Inflammatory markers and risk of developing type 2 diabetes in women.

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.

[1]  R. Henry,et al.  The expression of TNF alpha by human muscle. Relationship to insulin resistance. , 1996, The Journal of clinical investigation.

[2]  P W Macfarlane,et al.  Pravastatin and the Development of Diabetes Mellitus: Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study , 2001, Circulation.

[3]  M. Fantone,et al.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus , 1997, Diabetes Care.

[4]  S. Coppack,et al.  C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[5]  U. Das.  Is obesity an inflammatory condition? , 2001, Nutrition.

[6]  P. Ridker,et al.  Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. , 1997, The New England journal of medicine.

[7]  S. Haffner,et al.  Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. , 2002, Diabetes.

[8]  T. Funahashi,et al.  Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. , 2003, Diabetes care.

[9]  J. Wilding.  Obesity and Type 2 diabetes mellitus , 2000, Diabetic medicine : a journal of the British Diabetic Association.

[10]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[11]  J. Pankow,et al.  Low-grade systemic inflammation and the development of type 2 diabetes mellitus [ndash] : the ARIC Study , 2003 .

[12]  S. Haffner,et al.  Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). , 2000, Circulation.

[13]  A. Ducharme,et al.  Enalapril Reduces the Incidence of Diabetes in Patients With Chronic Heart Failure: Insight From the Studies Of Left Ventricular Dysfunction (SOLVD) , 2003 .

[14]  M. A. Crook,et al.  Is Type II diabetes mellitus a disease of the innate immune system? , 1998, Diabetologia.

[15]  E. Rimm,et al.  Glycemic status and soluble tumor necrosis factor receptor levels in relation to plasma leptin concentrations among normal weight and overweight US men , 2000, International Journal of Obesity.

[16]  C. Meisinger,et al.  C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984-1998. , 2003, Archives of internal medicine.

[17]  Mustafa.  Abstract , 1952 .

[18]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[19]  J. Manson,et al.  C-Reactive Protein Is Independently Associated With Fasting Insulin in Nondiabetic Women , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[20]  K. Lam,et al.  Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus. , 2002, The Journal of clinical endocrinology and metabolism.

[21]  T. Valle,et al.  Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. , 2001, The New England journal of medicine.

[22]  B. Spiegelman,et al.  Tumor Necrosis Factor α: A Key Component of the Obesity-Diabetes Link , 1994, Diabetes.

[23]  Classification and Diagnosis of Diabetes Mellitus and Other Categories of Glucose Intolerance , 1979, Diabetes.

[24]  P. Manns,et al.  Physical activity, body fat, and serum c‐reactive protein in postmenopausal women with and without hormone replacement , 2003, American journal of human biology : the official journal of the Human Biology Council.

[25]  E. Rimm,et al.  Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. , 2001, Atherosclerosis.

[26]  L. Kuller,et al.  The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. , 2001, Diabetes.

[27]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[28]  Alessandro Pontillo,et al.  Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. , 2003, JAMA.

[29]  C. Chute,et al.  Effect of transport conditions on the stability of biochemical markers in blood. , 1989, Clinical chemistry.

[30]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[31]  S. Fowler,et al.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. , 2002 .

[32]  J. Pickup,et al.  Textbook of Diabetes , 1991 .

[33]  B. Spiegelman,et al.  Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. , 1995, The Journal of clinical investigation.

[34]  D. Green,et al.  Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. , 1999, Journal of the American College of Cardiology.

[35]  J. Manson,et al.  A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. , 1991, Archives of internal medicine.

[36]  F. Hu,et al.  Is type 2 diabetes mellitus a vascular condition? , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[37]  S. Yusuf,et al.  Ramipril and the development of diabetes. , 2001, JAMA.

[38]  P. Ridker,et al.  Do atherosclerosis and type 2 diabetes share a common inflammatory basis? , 2002, European heart journal.

[39]  F. Logerfo,et al.  Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. , 1999, Diabetes.

[40]  G A Colditz,et al.  Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. , 1999, JAMA.

[41]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[42]  G A Colditz,et al.  Impact of overweight on the risk of developing common chronic diseases during a 10-year period. , 2001, Archives of internal medicine.

[43]  Joachim Spranger,et al.  Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. , 2003, Diabetes.

[44]  N. Sattar,et al.  C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. , 2002, Diabetes.

[45]  P. Ridker.  Clinical application of C-reactive protein for cardiovascular disease detection and prevention. , 2003, Circulation.

[46]  Graham A. Colditz,et al.  Body weight and mortality among women , 1995 .

[47]  N. Sattar,et al.  Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. , 2002, Diabetes care.

[48]  P. Macfarlane,et al.  The prognostic value of the electrocardiogram in the west of Scotland coronary prevention study , 2002 .

[49]  W. Willett,et al.  Reproducibility and validity of a semiquantitative food frequency questionnaire. , 1985, American journal of epidemiology.

[50]  G A Colditz,et al.  Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses' Health Study. , 1997, American journal of epidemiology.

[51]  M. Visser,et al.  Elevated C-reactive protein levels in overweight and obese adults. , 1999, JAMA.

[52]  Anson,et al.  DIET , LIFESTYLE , AND THE RISK OF TYPE 2 DIABETES MELLITUS IN WOMEN , 2001 .