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Journal ArticleDOI

Complement C3 is a risk factor for the development of diabetes: a population-based cohort study.

01 Feb 2005-Diabetes (American Diabetes Association)-Vol. 54, Iss: 2, pp 570-575
TL;DR: It is concluded that the risk of developing diabetes is related to levels of complement C3, and only C3 was significantly associated with diabetes development after further adjustments for potential confounders, including BMI, insulin, and other inflammatory markers.
Abstract: Cross-sectional studies have reported strong correlations between plasma levels of complement C3, insulin, and glucose. This prospective study explored whether elevated levels of C3, C4, and other inflammation-sensitive plasma proteins (ISPs; fibrinogen, orosomucoid, alpha1-antitrypsin, haptoglobin, and ceruloplasmin) are associated with the development of diabetes. Plasma proteins were measured in 2,815 nondiabetic healthy men, age 38-50 years, who were reexamined after a mean follow-up of 6.1 years. Diabetes development (n = 123) was studied in relation to baseline levels of plasma proteins. After adjusting for age, screening year, and glucose at baseline, the odds ratio (95% CI) for developing diabetes was 1.00, 2.4 (1.1-5.3), 2.9 (1.4-6.0), and 5.6 (2.8-10.9), respectively, for men with C3 in the 1st, 2nd, 3rd, and 4th quartiles (trend: P < 0.00001). Fibrinogen, haptoglobin, C4, and the number of elevated ISPs were also related to future diabetes in this model. Only C3 was significantly associated with diabetes development after further adjustments for potential confounders, including BMI, insulin, and other inflammatory markers. We concluded that the risk of developing diabetes is related to levels of complement C3.
Citations
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Journal ArticleDOI
TL;DR: Traffic-related air pollution is associated with incident type 2 diabetes among elderly women, and C3c was associated with PM pollution at baseline and was a strong independent predictor of incident diabetes.
Abstract: BackgroundCross-sectional and ecological studies indicate that air pollution may be a risk factor for type 2 diabetes, but prospective data are lacking.ObjectiveWe examined the association between ...

365 citations


Cites result from "Complement C3 is a risk factor for ..."

  • ...Second, elevated C3 levels were associated with incident type 2 diabetes in our study population, which confirms results from a population-based cohort study in Sweden (Engström et al. 2005)....

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Patent
08 Jun 2006
TL;DR: In this article, small interfering RNAs which are specific for the vascular endothelial growth factor (VEGF) gene and the VEGF receptor genes Flt-1 and Flk-1/KDR inhibit expression of these genes.
Abstract: RNA interference using small interfering RNAs which are specific for the vascular endothelial growth factor (VEGF) gene and the VEGF receptor genes Flt-1 and Flk-1/KDR inhibit expression of these genes. Diseases which involve angiogenesis stimulated by overexpression of VEGF, such as diabetic retinopathy, age related macular degeneration and many types of cancer, can be treated by administering the small interfering RNAs.

278 citations

Journal ArticleDOI
TL;DR: Biomarker panels for frailty would be of high value and better than single markers.

267 citations


Cites background from "Complement C3 is a risk factor for ..."

  • ...(Engstrom et al., 2005), these proteins were also found to be involved in atherosclerosis, although their...

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  • ...While C1qb is a clinical predictor (Peters et al., 2017) and C3 a risk factor for type 2 diabetes (Engstrom et al., 2005), these proteins were also found to be involved in atherosclerosis, although their role is still controversial....

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Journal ArticleDOI
01 May 2010-Obesity
TL;DR: VAT in T2D expresses higher levels of adipokines involved in inflammation, which may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.
Abstract: Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age- and gender- matched controls). Metabolic parameters were measured in the fasted state: body composition by dual-energy X-ray absorptiometry and insulin action by hyperinsulinemic-euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase-PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein (MIP), interleukin-8 (IL-8)). Fasting glucose related to VAT expression of TNFalpha, MIP, serum amyloid A (SAA), IL-1alpha, IL-1beta, IL-8, and IL-8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element-binding protein (CREBP), IL-1beta, and IL-8. Insulin action related inversely to VAT complement C3 expression only. There were depot-specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol-binding protein-4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.

264 citations


Cites background from "Complement C3 is a risk factor for ..."

  • ...Prospective studies have shown fasting serum complement C3 levels predict incident T2D (16)....

