Circulating tumor necrosis factor-alpha concentrations in a native Canadian population with high rates of type 2 diabetes mellitus.

Recent research suggests that tumor necrosis factor-alpha (TNF alpha) may play an important role in obesity-associated insulin resistance and diabetes. We studied the relationship between TNF alpha and the anthropometric and physiological variables associated with insulin resistance and diabetes in an isolated Native Canadian population with very high rates of type 2 diabetes mellitus (DM). A stratified random sample (n = 80) of participants was selected from a population-based survey designed to determine the prevalence of type 2 DM and its associated risk factors. Fasting blood samples for glucose, insulin, triglyceride, leptin, and TNF alpha were collected; a 75-g oral glucose tolerance test was administered, and a second blood sample was drawn after 120 min. Insulin resistance was estimated using the homeostasis assessment (HOMA) model. Systolic and diastolic blood pressure (BP), height, weight, and waist and hip circumferences were determined, and percent body fat was estimated using biological impedance analysis. The relationship between circulating concentrations of TNF alpha and the other variables was assessed using Spearman correlation coefficients, analysis of covariance, and multiple linear regression. The mean TNF alpha concentration was 5.6 pg/mL (SD = 2.18) and ranged from 2.0-12.9 pg/mL, with no difference between men and women (P = 0.67). There were moderate, but statistically significant, correlations between TNF alpha and fasting insulin, HOMA insulin resistance (HOMA IR) waist circumference, fasting triglyceride, and systolic BP (r = 0.23-0.34; all P < 0.05); in all cases, coefficients for females were stronger than those for males. Individuals with normal glucose tolerance had lower log TNF alpha concentrations than those with impaired glucose tolerance or type 2 DM (both P = 0.03, adjusted for age and sex), although differences were not significant after adjustment for HOMA IR (both P > 0.25). Regression analysis indicated that log HOMA IR and log systolic BP were significant independent contributors to variations in log TNF alpha concentration (model r2 = 0.32). We conclude that in this homogeneous Native Canadian population, circulating TNF alpha concentrations are positively correlated with insulin resistance across a spectrum of glucose tolerance. The data suggest a possible role for TNF alpha in the pathophysiology of insulin resistance.

[1]  B. Zinman,et al.  Bioelectrical impedance analysis (BIA) using bipolar foot electrodes in the assessment of body composition in Type 2 diabetes mellitus , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[2]  T. Chou,et al.  Alterations of nitric oxide synthase expression with aging and hypertension in rats. , 1998, Hypertension.

[3]  J. Mcgiff,et al.  Tumor necrosis factor‐α‐angiotensin interactions and regulation of blood pressure , 1997 .

[4]  J S Yudkin,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-�, in Vivo* , 2022 .

[5]  C. Mantzoros,et al.  Leptin concentrations in relation to body mass index and the tumor necrosis factor-α system in humans , 1997 .

[6]  S. Umemura,et al.  Tissue angiotensinogen gene expression induced by lipopolysaccharide in hypertensive rats. , 1997, Hypertension.

[7]  W. Ricart,et al.  The TNF-α Gene Neo I Polymorphism Influences the Relationship Among Insulin Resistance, Percent Body Fat, and Increased Serum Leptin Levels , 1997, Diabetes.

[8]  Margaret S. Wu,et al.  Targeted Disruption of the Tumor Necrosis Factor-α Gene: Metabolic Consequences in Obese and Nonobese Mice , 1997, Diabetes.

[9]  S B Heymsfield,et al.  Bioimpedance analysis: evaluation of leg-to-leg system based on pressure contact footpad electrodes. , 1997, Medicine and science in sports and exercise.

[10]  A. Pfeiffer,et al.  Circulating Tumor Necrosis Factor α is Elevated in Male but Not in Female Patients With Type II Diabetes Mellitus , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[11]  B. Spiegelman,et al.  Differential Regulation of the p80 Tumor Necrosis Factor Receptor in Human Obesity and Insulin Resistance , 1997, Diabetes.

[12]  B. Zinman,et al.  The Prevalence of NIDDM and Associated Risk Factors in Native Canadians , 1997, Diabetes Care.

[13]  J. Stephens,et al.  Tumor Necrosis Factor-α-induced Insulin Resistance in 3T3-L1 Adipocytes Is Accompanied by a Loss of Insulin Receptor Substrate-1 and GLUT4 Expression without a Loss of Insulin Receptor-mediated Signal Transduction* , 1997, The Journal of Biological Chemistry.

