mechanisms may be proposed linking insulin resistance and endothelial dysfunction including (i) abnormalities of common signal transduction mechanisms, (ii) alterations in cell membrane fluidity altering the expression and/or presentation of a wide range of receptors, or (iii) changes in oxidative stress. It is intuitively unlikely that the alteration of a single signal transduction mechanism could be a common cause, particularly as aspects of endothelial dysfunction implicate different mechanisms. Accordingly, changes in oxidative stress, either stemming from glucose-mediated increased free-radical generation and/or reduction of antioxidant capacity, are strong contender mechanisms. Not only may increased oxidative stress result in the quenching of nitric oxide, neutralizing its many protective functions, but it may also damage DNA, protein structure, and membrane properties. Elucidating the links between oxidative stress, endothelial function, and insulin resistance has important implications for the prevention of Diabetic Angiopathy and perhaps for the prevention of diabetes itself.
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Diabetic Angiopathy : Tracking down the culprits
Journal of diabetes and its complications, 1996Co-Authors: John E. Tooke, Angela C. Shore, Richard A. Cohen, Cornelis KluftAbstract:espite the considerable morbidity and excess mortality attributable to Diabetic Angiopathy, it is a sobering fact that the physician possesses few therapeutic weapons with which to combat the condition. The clear exception is of course glycemic control and the publication of the Diabetes Control and Complication Trial has established that intensive control of young insulin-dependent Diabetic patients significantly retards the development and/or progression of the microangiopathic process) Despite the clear support for the strategy of good glycemic control that this study provides, it is equally clear that the levels of glycemic control achieved by patients in the intensified control group are not achievable by all patients in clinical practice, and in some groups, e.g., those with hypoglycemia unawareness, the risks would outweigh any long-term benefit. In a curious way, this confirmation of one major therapeutic strategy (which many clinicians were pursuing on the basis of intuition rather than firm scientific proof) has provided a further stimulus to the identification of adjunctive therapeutic approaches. It is well accepted that new therapies are likely to derive from a clearer understanding of the cellular and molecular
Pierre-jean Guillausseau - One of the best experts on this subject based on the ideXlab platform.
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Advanced glycation end products, their receptors and Diabetic Angiopathy
Diabetes & Metabolism, 2001Co-Authors: Jean-luc Wautier, Pierre-jean GuillausseauAbstract:SUMMARY - The role of chronic hyperglycemia in the development of Diabetic microvascular complications and in neuropathy has been clearly established by intervention studies. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. This review focuses on the consequences of hyperglycemia on the formation of advanced glycation end-products (AGEs), and on the role of AGEs and of their specific receptors (RAGE) in the functional and anatomical alterations of the vascular wall. AGEs are formed during the Maillard reaction by the binding of aldoses on free NH2 groups of proteins, which, after a cascade of molecular rearrangements, result in molecules of brown color and specific fluorescence. Experimental studies have indicated that the binding of AGEs to RAGE activates cells, particularly monocytes and endothelial cells. Activated endothelial cells produce cytokines, and express adhesion molecules and tissue factor. The role of AGEs in increased oxidative stress, and in the functional alterations in vascular tone control observed in diabetes, in part related to a reduction in nitric oxide, is also discussed. The microvascular retinal, glomerular and nerve lesions induced by experimental diabetes in animals are prevented by an inhibitor of AGEs formation, aminoguanidine. The administration in Diabetic animals of recombinant RAGE, which hinders AGEs-RAGE interaction, prevents hyperpermeability and vascular lesions. These data suggest a central role of AGEs and RAGE in the development of chronic complications of diabetes.
