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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor kappaB) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-alphaa, (TNF-alphaa), IL-1alphab, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor kappaB activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-alphaa, and IL-1alphab. Another signaling cascade by which GSA activates VSMCs is the ERK-->c-Fos-->AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs.
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PMID:Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). 1179 73

Evidence points to an increased cytokine response in type 2 diabetes, especially the proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha. Genetics, age, and, nutrition are important signals for this increased response and as reported more recently, infections and inflammation. Persistent elevation of IL-1 beta, IL-6, and TNF-alpha in the diabetic state have an effect on the liver, stimulate the release of acute-phase proteins, produce the characteristic dysregulation of lipid metabolism associated with type 2 diabetes, and have effects on pancreatic beta cells as well. In addition, TNF-alpha, a potent inhibitor of the tyrosine kinase activity of the insulin receptor, has been implicated as an etiologic factor for insulin resistance. Collectively, the evidence supports a role for cytokine elevation in the pathophysiology and metabolic abnormalities associated with diabetes. Periodontitis is an infection that is twice as prevalent in diabetic individuals compared to non-diabetics. Porphyromonas gingivalis, one of the microorganisms responsible for this infection, is able to invade endothelial cells and is a potent signal for monocyte and macrophage activation. Thus, once established in the diabetic host, this chronic infection complicates diabetes control and increases the occurrence and severity of microvascular and macrovascular complications. Unlike treatment of acute infections, modalities of treatment for chronic infections are a matter of debate. Evidence indicates that mechanical removal of subgingival infection does not result in complete elimination of periodontal infection and consequently there is no effect on diabetes control measured as reduction in glycated hemoglobin. On the other hand, studies incorporating systemic antibiotics as adjuncts to mechanical debridement result in a reduction of P. gingivalis to nondetectable levels and a concomitant reduction in glycated hemoglobin, independent of the hypoglycemic effects of diabetes drugs or insulin. The evidence supports the notion that treatment of chronic periodontal infection is essential in the diabetic patient. Assessment of infection status in diabetic patients is fundamental for appropriate treatment decisions.
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PMID:Treatment of periodontal disease and control of diabetes: an assessment of the evidence and need for future research. 1188 56

Nonobese diabetic (NOD) mice spontaneously develop diabetes, an auto-immune disease characterized by the destruction of insulin-secreting beta-cells by autoreactive T cells. Defects in development and/or functions of dendritic cells (DC) might be critical in eliciting the auto-immune reaction to beta cells in this model. In this paper, DC differentiation in NOD mice was investigated in vitro using bone marrow-derived progenitors (BM-DC) in the presence of GM-CSF and IL-4 or spleen-derived progenitors in the presence of GM-CSF and early acting cytokines such as Flt-3L and IL-6 (SPL-DC). In both culture systems, the absolute number of NOD DC generated was strongly reduced as compared to control strains. In addition, both BM-DC and SPL-DC from NOD mice show defective differentiation into mature DC in conventional culture conditions as indicated by low expression of MHC class II and CD80 molecules among CD11c positive cells and low capacity to stimulate allogeneic T cells. However, DC achieved full maturation when exposed to LPS, except for MHC class II expression that remained decreased. Ex vivo analysis confirmed an unusual phenotype of NOD DC. Both sets of results are thus consistent with a specific defect of DC maturation in these mice.
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PMID:Altered dendritic cells (DC) might be responsible for regulatory T cell imbalance and autoimmunity in nonobese diabetic (NOD) mice. 1195 18

In the early 1980s, we proposed a unifying model for beta-cell damage (The OKAMOTO model), in which poly(ADP-ribose) synthetase/polymerase (PARP) activation plays an essential role in the consumption of NAD+, which leads to energy depletion and necrotic cell death. In 1984, we demonstrated that the administration of PARP inhibitors to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library we isolated Reg (Regenerating Gene) and demonstrated that Reg protein induces beta-cell replication via the Reg receptor and ameliorates experimental diabetes. More recently, we showed that the combined addition of IL-6 and dexamethasone induces the Reg gene expression in beta-cells and that PARP inhibitors enhance the expression. In 1993, we found that cyclic ADP-ribose (cADPR), a product synthesized from NAD+, is a second messenger for intracellular Ca2+ mobilization for insulin secretion by glucose, and proposed a novel mechanism of insulin secretion, the CD38-cADPR signal system. Therefore, PARP inhibitors prevent beta-cell necrosis, induce beta-cell replication and maintain insulin secretion.
Int J Exp Diabetes Res
PMID:Pancreatic beta-cell death, regeneration and insulin secretion: roles of poly(ADP-ribose) polymerase and cyclic ADP-ribose. 1199 Dec 1