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Journal Article
TL;DR: This review focuses on the known and emerging relations between inflammation and T2D, and the detrimental roles of proinflammatory cytokines and fatty acids on insulin signalling and β-cell function.
Abstract: The epidemic of overweight and obesity is a major problem because of the plethora of health and economic issues that it induces. Key among these is the sharply increasing prevalence of type 2 diabetes (T2D) and cardiovascular disease. The development of T2D is characterised by two processes: 1) insulin resistance, resulting from impaired insulin signalling and leading to an increased demand for insulin, which must be met by increased insulin production by pancreatic β-cells (compensatory β-cell function); and 2) β-cell dysfunction, with T2D developing when the amount of insulin that is produced is insufficient to meet the demand. Overweight and obesity, especially in case of abdominal fat accumulation, are associated with systemic low-grade inf lammation. This low-grade inf lammation is characterised by, among other things, higher levels of circulating proinflammatory cytokines and fatty acids. These can interfere with normal insulin function and thereby induce insulin resistance, and have also been implicated in β-cell dysfunction. This review focuses on the known and emerging relations between inflammation and T2D. We first discuss current views on the effects of fat distribution on adipose tissue inflammation and adipose tissue dysfunction. Next we focus on the detrimental roles of proinflammatory cytokines and fatty acids on insulin signalling and β-cell function. In the last part of this review we provide some insight into novel players in (the initiation of) inflammation in overweight and obesity, and their effects on T2D and vascular dysfunction.

208 citations


Cites background from "Complement C3 is a risk factor for ..."

  • ...Higher systemic C3 concentrations have been associated with several diabetes risk factors, including obesity, insulin resistance and NAFLD,(137,138) and were shown to be independently associated with incidence of T2D, at least in men.(139) Various lines of evidence suggest a biologically relevant,...

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References
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Journal ArticleDOI
TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

29,217 citations

Journal ArticleDOI
18 Jul 2001-JAMA
TL;DR: Elevated levels of CRP and IL-6 predict the development of type 2 DM, and data support a possible role for inflammation in diabetogenesis.
Abstract: Results Baseline levels of IL-6 (P,001) and CRP (P,001) were significantly higher among cases than among controls The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 75 for IL-6 (95% confidence interval [CI], 37-154) and 157 for CRP (95% CI, 65-379) Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 23 for IL-6 (95% CI, 09-56; P for trend=07) and 42 for CRP (95% CI, 15-120; P for trend=001) Similar results were observed in analyses limited to women with a baseline hemoglobin A1c of 60% or less and after adjustment for fasting insulin level

4,107 citations

Journal ArticleDOI
TL;DR: The data suggest that adipose tissue is an important determinant of a low level, chronic inflammatory state as reflected by levels of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, and that infection with H pylori, C pneumoniae, and cytomegalovirus is not.
Abstract: C-reactive protein, a hepatic acute phase protein largely regulated by circulating levels of interleukin-6, predicts coronary heart disease incidence in healthy subjects. We have shown that subcutaneous adipose tissue secretes interleukin-6 in vivo. In this study we have sought associations of levels of C-reactive protein and interleukin-6 with measures of obesity and of chronic infection as their putative determinants. We have also related levels of C-reactive protein and interleukin-6 to markers of the insulin resistance syndrome and of endothelial dysfunction. We performed a cross- sectional study in 107 nondiabetic subjects: (1) Levels of C-reactive protein, and concentrations of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, were related to all measures of obesity, but titers of antibodies to Helicobacter pylori were only weakly and those of Chlamydia pneumoniae and cytomegalovirus were not significantly correlated with levels of these molecules. Levels of C-reactive protein were significantly related to those of interleukin-6 (r=0.37, P<0.0005) and tumor necrosis factor-α (r=0.46, P<0.0001). (2) Concentrations of C-reactive protein were related to insulin resistance as calculated from the homoeostasis model assessment model, blood pressure, HDL, and triglyceride, and to markers of endothelial dysfunction (plasma levels of von Willebrand factor, tissue plasminogen activator, and cellular fibronectin). A mean standard deviation score of levels of acute phase markers correlated closely with a similar score of insulin resistance syndrome variables (r=0.59, P<0.00005), this relationship being weakened only marginally by removing measures of obesity from the insulin resistance score (r=0.53, P<0.00005). These data suggest that adipose tissue is an important determinant of a low level, chronic inflammatory state as reflected by levels of interleukin-6, tumor necrosis factor-α, and C-reactive protein, and that infection with H pylori, C pneumoniae, and cytomegalovirus is not. Moreover, our data support the concept that such a low-level, chronic inflammatory state may induce insulin resistance and endothelial dysfunction and thus link the latter phenomena with obesity and cardiovascular disease.

2,586 citations

Journal ArticleDOI
01 Apr 2002-Diabetes
TL;DR: Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 1 diabetes independent of insulin resistance and other known risk factors for diabetes.
Abstract: Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.

1,070 citations

Journal ArticleDOI
TL;DR: It is suggested that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair.
Abstract: Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, α-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acute-phase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair. [Diabetologia (1998) 41: 1241–1248]

1,023 citations