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Advanced glycation end products, their receptors and Diabetic Angiopathy
Diabetes & Metabolism, 2001Co-Authors: J L Wautier, Pierre-jean GuillausseauAbstract:SUMMARY - The role of chronic hyperglycemia in the development of Diabetic microvascular complications and in neuropathy has been clearly established by intervention studies. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. This review focuses on the consequences of hyperglycemia on the formation of advanced glycation end-products (AGEs), and on the role of AGEs and of their specific receptors (RAGE) in the functional and anatomical alterations of the vascular wall. AGEs are formed during the Maillard reaction by the binding of aldoses on free NH2 groups of proteins, which, after a cascade of molecular rearrangements, result in molecules of brown color and specific fluorescence. Experimental studies have indicated that the binding of AGEs to RAGE activates cells, particularly monocytes and endothelial cells. Activated endothelial cells produce cytokines, and express adhesion molecules and tissue factor. The role of AGEs in increased oxidative stress, and in the functional alterations in vascular tone control observed in diabetes, in part related to a reduction in nitric oxide, is also discussed. The microvascular retinal, glomerular and nerve lesions induced by experimental diabetes in animals are prevented by an inhibitor of AGEs formation, aminoguanidine. The administration in Diabetic animals of recombinant RAGE, which hinders AGEs-RAGE interaction, prevents hyperpermeability and vascular lesions. These data suggest a central role of AGEs and RAGE in the development of chronic complications of diabetes.
Alberto Verrotti - One of the best experts on this subject based on the ideXlab platform.
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Effects of Irbesartan on Intracellular Antioxidant Enzyme Expression and Activity in Adolescents and Young Adults With Early Diabetic Angiopathy
Diabetes care, 2005Co-Authors: Francesco Chiarelli, Francesco Cipollone, Andrea Mezzetti, Francesca Santilli, Daniele Di Marzio, Angelika Mohn, Annalisa Blasetti, Alberto VerrottiAbstract:OBJECTIVE —Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with Diabetic nephropathy. The objective of this study was to evaluate the effects of irbesartan, an angiotensin II receptor antagonist, on IAP in adolescents and young adults with type 1 diabetes and early signs of retinopathy and nephropathy. RESEARCH DESIGN AND METHODS —This prospective, matched case-control study was conducted between November 2001 and December 2002 among 14 type 1 Diabetic patients with early signs of Angiopathy (ages 14–21 years), 11 type 1 Diabetic patients without Angiopathy (ages 12–22 years), and 10 healthy volunteers (ages 16–22 years). Skin fibroblasts were obtained by skin biopsies from the anterior part of the forearm and cultured in Dulbecco’s modified Eagle’s medium. The activity and mRNA expression of CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) were measured before and after 6 months of treatment with irbesartan (150 mg/day); on both occasions, antioxidant enzyme activity was evaluated at different glucose concentrations (5 and 22 mmol/l). RESULTS —At a normal glucose concentration (5 mmol/l), the activity and mRNA expression of CuZnSOD (0.50 ± 0.21 units/mg protein, 4.4 ± 1.5 mRNA/glyceraldehyde-3-phosphate dehydrogenase), MnSOD (0.26 ± 0.04 units/mg protein, 0.08 ± 0.07 mRNA), CAT (0.32 ± 0.08 units/mg protein, 4.8 ± 1.3 mRNA), and GPX (0.53 ± 0.09 units/mg protein, 2.2 ± 0.9 mRNA) were not different among the three groups (only values of Diabetic subjects with Angiopathy are shown). At high glucose concentrations, the activity and mRNA expression of CuZnSOD increased similarly in all groups (Diabetic subjects with Angiopathy: 0.93 ± 0.26 units/mg protein, 9.4 ± 2.1 mRNA); that of CAT and GPX increased in only control subjects and Diabetic subjects without Angiopathy (Diabetic subjects with Angiopathy: 0.33 ± 0.09 units/mg protein and 5.0 ± 1.4 mRNA; 0.54 ± 0.10 units/mg protein and 2.3 ± 1.0 mRNA, respectively). MnSOD did not change in any group. Treatment with irbesartan in adolescents with Diabetic Angiopathy was able to restore CAT and GPX activity and mRNA expression after exposure to high glucose concentrations. Markers of oxidative stress (serum malondialdehyde, fluorescent products of lipid peroxidation, monocyte chemoattractant protein-1, and 8-isoprostanes prostaglandin F2α) were significantly reduced after treatment with irbesartan. CONCLUSIONS —Adolescents and young adults with early signs of Diabetic Angiopathy have defective intracellular antioxidant enzyme production and activity. Treatment with irbesartan can substantially improve the activity and production of these enzymes in skin fibroblasts.