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.
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PMID:Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. 1199 45

The rheological properties of plasma and blood cells are markedly influenced by the surrounding milieu: physicochemical factors, metabolism and hormones. Acid/base status, osmolality, lipid status and plasma protein pattern are well known to exert a major influence. The oxidative stress induced by increased free radicals production decreases red cell deformability. Among circulating substances, the divalent cations magnesium and zinc improve red cell deformability probably via calcium antagonistic effects. Some metabolites like lactate or ketone bodies decrease red cell deformability, although the former has apparently the opposite effect in highly trained individuals. Endothelium-derived factors such as nitric oxide (NO) and several arachidonic acid derivatives modulate both RBC and white cell mechanics. Endothelium regulates also blood rheology via the release of PAI-1 which governs plasma fibrinogen levels. However, endothelium is not the only organ involved in the regulation of blood rheology: the kidney (by releasing erythropoietin which is a major "viscoregulatory" factor), the endocrine pancreas (via the action of insulin and glucagon on red cells), the adrenal gland (norepinephrine) and the endocrine heart (atrial natriuretic peptide) are also likely to exert important effects. Recently, increasing evidence is accumulating for a role of two other endocrine tissues in the regulation of blood rheology: the adipose tissue (free fatty acids, PAI-1, IL-6, leptin) and the pituitary gland (growth hormone-somatomedin axis, including the somatomedin carrier protein IGFBP1). These organs provide a link between body composition and hemorheology, since GH and somatomedins are major regulators of the body content in fat and water while the endocrine activity of fat mass is apparently proportional to its size. These mechanisms explain to some extent why many situations, either physiological (diet, exercise) or pathological (diabetes, uremia) are associated with marked changes in blood rheology that may in turn modify micro and macrocirculatory hemodynamics and the distribution of O(2) and fuels to tissues.
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PMID:Hormones, metabolism and body composition as major determinants of blood rheology: potential pathophysiological meaning. 1208 54

Although hypertension, hyperlipidemia, diabetes and smoking are known risk factors of atherosclerosis in Caucasians, their relative contributions to early atherosclerosis among Japanese are unknown. Decrease in flow-mediated dilation (FMD) of the brachial artery is a useful marker of endothelial dysfunction and early atherosclerosis. To evaluate the relative contribution of hypertension to early atherogenesis, we determined FMD, as well as plasma levels of tissue-type plasminogen activator (t-PA; a sensitive index of endothelial damage) and tumor necrosis factor (TNF)-a and interleukin (IL)-6 (established markers of inflammation) in normotensive and hypertensive patients under treatment. FMD was significantly reduced as the number of risk factors increased, suggesting that accumulations of risk factors were related to endothelial dysfunction. FMD was reduced in hypertensives (9.9 +/- 5.8 (SD) %) compared to normotensives (14.6 +/- 7.6, p<0.01) despite good blood pressure control (139 +/- 20/80 +/- 14 mmHg in hypertensives). Nitroglycerine-induced endothelium-independent vasodilation was not altered in hypertensives (16.0 +/- 6.3%) as compared to normotensives (16.7 +/- 5.8). Plasma t-PA, TNF-alpha, and IL-6 levels were increased in hypertensives despite good blood pressure control. Thus, hypertension alone is a high risk for early atherosclerosis. Persistent endothelial damage and moderate inflammation may increase the risk of early atherosclerosis synergistically under the presence of hypertension in Japanese.
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PMID:Association of cardiovascular risk factors and endothelial dysfunction in japanese hypertensive patients: implications for early atherosclerosis. 1213 29

