Early Carotid Atherosclerosis in Overweight Non-diabetic Individuals is Associated with Subclinical Chronic Inflammation Independent of Underlying Insulin Resistance

Abstract

Overweight in children and young adults is an increasing problem in Western industrialized countries with potential impact on cardiovascular morbidity. Whether early arterial wall thickening in these subjects mainly results from the often associated insulin resistance syndrome or from increased subclinical chronic inflammation probably triggered by adipose tissue is still under discussion. We therefore determined insulin sensitivity index (ISI) by performing an euglycaemic hyperinsulinaemic glucose clamp (insulin infusion rate 1 mU/kg/min) and high-sensitivity C-reactive protein (hsCRP) levels in relation to the intima-media thickness (IMT) at the common carotid artery (high resolution ultrasound; 13 MHz) in 81 young (age 33 ± 1 years), moderately overweight subjects. To reduce the number of confounding variables, subjects with disturbances in glucose metabolism (75 g oral glucose tolerance test) and hypertension were excluded. As expected, higher BMI was positively correlated with increased IMT (r = 0.358; p = 0.001). After multiple regression analysis, hsCRP levels independently correlated to IMT (r = 0.251; p = 0.03), even after adjusting for age, sex, BMI, ISI, LDL cholesterol and smoking as cofactors. However, taking all above listed factors into account, glucose-clamp assessed insulin sensitivity was not correlated with IMT. Thus, overweight might trigger inflammatory mechanisms leading to vascular wall hypertrophy independent of the insulin resistance syndrome already early in life.

Key words

Glucose clamp technique - Tunica intima - Body weight - Atheriosclerosis - C-reactive protein - Insulin resistance - Cell adhesion Molecules - Ultrasonography - Cholesterol - Glucose tolerance test

References

• 1 Zimmet P, Alberti K G, Shaw J. Global and societal implications of the diabetes epidemic.  Nature. 2001;  414 782-787
• 2 Balletshofer B M, Haring H U. Type 2-diabetes, insulin resistance and endothelial dysfunction.  Hämostaseologie. 2001;  21 159-166
• 3 Balletshofer B M, Rittig K, Enderle M D, Volk A, Maerker E, Jacob S. et al . Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance.  Circulation. 2000;  101 1780-1784
• 4 Caballero A E, Arora S, Saouaf R, Lim S C, Smakowski P, Park J Y. et al . Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.  Diabetes. 1999;  48 1856-1862
• 5 Balletshofer B M, Rittig K, Stock J, Lehn-Stefan A, Overkamp D, Dietz K. et al . Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intima-media thickness.  Atherosclerosis. 2003;  171 303-309
• 6 Jarvisalo M J, Harmoinen A, Hakanen M, Paakunainen U, Viikari J, Hartiala J. et al . Elevated serum C-reactive protein levels and early arterial changes in healthy children.  Arteriosclerosis Thrombosis and Vascular Biology. 2002;  22 1323-1328
• 7 Knoflach M, Kiechl S, Kind M, Said M, Sief R, Gisinger M. et al . Cardiovascular risk factors and atherosclerosis in young males - ARMY study (atherosclerosis risk-factors in male youngsters).  Circulation. 2003;  108 1064-1069
• 8 Geroulakos G, O"Gorman D J, Kalodiki E, Sheridan D J, Nicolaides A N. The carotid intima-media thickness as a marker of the presence of severe symptomatic coronary artery disease.  Eur Heart J. 1994;  15 781-785
• 9 O'Leary D H, Polak J F, Kronmal R A, Manolio T A, Burke G L, Wolfson S K Jr.. Cardiovascular Health Study Collaborative Research Group.  N Engl J Med. 1999;  340 14-22
• 10 DeFronzo R A, Tobin J D, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Physiol. 1979;  237 E214-E223
• 11 Ferrannini E, Vichi S, Beck-Nielsen H, Laakso M, Paolisso G, Smith U. Insulin action and age. European Group for the Study of Insulin Resistance (EGIR).  Diabetes. 1996;  45 947-953
• 12 Balletshofer B M, Rittig K, Stock J, Haring H U. Indicators of incipient atherosclerosis: Demonstration of endothelial dysfunction with high-resolution ultrasound.  Ultraschall in der Medizin. 2003;  24 153-161
• 13 Wendelhag I, Gustavsson T, Suurkula M, Berglund G, Wikstrand J. Ultrasound measurement of wall thickness in the carotid artery: fundamental principles and description of a computerized analysing system.  Clin Physiol. 1991;  11 565-577
• 14 Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.  Circulation. 1986;  74 1399-1406
• 15 Kanters S D, Algra A, van Leeuwen M S, Banga J D. Reproducibility of in vivo carotid intima-media thickness measurements: a review.  Stroke. 1997;  28 665-671
• 16 Festa A, D'Agostino R Jr, Williams K, Karter A J, Mayer-Davis E J, Tracy R P. et al . The relation of body fat mass and distribution to markers of chronic inflammation.  Int J Obes Relat Metab Disord. 2001;  25 1407-1415
• 17 Golden S H, Folsom A R, Coresh J, Sharrett A R, Szklo M, Brancati F. Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the atherosclerosis risk in communities study.  Diabetes. 2002;  51 3069-3076
• 18 Temelkova-Kurktschiev T, Koehler C, Schaper F, Henkel E, Hahnefeld A, Fuecker K. et al . Relationship between fasting plasma glucose, atherosclerosis risk factors and carotid intima-media thickness in non-diabetic individuals.  Diabetologia. 1998;  41 706-712
• 19 Thomas G N, Chook P, Qiao M, Huang X S, Leong H C, Celermajer D S. et al . Deleterious impact of “high normal” glucose levels and other metabolic syndrome components on arterial endothelial function and intima-media thickness in apparently healthy Chinese subjects: the CATHAY study.  Arterioscler Thromb Vasc Biol. 2004;  24 739-743
• 20 Ross R. Atherosclerosis-an inflammatory disease.  N Engl J Med. 1999;  340 115-126
• 21 Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.  Nat Med. 2002;  8 1211-1217
• 22 Baron A D. Hemodynamic actions of insulin.  Am J Physiol. 1994;  267 E187-E202
• 23 Laight D W, Carrier M J, Anggard E E. Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy.  Diabetes Metab Res Rev. 1999;  15 274-282
• 24 Yudkin J S. Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent?.  Diabetes Care. 1999;  22 Suppl 3 C25-C30
• 25 Halcox J P, Schenke W H, Zalos G, Mincemoyer R, Prasad A, Waclawiw M A. et al . Prognostic value of coronary vascular endothelial dysfunction.  Circulation. 2002;  106 653-658
• 26 Schachinger V, Britten M B, Zeiher A M. Prognostic impact of coronary vasodilator dysfunction on adverse long- term outcome of coronary heart disease.  Circulation. 2000;  101 1899-1906
• 27 Funahashi T, Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M. et al . Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.  Intern Med. 1999;  38 202-206
• 28 Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of vascular disease in metabolic syndrome X.  J Diabetes Complications. 2002;  16 17-18