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advanced glycation end products in adolescents and young adults with Diabetic Angiopathy
Pediatric Nephrology, 2000Co-Authors: Francesco Chiarelli, M Catino, Stefano Tumini, Francesco Cipollone, Andrea Mezzetti, M Vanelli, Alberto VerrottiAbstract:The aim of this study was to evaluate serum advanced glycation end products (S-AGEs) in a group of adolescents and young adults with type 1 (insulin-dependent) diabetes mellitus and with Diabetic microvascular complications (nephropathy or retinopathy). Fifty-two patients were included in the study (age range 14.2–28.8 years, onset of diabetes before the age of 12 years, duration of diabetes longer than 7 years); 45 patients without Diabetic Angiopathy and 63 healthy controls were also selected. S-AGEs were significantly increased in patients with Diabetic Angiopathy compared with controls (19.9±3.8 vs. 11.8±2.8 U/ml, P 100 µg/min per 1.73 m2, S-AGE levels were 23.1±2.4 U/ml; when the AER was 50–100 μg/min per 1.73 m2 levels were 19.8±1.9 U/ml, and for an AER of 20–50 μg/min per 1.73 m2 the corresponding value was 16.1±2.1 U/ml (P<0.005). Patients with proliferative retinopathy had S-AGE levels of 22.2±2.6 U/ml, those with preproliferative retinopathy 20.7±2.2 U/ml, and background retinopathy 17.6±1.9 U/ml (P<0.01). A significant correlation was found between levels of glycosylated hemoglobin (HbA1c) and S-AGE (r=0.43, P<0.01). S-AGE concentrations are markedly increased in type 1 Diabetic adolescents and young adults with Diabetic nephropathy and retinopathy. The severity of Diabetic Angiopathy is related to the serum levels of AGEs.
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Advanced glycation end products in adolescents and young adults with Diabetic Angiopathy.
Pediatric nephrology (Berlin Germany), 2000Co-Authors: Francesco Chiarelli, M Catino, Stefano Tumini, Francesco Cipollone, Andrea Mezzetti, M Vanelli, Alberto VerrottiAbstract:The aim of this study was to evaluate serum advanced glycation end products (S-AGEs) in a group of adolescents and young adults with type 1 (insulin-dependent) diabetes mellitus and with Diabetic microvascular complications (nephropathy or retinopathy). Fifty-two patients were included in the study (age range 14.2-28.8 years, onset of diabetes before the age of 12 years, duration of diabetes longer than 7 years); 45 patients without Diabetic Angiopathy and 63 healthy controls were also selected. S-AGEs were significantly increased in patients with Diabetic Angiopathy compared with controls (19.9+/-3.8 vs. 11.8+/-2.8 U/ml, P100 microg/min per 1.73 m2, S-AGE levels were 23.1+/-2.4 U/ml; when the AER was 50-100 microg/min per 1.73 m2 levels were 19.8+/-1.9 U/ml, and for an AER of 20-50 microg/min per 1.73 m2 the corresponding value was 16.1+/-2.1 U/ml (P
Francesco Chiarelli - One of the best experts on this subject based on the ideXlab platform.