The assessment of markers of systemic inflammation, such as C-reactive protein (CRP) and interleukin 6 (IL6), could be used to identify persons at high risk of coronary heart disease (CHD). This study evaluates the relationship of CRP and IL6 with CHD risk factors in patients with type 2 diabetes mellitus (DM) with CHD and age and sex matched type 2 DM controls without CHD. CRP, IL-6, total plasma homocysteine (tHcy), lipoprotein (a) [Lp(a)] and sialic acid (SA) were determined in 55 type 2 diabetic patients with CHD and 51 age- and sex-matched type 2 diabetic controls without CHD. Multivariate and logistic regression analyses were used to relate these markers with CHD risk factors. CRP (P=0.02) and tHcy (P=0.03) were significantly higher in patients with CHD compared with the control group even after correction for age and sex. IL6, Lp(a), SA and lipid parameters were not significantly different between the two groups of patients. After adjustment for potential confounders, the odds ratio (OR) for elevated CRP was 2.00 (95% confidence interval [CI], 1.12-3.58) (P=0.02) but the OR for IL6 was 3.41 95% CI, 0.70-17.17 (P=0.14). Partial correlation analyses of CRP and IL6 with other variables showed significant correlation of CRP with tHcy, and SA in patients with CHD only. Our results support the inclusion of CRP (high-sensitivity assay), in the risk assessment of diabetic subjects.
Diabetes Res Clin Pract 2002 Oct
PMID:Association of C-reactive protein with coronary heart disease risk factors in patients with type 2 diabetes mellitus. 1216 Oct 55

Linomide prevents the development of autoimmune insulitis and insulin-deficient diabetes mellitus in female NOD mice. Linomide prevents development of autoimmune manifestations in other experimentally induced and spontaneous autoimmune diseases as well, but the mechanism of action is unknown. The present report summarizes our investigations on the effect of Linomide on different functional T cell subsets in NOD mice analyzed according to their cytokine profile. Supernatants from cultured splenocytes and peritoneal cells taken from Linomide-treated mice contained lower levels of TNFalpha, IL-1 beta, IFN gamma and IL-12 versus higher levels of IL-4, IL-6 and IL-10 in comparison with supernatants from cultures of untreated mice. Our results suggest that regulation of autoimmunity following oral Linomide administration in NOD mice induces a shift from Th(1) to Th(2) phenotype response, thereby preventing the development of diabetes by active cytokine-induced immunoregulation of T cell subsets, including downregulation of Th(1) and upregulation of Th(2).
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PMID:Cytokine production in Linomide-treated nod mice and the potential role of a Th (1)/Th(2) shift on autoimmune and anti-inflammatory processes. 1218 43

We have conducted three studies to examine the role of TNFalpha in islet destruction in female nonobese diabetic mouse (NOD) mice, a model of human autoimmune diabetes, using polyethylene glycolated (PEGylated) soluble TNF receptor type I (PEG sTNF-RI) as TNFalpha antagonist. PEG sTNF-RI (3 mg/kg, sc) was given every other day to NOD mice from age wk 8 for 12 wk (study 1), from age wk 12 for 8 wk (study 2), or from age wk 8 for 3 wk, with cyclophosphamide (6 mg/mouse) injected at wk 9 to accelerate the onset of diabetes (study 3). Diabetic incidence was reduced (control vs. PEG sTNF-RI) from 68.7% (11 of 16) to 18.3% (3 of 16) in study 1, from 84.6% (11 of 13) to 28.5% (4 of 14) in study 2, and from 66.6% (8 of 12) to 23.1% (3 of 13) in study 3, respectively. The incidence of insulitis was also reduced from 91.6% (11 of 12) to 12.5% (2 of 16) in study 1 and from 100% (7 of 7) to 16.6% (2 of 12) in study 2 by PEG sTNF-RI. PEG sTNF-RI also largely preserved islet insulin content, reduced mRNA of inducible nitric oxide synthase and IL-6 in pancreases, and lowered plasma corticosterone, glycerol, and free fatty acid levels. These results confirm a pathogenic role of TNFalpha in mediating insulitis in NOD mice and suggest the prophylactic and therapeutic potential of PEG sTNF-RI for human autoimmune diabetes.
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PMID:Polyethylene glycolated recombinant TNF receptor I improves insulitis and reduces incidence of spontaneous and cyclophosphamide-accelerated diabetes in nonobese diabetic mice. 1219 62


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