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

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.
Diabetes 2003 Jul
PMID:Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. 1282 59

The aim of the present study was to investigate the effect of hypoglycaemia on the production capacity of the proinflammatory cytokines tumour necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) in subjects with and without diabetes. Hyperinsulinaemic (360 pmolm(-2) x min(-1)) stepped hypoglycaemic (5.0-3.5-2.5 mmoll(-1)) glucose clamps were performed in eight diabetic patients and in six non-diabetic subjects, and hyperinsulinaemic normoglycaemia (5.0 mmoll(-1)) control experiments were performed in four non-diabetic subjects. Circulating levels of cytokines and endotoxin-induced production of TNFalpha, IL-1beta, IL-6, and IL-10 were assessed. The effects of insulin and adrenaline were measured in separate in vitro experiments. In non-diabetic subjects, hypoglycaemia downregulated the production capacity of TNFalpha in a concentration-dependent fashion (P=0.007), but not of IL-1beta, IL-6, or IL-10. Compared to controls, the production capacity of TNFalpha in diabetic patients was already suppressed at normoglycaemia (P=0.02) and only fell in response to hypoglycaemic nadir (P=0.04). The downregulation of TNFalpha could not be explained by increased insulin or adrenaline levels. We conclude that hypoglycaemia specifically downregulates TNFalpha production capacity. Diabetic patients already have a suppressed TNFalpha production capacity at non-hypoglycaemic levels.
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PMID:Hypoglycaemia downregulates endotoxin-induced production of tumour necrosis factor-alpha, but does not affect IL-1beta, IL-6, or IL-10. 1284 5

Acute-phase biomarkers such as C-reactive protein (CRP) and IL-6 have emerged as predictors of incident type 2 diabetes mellitus, implicating chronic subclinical inflammation as a factor in the pathophysiology of diabetes. Gestational diabetes (GDM) identifies a population of women at high risk of subsequent type 2 diabetes mellitus, representing an early stage in the natural history of the disease. In this context, we performed a cross-sectional study to determine whether markers of subclinical inflammation are elevated in patients with GDM. We studied 180 healthy pregnant women undergoing oral glucose tolerance testing in the late second or early third trimester. Based on oral glucose tolerance testing and prepregnancy body mass index (BMI), participants were stratified into four groups: 1) normal glucose tolerance (NGT) lean (BMI, <25 kg/m(2)) (n = 65); 2) NGT overweight (n = 28); 3) impaired glucose tolerance (n = 39); and 4) GDM (n = 48). Median CRP level was highest in overweight NGT subjects (8.8 mg/liter), followed by GDM (5.5 mg/liter), impaired glucose tolerance (4.4 mg/liter), and lean NGT (4.4 mg/liter) (overall P = 0.0297). CRP was significantly correlated with prepregnancy BMI (r = 0.38, P < 0.0001), followed by fasting insulin (r = 0.27, P = 0.0002) and fasting blood glucose (r = 0.18, P = 0.016). In multivariate linear regression analysis, prepregnancy BMI emerged as the most important determinant of CRP concentration, whereas glycemic tolerance status was not a significant factor. Furthermore, the observed stepwise increase in CRP per tertile of prepregnancy BMI was not significantly attenuated by glycemic tolerance status or factors known to be associated with GDM. In summary, we demonstrate that maternal serum levels of CRP are not related to GDM but rather correlate significantly with prepregnancy obesity. An independent contribution of CRP to risk of GDM could not be confirmed. These data suggest a model in which obesity mediates a systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and glucose dysregulation.
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PMID:C-reactive protein and gestational diabetes: the central role of maternal obesity. 1291 26

The nonobese mouse model of autoimmune diabetes (NOD mouse) exhibits a strain-dependent preponderance of disease in females. Castration of male NOD mice leads to an increased incidence of diabetes, suggesting that testosterone directly modulates the expression of diabetes in the NOD mouse. However, castration also modulates hypothalamic and pituitary hormone production via removal of the negative feedback effects of testosterone. One hypothalamic hormone with immunomodulatory properties whose expression is increased by castration is GnRH. To test whether the increased incidence of diabetes in castrated male NOD mice is related to an increase in GnRH activity, we treated castrated male NOD mice with Antide, a GnRH receptor antagonist, to determine the effect on the incidence and timing of onset of diabetes. The prevalence of diabetes at 40 wk of age in male NOD mice was 50% in sham-operated mice, compared with an 83% prevalence in castrated males. Antide administration prevented the increased incidence of diabetes in the castrated male mice. Antide reduced total serum IgG levels, IL-6 cytokine expression in cultured splenocytes, and the lymphocytic infiltration of islets. GnRH administration exerted reciprocal effects, leading to earlier timing of onset of diabetes and increases in serum total IgG levels. We conclude that GnRH modulates the expression of diabetes in the NOD mouse independently of gonadal steroids.
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PMID:Modulation of diabetes with gonadotropin-releasing hormone antagonists in the nonobese mouse model of autoimmune diabetes. 1295 92