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Effects of Irbesartan on Intracellular Antioxidant Enzyme Expression and Activity in Adolescents and Young Adults With Early Diabetic Angiopathy
Diabetes care, 2005Co-Authors: Francesco Chiarelli, Francesco Cipollone, Andrea Mezzetti, Francesca Santilli, Daniele Di Marzio, Angelika Mohn, Annalisa Blasetti, Alberto VerrottiAbstract:OBJECTIVE —Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with Diabetic nephropathy. The objective of this study was to evaluate the effects of irbesartan, an angiotensin II receptor antagonist, on IAP in adolescents and young adults with type 1 diabetes and early signs of retinopathy and nephropathy. RESEARCH DESIGN AND METHODS —This prospective, matched case-control study was conducted between November 2001 and December 2002 among 14 type 1 Diabetic patients with early signs of Angiopathy (ages 14–21 years), 11 type 1 Diabetic patients without Angiopathy (ages 12–22 years), and 10 healthy volunteers (ages 16–22 years). Skin fibroblasts were obtained by skin biopsies from the anterior part of the forearm and cultured in Dulbecco’s modified Eagle’s medium. The activity and mRNA expression of CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) were measured before and after 6 months of treatment with irbesartan (150 mg/day); on both occasions, antioxidant enzyme activity was evaluated at different glucose concentrations (5 and 22 mmol/l). RESULTS —At a normal glucose concentration (5 mmol/l), the activity and mRNA expression of CuZnSOD (0.50 ± 0.21 units/mg protein, 4.4 ± 1.5 mRNA/glyceraldehyde-3-phosphate dehydrogenase), MnSOD (0.26 ± 0.04 units/mg protein, 0.08 ± 0.07 mRNA), CAT (0.32 ± 0.08 units/mg protein, 4.8 ± 1.3 mRNA), and GPX (0.53 ± 0.09 units/mg protein, 2.2 ± 0.9 mRNA) were not different among the three groups (only values of Diabetic subjects with Angiopathy are shown). At high glucose concentrations, the activity and mRNA expression of CuZnSOD increased similarly in all groups (Diabetic subjects with Angiopathy: 0.93 ± 0.26 units/mg protein, 9.4 ± 2.1 mRNA); that of CAT and GPX increased in only control subjects and Diabetic subjects without Angiopathy (Diabetic subjects with Angiopathy: 0.33 ± 0.09 units/mg protein and 5.0 ± 1.4 mRNA; 0.54 ± 0.10 units/mg protein and 2.3 ± 1.0 mRNA, respectively). MnSOD did not change in any group. Treatment with irbesartan in adolescents with Diabetic Angiopathy was able to restore CAT and GPX activity and mRNA expression after exposure to high glucose concentrations. Markers of oxidative stress (serum malondialdehyde, fluorescent products of lipid peroxidation, monocyte chemoattractant protein-1, and 8-isoprostanes prostaglandin F2α) were significantly reduced after treatment with irbesartan. CONCLUSIONS —Adolescents and young adults with early signs of Diabetic Angiopathy have defective intracellular antioxidant enzyme production and activity. Treatment with irbesartan can substantially improve the activity and production of these enzymes in skin fibroblasts.
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The role of nitric oxide in the development of Diabetic Angiopathy.
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2004Co-Authors: Francesca Santilli, Andrea Mezzetti, Francesco Cipollone, Francesco ChiarelliAbstract:Diabetic Angiopathy is the main cause of morbidity and mortality in patients with diabetes mellitus. Clinical manifestations and pathophysiological mechanisms of Diabetic Angiopathy can be traced back to the development of endothelial cell dysfunction with alterations in the eNOS/NO system production or availability as the primum movens in its natural history. Hyperglycemia per se or through the accumulation of AGEs, increased oxidative stress, leading to NOS uncoupling and NO-quenching by excess superoxide and peroxynitrite, and individual genetic background are thought to be responsible for this NO metabolism imbalance. The complex interplay of these mechanisms results in a perturbation of the physiological properties of NO in the maintenance of endothelial homeostasis, such as vasodilation, anticoagulation, leukocyte adhesion, smooth muscle cell proliferation, and antioxidant capacity. Hence, abnormality in NO availability results in generalized accelerated atherosclerosis, hyperfiltration, glomerulosclerosis, tubulointerstitial fibrosis and progressive decline in glomerular filtration rate, and apoptosis and neovascularization in the retina. Indeed, the parallel development of nephropathy, retinopathy, and macroAngiopathy may be considered as manifestations of endothelial dysfunction at distinct vascular sites. Given this scenario, intervention targeting any of the pathways involved in the NOS/NO system cascade may prove potential therapeutic targets in the prevention of long-term Diabetic complications.