[14]  L. Groop,et al.  Circulating TNF-alpha and Leptin Levels in Offspring of NIDDM Patients Do Not Correlate to Individual Insulin Sensitivity , 1996, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[15]  B. Zinman,et al.  Use of Ethnographic Methods for Applied Research on Diabetes Among the Ojibway-Cree in Northern Ontario , 1996, Health education quarterly.

[16]  Roy Taylor,et al.  Effects of an Engineered Human Anti–TNF-α Antibody (CDP571) on Insulin Sensitivity and Glycemic Control in Patients With NIDDM , 1996, Diabetes.

[17]  R. McCarron,et al.  Evidence for activation of endothelium and monocytes in hypertensive rats. , 1996, The American journal of physiology.

[18]  B. Spiegelman,et al.  Tumor Necrosis Factor (TNF)-α Inhibits Insulin Signaling through Stimulation of the p55 TNF Receptor and Activation of Sphingomyelinase* , 1996, The Journal of Biological Chemistry.

[19]  M. Papa,et al.  Sphingomyelinase and Ceramide Suppress Insulin-induced Tyrosine Phosphorylation of the Insulin Receptor Substrate-1 (*) , 1996, The Journal of Biological Chemistry.

[20]  D. Moller,et al.  Candidate Genes for Insulin Resistance , 1996, Diabetes Care.

[21]  M. Sormani,et al.  Serum p55 and p75 tumour necrosis factor receptors as markers of disease activity in juvenile chronic arthritis. , 1996, Annals of the rheumatic diseases.

[22]  A. Brasier,et al.  Tumor necrosis factor activates angiotensinogen gene expression by the Rel A transactivator. , 1996, Hypertension.

[23]  W A Buurman,et al.  Tumor necrosis factor: function, release and clearance. , 1996, Critical reviews in immunology.

[24]  M. Papa,et al.  Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. , 1995, The Journal of biological chemistry.

[25]  S. Haffner.  Risk factors for non-insulin-dependent diabetes mellitus , 1995, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[26]  E. Ravussin,et al.  Linkage between obesity and a marker near the tumor necrosis factor-alpha locus in Pima Indians. , 1995, The Journal of clinical investigation.

[27]  C. Mantzoros,et al.  Genetic Variability in the TNF-α Promoter Is Not Associated with Type II Diabetes Mellitus (NIDDM) , 1995 .

[28]  R. Simsolo,et al.  The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. , 1995, The Journal of clinical investigation.

[29]  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.

[30]  G. Salles,et al.  Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. , 1995, European cytokine network.

[31]  D. Fuchs,et al.  Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus , 1995, Lupus.

[32]  G. Tilz,et al.  Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis , 1995, European journal of haematology.

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

[34]  B. Spiegelman,et al.  Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. , 1994, The Journal of clinical investigation.

[35]  B. Spiegelman,et al.  Tumor necrosis factor alpha inhibits signaling from the insulin receptor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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

[37]  H. Delisle,et al.  Prevalence of non-insulin-dependent diabetes mellitus and impaired glucose tolerance in two Algonquin communities in Quebec. , 1993, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[38]  S. Joel,et al.  Measuring cytokine levels in blood. Importance of anticoagulants, processing, and storage conditions. , 1992, Journal of immunological methods.

[39]  P. Dawson.  Effect of formulation and freeze-drying on the long-term stability of rDNA-derived cytokines. , 1992, Developments in biological standardization.

[40]  P. Zimmet,et al.  Hyperinsulinaemia is a predictor of non-insulin-dependent diabetes mellitus. , 1991, Diabete & metabolisme.

[41]  R. DeFronzo,et al.  Insulin Resistance: A Multifaceted Syndrome Responsible for NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease , 1991, Diabetes Care.

[42]  G. Reaven.  Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[43]  T. K. Young.  Health Care and Cultural Change: The Indian Experience in the Central Subarctic , 1988 .

[44]  T. K. Young.  Are subarctic Indians undergoing the epidemiologic transition? , 1988, Social science & medicine.

[45]  L. Mcintyre,et al.  Prevalence of hypertension, obesity and smoking in three Indian communities in northwestern Ontario. , 1986, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[46]  Diabetes mellitus. Report of a WHO Study Group. , 1985, World Health Organization technical report series.