Hypertension is proposed as a risk factor among others (high age, diabetes mellitus, and pre- and intraoperative bleeding) for adverse outcomes, such as severe infections, leading to sepsis and to multiple organ failure as the most deleterious complication. Hypertension was modeled with spontaneous hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats and the infective complication by polymicrobial, peritoneal contamination, and infection (PCI). The concept of clinic modeling randomized trials was used to simulate clinical complexity, including a relevant antibiotic prophylaxis in combination with granulocyte-colony stimulating factor (G-CSF) and clinical trial conditions. Outcome parameters were: survival, systemic cytokines (protein), and organ-specific cytokine levels (mRNA). With low complexity (no prophylaxis), 28% of the animals in the Wistar and 50% in the SHR group survived (P=0.17). Tumor necrosis factor-alpha levels were lower in the liver of SHR vs. Wistar rats with PCI (P<0.01). The anti-inflammatory cytokine interleukin (IL)-10 was expressed on a higher level in SHR with PCI compared with Wistar rats (P<0.01). With increased complexity (antibiotic and G-CSF prophylaxis) the survival rate was increased from 50% in Wistar rats to 89% in SHR (P<0.01) and the mRNA expression of IL-6 was decreased in the kidney of SHR (P<0.05). Survival rate was 44% in the DS rats vs. 67% of the Wistar rats (P=0.18). The mRNA expression of tumor necrosis factor-alpha and IL-10 was reduced (P<0.01) by pretreatment in the liver of DS rats with PCI. The hypertensive, genetically distinct SHR and DS rats express different patterns of pro- and anti-inflammatory cytokine levels after PCI. G-CSF and antibiotic prophylaxis increases only in SHR survival and decreases IL-6 mRNA expression in the kidney significantly.
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PMID:The genetic background of hypertensive, septic rats determines outcome improvement with antibiotic and G-CSF prophylaxis. 1450 46

Failure of insulin producing pancreatic beta-cells is a common characteristic of type 1 (insulin-dependent) and type 2 (insulin non-dependent) diabetes mellitus. Accumulating evidence suggests that programmed cell death (apoptosis) is the main form of beta-cell death in these disorders. The beta-cell is particularly sensitive to apoptotic stimuli due to the inherent features of the specialized beta-cell phenotype. In type 1 diabetes anti-beta-cell autoimmune reactivity delivers the apoptotic signals in the form of inflammatory mediators or T-cell effectors. In type 2 diabetes, the metabolic derangement is associated with production of inflammatory mediators in insulin-sensitive tissues leading elevated levels of circulating inflammatory mediators such as IL-6 and TNF. Further glucose has been suggested to induce beta-cell apoptosis via the induction of beta-cell synthesis of IL-1 which via autocrine action may elicit signalling cascades analogous to those seen in beta-cell destruction in type 1 diabetes. Considering the apparent importance of IL-1-beta signalling in beta-cell failure in both type 1 and type 2 diabetes, we here review the modulatory effect exerted on IL-1signalling by cellular characteristics related to the specialized beta-cell phenotype. We conclude that beta-cell differentiation signals (Pdx-1), glucose metabolism, calcium handling as well as regulation of naturally occurring inhibitors of cytokine signalling contribute to sensitize the beta-cell to apoptotic stimuli. We hypothesize that immunological stimuli in type 1 diabetes and metabolic/inflammatory signals in type 2 diabetes converge on common signalling pathways leading to beta-cell failure and destruction in these two diseases.
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PMID:Apoptotic signal transduction pathways in diabetes. 1455 18

Patients with diabetes are at increased risk for adverse events after coronary stenting, perhaps reflecting a pro-inflammatory state. To characterize the inflammatory response to coronary stenting in patients with and without diabetes, blood samples were obtained from 75 patients before stenting and 10 minutes, 1 hour, and 24 hours later. C-reactive protein (CRP, microg/ml), interleukin (IL)-6 (pg/ml), IL-1 receptor antagonist (pg/ml), and soluble CD40 ligand (ng/ml) were assayed in each sample by enzyme-linked immunosorbent assay. Concentration changes after stenting were identified by repeated-measures analysis of variance. Multivariate analysis was performed to delineate independent predictors of increased concentrations of inflammation markers. Overall, 88% of patients had acute coronary syndromes; 36% had elevated markers of cardiac injury. The preprocedural concentrations of CRP in those with diabetes were more than twice as high as those in patients without diabetes. Two independent predictors of elevated preprocedural CRP concentrations were diabetes (odds ratio 3.95, 95% confidence interval 1.17 to 13.4) and a cardiac marker-positive acute coronary syndrome (odds ratio 3.70, 95% confidence interval 1.22 to 11.2). Preprocedural concentrations of IL-6, IL-1 receptor antagonist, and soluble CD40 ligand tended to be greater in patients with diabetes. The increase in CRP after stenting was much greater for patients without diabetes compared with that in patients with diabetes such that the apparent intensity of inflammation after 24 hours was similar in those with and without diabetes. Thus, patients with and without diabetes exhibit different inflammatory responses to stenting, reflecting the lower preprocedural inflammation in those without diabetes versus those with diabetes.
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PMID:Comparison of inflammatory markers in patients with diabetes mellitus versus those without before and after coronary arterial stenting. 1455 67

Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. Importantly, the sixfold elevation of IL-6 attained with constant infusion was similar to levels reached in obesity. Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. IL-6 had no effect on the mass of these proteins. IL-6 also decreased refeeding-dependent glucokinase mRNA induction by approximately 40%. Insulin tolerance tests revealed reduced insulin sensitivity. In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity.
Diabetes 2003 Nov
PMID:Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. 1457 97

Although approximately 1 million islets exist in the adult human pancreas, current pancreas preservation and islet isolation techniques recover <50%. Presently, cadaveric donors remain the sole source of pancreatic tissue for transplantation. Brain death is characterized by activation of proinflammatory cytokines and organ injury during preservation and reperfusion. In this study, we assessed the effects of brain death on islet isolation yields and functionality. Brain death was induced in male 250- to 350-g Lewis rats by inflation of a Fogarty catheter placed intracranially. The rats were mechanically ventilated for 2, 4, and 6 h before removal of the pancreas (n = 6). In controls, the catheter was not inflated (n = 6). Shortly after brain death induction, a significant increase in serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 was demonstrated in a time-dependent manner. Upregulation of TNF-alpha, IL-1beta, and IL-6 mRNA was noted in the pancreas. Brain death donors presented lower insulin release after glucose stimulation assessed by in situ perfusion of the pancreas. Islet recovery was reduced in brain death donors compared with controls (at 6 h 602.3 +/- 233.4 vs. 1,792.5 +/- 325.4 islet equivalents, respectively; P < 0.05). Islet viability assessed in dissociated islet cells and in intact cultured islets was reduced in islets recovered from brain death donors, an effect associated with higher nuclear activities of NF-kappaB p50, c-Jun, and ATF-2. Islet functionality evaluated in vitro by static incubation and in vivo after intraportal transplantation in syngeneic streptozotocin-induced diabetic rats was significantly reduced in preparations obtained from brain death donors. In conclusion, brain death significantly reduced islet yields and functionality. These observations may lead to strategies to reduce the effects of brain death on pancreatic islets and improve the results in clinical transplantation.
Diabetes 2003 Dec
PMID:Brain death significantly reduces isolated pancreatic islet yields and functionality in vitro and in vivo after transplantation in rats. 1463 54

Several studies have demonstrated that diabetes is a risk factor for developing periodontal disease, increasing its prevalence and severity. Furthermore, periodontitis may impair the metabolic control and adequate treatment of diabetic patients. LPS from Gram-negative bacteria penetrates the periodontal tissues and subsequently recruits and activates immune cells. Progression to severe periodontitis with loss of supporting structures is mediated by several factors, including secretion of a broad spectrum of inflammatory and destructive (PGE2). mediators such as cytokines (TNF-alpha, IL-1b and IL-6), chemokines (IL-8) and prostaglandin E2. The aim of this work is to investigate differences in the TNF-a, IL-1b and IL-6 expression and prostaglandin E2 (PGE2) release in blood from diabetic patients with and without aggressive periodontitis (AP) stimulated with lipopolysaccharide (LPS). For this purpose we recruited 29 Type 1 diabetes mellitus (DM) patients, 14 with AP and 15 without AP. Fourteen healthy individuals formed the control group. For cytokine expression and PGE2 secretion, an ex vivo whole blood culture system was used. Cytokines and PGE2 were detected by commercial immunometric assays. A wide range of inter-individual variability in spontaneous and LPS-induced TNF-alpha, IL-1b and IL-6 levels in patient groups and controls was found. The mean of spontaneous and LPS-induced TNF-alpha and IL-1b levels did not differ significantly (p > 0.5) when patients were compared to control individuals. Although not significant, the spontaneous TNF-alpha, IL-1b and IL-6 levels in the group of Type 1 DM with AP were higher than in controls, while in diabetic patients without AP, these values were depressed in comparison with controls. In both groups of patients, the means of LPS-induced IL-6 levels were higher than the controls but the differences observed were not significant (p = 0.07). However, the LPS-induced PGE2 levels varied significantly when all groups were compared (p = 0.007). The means of LPS-induced PGE2 levels for Type 1 diabetic patients with AP (p = 0.0009) and without AP (p = 0.024) were significantly higher than the levels observed for healthy controls. Finally, we conclude that Type 1 diabetic patients with or without AP did not express higher LPS-induced TNF-a, IL-1b and IL-6 levels than controls. However, the PGE2 levels released were significantly higher than those detected in controls.
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PMID:Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha, IL-1beta, IL-6 and PGE2 secretion in whole blood from Type 1 diabetes mellitus patients with or without aggressive periodontitis. 1465 85


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