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endothelial perturbation in children and adolescents with type 1 diabetes association with markers of the inflammatory reaction
Diabetes Care, 2001Co-Authors: Mario Romano, Francesco Chiarelli, Mariapina Pomilio, S Vigneri, Angela Falco, Pierluigi Lelli Chiesa, Giovanni DaviAbstract:OBJECTIVE —The progression of Diabetic Angiopathy is, in most cases, unpredictable. The aim of this study was to investigate early events that could influence the development of Diabetic Angiopathy. RESEARCH DESIGN AND METHODS —Circulating levels of von Willebrand factor (vWF) and tissue-plasminogen activator (tPA), defining endothelial perturbation, were measured in 40 young patients with type 1 diabetes. Patients were divided into two groups according to the duration of diabetes (group A, 1 year) and compared with a control group of age- and sex-matched healthy individuals. Prothrombin fragment 1 and 2 (F 1+2 ), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) levels were also determined as markers of a prothrombotic state and inflammatory response. A total of 16 of the 20 children in group A were re-examined after 12 months. RESULTS —Compared with either normal subjects or patients in group B, children in group A showed increased levels of vWF, tPA, F 1+2 , TNF-α, and CRP. Significant direct correlations between TNF-α or CRP and either vWF, tPA, or F 1+2 were observed. Endothelial perturbation was shown in 70% of group A and 20% of group B. After 1 year, 16 of the 20 patients in group A showed a significant reduction in vWF, tPA, F 1+2 , TNF-α, and CRP levels, whereas endothelial perturbation was reversed in 5 of these patients. CONCLUSIONS —Endothelial perturbation represents an early and, in some cases, reversible event in the chronology of type 1 diabetes in children. A correlation might exist between the initial inflammatory reaction and the appearance of endothelial perturbation.
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advanced glycation end products in adolescents and young adults with Diabetic Angiopathy
Pediatric Nephrology, 2000Co-Authors: Francesco Chiarelli, M Catino, Stefano Tumini, Francesco Cipollone, Andrea Mezzetti, M Vanelli, Alberto VerrottiAbstract:The aim of this study was to evaluate serum advanced glycation end products (S-AGEs) in a group of adolescents and young adults with type 1 (insulin-dependent) diabetes mellitus and with Diabetic microvascular complications (nephropathy or retinopathy). Fifty-two patients were included in the study (age range 14.2–28.8 years, onset of diabetes before the age of 12 years, duration of diabetes longer than 7 years); 45 patients without Diabetic Angiopathy and 63 healthy controls were also selected. S-AGEs were significantly increased in patients with Diabetic Angiopathy compared with controls (19.9±3.8 vs. 11.8±2.8 U/ml, P 100 µg/min per 1.73 m2, S-AGE levels were 23.1±2.4 U/ml; when the AER was 50–100 μg/min per 1.73 m2 levels were 19.8±1.9 U/ml, and for an AER of 20–50 μg/min per 1.73 m2 the corresponding value was 16.1±2.1 U/ml (P<0.005). Patients with proliferative retinopathy had S-AGE levels of 22.2±2.6 U/ml, those with preproliferative retinopathy 20.7±2.2 U/ml, and background retinopathy 17.6±1.9 U/ml (P<0.01). A significant correlation was found between levels of glycosylated hemoglobin (HbA1c) and S-AGE (r=0.43, P<0.01). S-AGE concentrations are markedly increased in type 1 Diabetic adolescents and young adults with Diabetic nephropathy and retinopathy. The severity of Diabetic Angiopathy is related to the serum levels of AGEs.
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Advanced glycation end products in adolescents and young adults with Diabetic Angiopathy.
Pediatric nephrology (Berlin Germany), 2000Co-Authors: Francesco Chiarelli, M Catino, Stefano Tumini, Francesco Cipollone, Andrea Mezzetti, M Vanelli, Alberto VerrottiAbstract:The aim of this study was to evaluate serum advanced glycation end products (S-AGEs) in a group of adolescents and young adults with type 1 (insulin-dependent) diabetes mellitus and with Diabetic microvascular complications (nephropathy or retinopathy). Fifty-two patients were included in the study (age range 14.2-28.8 years, onset of diabetes before the age of 12 years, duration of diabetes longer than 7 years); 45 patients without Diabetic Angiopathy and 63 healthy controls were also selected. S-AGEs were significantly increased in patients with Diabetic Angiopathy compared with controls (19.9+/-3.8 vs. 11.8+/-2.8 U/ml, P100 microg/min per 1.73 m2, S-AGE levels were 23.1+/-2.4 U/ml; when the AER was 50-100 microg/min per 1.73 m2 levels were 19.8+/-1.9 U/ml, and for an AER of 20-50 microg/min per 1.73 m2 the corresponding value was 16.1+/-2.1 U/ml (P