Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overproduction of IL-6, a proinflammatory cytokine, is associated with a spectrum of age-related conditions including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. To describe the pattern of change in IL-6 over 6 years among older adults undergoing a chronic stressor, this longitudinal community study assessed the relationship between chronic stress and IL-6 production in 119 men and women who were caregiving for a spouse with dementia and 106 noncaregivers, with a mean age at study entry of 70.58 (SD = 8.03) for the full sample. On entry into this portion of the longitudinal study, 28 of the caregivers' spouses had already died, and an additional 50 of the 119 spouses died during the 6 years of this study. Levels of IL-6 and health behaviors associated with IL-6 were measured across 6 years. Caregivers' average rate of increase in IL-6 was about four times as large as that of noncaregivers. Moreover, the mean annual changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse. There were no systematic group differences in chronic health problems, medications, or health-relevant behaviors that might have accounted for caregivers' steeper IL-6 slope. These data provide evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response.
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PMID:Chronic stress and age-related increases in the proinflammatory cytokine IL-6. 1284 Jan 46

To examine the influence of type 2 diabetes on cytokine release from the leg at rest and during exercise, 9 male type 2 diabetics (D) and 8 age-, gender-, Vo2peak-, weight- and body mass index (BMI)-matched control subjects (C) were studied before and after 25 minutes of supine bicycle exercise at 60% Vo2peak. Blood samples were obtained from a femoral artery and vein from 1 limb, and plasma was analyzed for glucose and the cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. Leg blood flow (LBF) was measured by thermodilution in the femoral vein, and net leg IL-6, TNF-alpha, and glucose balance were calculated as the product of LBF and femoral arteriovenous (fa-v) glucose, IL-6, and TNF-alpha difference. Arterial plasma glucose and IL-6 were higher (P<.05) at rest in D compared with C, but there were no differences in arterial TNF-alpha concentrations at rest when comparing groups. Despite measurable arterial levels of both IL-6 and TNF-alpha in both groups at rest, there was not net leg release of either cytokine at rest. Exercise increased (P<.05) IL-6 release and glucose uptake in both D and C, and contracting leg glucose uptake was similar when comparing D with C. While not significant, there was a trend (P=.1) for augmented exercise-induced IL-6 release in D compared with C. In contrast, exercise did not result in TNF-alpha release in either D or C. These data demonstrate that basal circulating TNF-alpha is not elevated in patients with type 2 diabetes when matched for BMI with control subjects. The results also suggest that neither type 2 diabetic nor healthy skeletal muscle releases these cytokines at rest, indicating that organs other than skeletal muscle contribute to the elevated basal IL-6 in type 2 diabetics. In contrast with IL-6, exercise does not result in the release of TNF-alpha from the contracting limbs of either healthy subjects or patients with type 2 diabetes.
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PMID:Skeletal muscle interleukin-6 and tumor necrosis factor-alpha release in healthy subjects and patients with type 2 diabetes at rest and during exercise. 1287 Jan 75

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

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

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.
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PMID:Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. 1457 97

IL-6 has emerged as an important cytokine upregulated in states of insulin resistance such as type 2 diabetes. We evaluated the chronic effect of IL-6 on insulin signaling in 3T3-F442A and 3T3-L1 adipocytes. First, cells responded to a chronic treatment with IL-6 by initiating an autoactivation process that increased IL-6 secretion. Second, IL-6-treated adipocytes showed a decreased protein expression of IR-beta subunit and IRS-1 but also an inhibition of the insulin-induced activation of IR-beta, Akt/PKB, and ERK1/2. Moreover, IL-6 suppressed the insulin-induced lipogenesis and glucose transport consistent with a diminished expression of GLUT4. IL-6-treated adipocytes failed to maintain their adipocyte phenotype as shown by the downregulation of the adipogenic markers FAS, GAPDH, aP2, PPAR-gamma, and C/EBP-alpha. IL-6 also induced the expression of SOCS-3, a potential inhibitor of insulin signaling. Finally, the effects of IL-6 could be prevented by rosiglitazone, an insulin-sensitizing agent. Thus, IL-6 may play an important role in the set-up of insulin resistance in adipose cell.
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PMID:Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. 1459 24

Oxidative stress is hypothesized to play a role in the development of diabetes with and without nephropathy. In addition, it has been suggested that some metabolic abormalities associated with diabetes may be due to cytokine overproduction. In the light of this knowledge, we aimed to measure MDA levels as a marker of oxidative stress and the IL-6 level in diabetes with and without different stages of nephropathy. Plasma MDA levels in the group of NIDDM patients with advanced nephropathy were significantly higher than in the group of NIDDM patients without nephropathy, which had significantly higher levels compared with the control group. Although IL-6 levels were elevated in diabetic groups with and without nephropathy in comparison with the control, no significant difference was found between patient groups. As a conclusion, oxidative stress may play an important role in diabetes with and without nephropathy, but the IL-6 level may not be useful in the evaluation of diabetic nephropathy.
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PMID:No association between oxidative stress and IL-6 in NIDDM patients with nephropathy. 1474 39

We conducted a prospective, nested, case-control study of inflammatory markers as predictors of type 2 diabetes among 32,826 women who provided blood samples in 1989 through 1990 in the Nurses' Health Study. Among women free of diabetes, cardiovascular disease, or cancer at baseline, 737 had developed diabetes by 2000. Control women (n = 785) were selected matched on age, fasting status, race, and BMI for cases in the top BMI decile. Baseline levels of tumor necrosis factor (TNF)-alpha receptor 2, interleukin (IL)-6, and C-reactive protein (CRP) were significantly higher among case than control subjects (all P </= 0.001). After adjusting for BMI and other lifestyle factors, all three biomarkers significantly predicted diabetes risk; the odds ratios (ORs) comparing extreme quintiles were 1.64 (95% CI 1.10-2.45) for TNF-alphaR2, 1.91 (1.27-2.86) for IL-6, and 4.36 (2.80-6.80) for CRP (P for trend <0.001 for all biomarkers). In a multivariate model simultaneously including the three biomarkers, only CRP levels were significantly associated with risk of diabetes (OR comparing extreme quintiles of CRP = 3.99, P for trend <0.001). These data support the role of inflammation in the pathogenesis of type 2 diabetes. Elevated CRP levels are a strong independent predictor of type 2 diabetes and may mediate associations of TNF-alphaR2 and IL-6 with type 2 diabetes.
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PMID:Inflammatory markers and risk of developing type 2 diabetes in women. 1498 54

Obesity is a risk factor for type 2 diabetes and cardiovascular diseases. The hypothesis that cytokines could play a role in the pathophysiology of obesity and insulin resistance is suggested in the last few years. We showed a positive correlation between circulating interleukin (IL-6) levels and obesity and insulin resistance suggesting that IL-6 could be involved in insulin resistance in humans. We showed a decrease of both circulating and adipose tissue IL-6 levels in non-diabetic obese subjects after a very low calorie diet program inducing weight loss. This suggests that adipose tissue could be involved in the regulation of circulating IL-6 levels in these subjects. Adipose tissue is also involved in lipodystrophies particularly in HIV patients on antiviral therapy. We showed an alteration of the SREBP-1 transcription step in subcutaneous abdominal adipose tissue from HIV patients. We found an inverse correlation between circulating adiponectin levels and both insulin resistance and cardiovascular risk factors such as CRP levels and apolipoprotein B/A1 ratio. These findings suggest that adipose tissue is involved in insulin resistance in humans particularly via adipocytokine secretion.
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PMID:[Insulin resistance and adipose tissue gene expression in humans]. 1504 87

The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. To determine the role of IL-6 in the development of insulin resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps in awake mice. Pretreatment of IL-6 blunted insulin's ability to suppress hepatic glucose production and insulin-stimulated insulin receptor substrate (IRS)-2-associated phosphatidylinositol (PI) 3-kinase activity in liver. Acute IL-6 treatment also reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1-associated PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. In contrast, we found that co-treatment of IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6-induced defects in hepatic insulin action and signaling activity. Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipid-induced defects in insulin action and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. This is the first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in vivo, and the mechanism may involve cytokine-induced alteration in intracellular fat contents. These findings implicate an important role of inflammatory cytokines in the pathogenesis of insulin resistance.
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PMID:Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. 1504 22


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