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Am J Physiol Endocrinol Metab 292: E347-E352, 2007. First published September 12, 2006; doi:10.1152/ajpendo.00291.2006
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Carotid artery intima-media thickness is associated with insulin-mediated glucose disposal in nondiabetic normotensive offspring of type 2 diabetic patients

Marina Cardellini,1 Maria Adelaide Marini,1 Simona Frontoni,1 Marta Letizia Hribal,2 Francesco Andreozzi,2 Francesco Perticone,2 Massimo Federici,1 Davide Lauro,1 and Giorgio Sesti2

1Department of Internal Medicine, University of Rome-Tor Vergata, Rome; and 2Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro, Italy

Submitted 20 July 2006 ; accepted in final form 30 August 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The aim of this study was to investigate whether insulin resistance is independently associated with early manifestations of atherosclerosis. To this end, 176 normotensive offspring of type 2 diabetic patients were subjected to euglycemic hyperinsulinemic clamp to assess insulin sensitivity. Early atherosclerosis was studied by ultrasonography of the common carotid artery. Of the total 176 subjects, 145 were glucose tolerant, 18 had impaired fasting glucose, and 13 had impaired glucose tolerance. Univariate correlations showed that age, body mass index, waist, blood pressure, 2-h postchallenge glucose, fasting insulin, triglycerides, interleukin-6, fibrinogen, and white blood cell count were significantly correlated with carotid intima-media thickness (IMT), whereas HDL cholesterol and glucose disposal showed a negative correlation. A stepwise multivariate regression analysis including sex, age, waist circumference, smoking status, systolic blood pressure, diastolic blood pressure, triglyceride, HDL cholesterol, 2-h postchallenge glucose, plasma IL-6, fibrinogen, white blood cell count, insulin-stimulated glucose disposal, and fasting insulin showed that the four variables that remained significantly associated with carotid IMT were waist circumference, insulin-stimulated glucose disposal, white blood cell count, and diastolic blood pressure, accounting for 33.7% of its variation. These findings support the concept that insulin sensitivity, rather than plasma insulin levels, is associated with early atherosclerosis in nondiabetic normotensive offspring of type 2 diabetic patients.

insulin sensitivity; atherosclerosis; plasma insulin levels; inflammation; white blood cell count

THE METABOLIC SYNDROME is a constellation of interrelated risk factors that confer an increased risk to develop type 2 diabetes and atherosclerotic cardiovascular disease (37). According to the definition of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), the metabolic syndrome is diagnosed when at least three of five risk factors are present, including an increased waist circumference, blood pressure (BP) elevation, low HDL cholesterol, high triglycerides, and hyperglycemia (30). Although there is still some debate about the nature of the metabolic syndrome (22), hyperinsulinemia and/or insulin resistance are thought to play a major pathogenetic role in clustering these risk factors. Many (7, 13, 14, 17, 19, 26, 35, 36, 52), but not all (6, 10, 27, 28, 49), studies have reported an association between hyperinsulinemia and/or insulin resistance and cardiovascular diseases. However, the extent to which an elevated risk of atherosclerotic cardiovascular disease is due to insulin resistance per se vs. isolated hyperinsulinemia, which is only a surrogate measure of insulin resistance, is still undefined. Investigating the relative role of hyperinsulinemia vs. insulin resistance requires an independent assessment of the two phenomena by gold standard techniques and the use of multivariate statistical models, including all components of the metabolic syndrome. The measurement of intima-media thickness (IMT) of the common carotid artery is a generally accepted method for monitoring the early stages of atherosclerosis, and its increase precedes the development of plaque and stenosis in the arterial wall. IMT of the common carotid artery has been shown to be related to cardiovascular risk factors and to predict future development of myocardial infarction and stroke (31).

Accumulating evidence suggests that inflammation plays a role in the pathogenesis of insulin resistance, type 2 diabetes, and atherosclerosis (11, 33, 40). Circulating markers of systemic inflammation, including highly sensitive C-reactive protein (38), fibrinogen (51), the plasma cytokine interleukin-6 (IL-6) (39), and white blood cell count (23, 51), have been shown to predict future cardiovascular events. Interestingly, these inflammatory markers have been shown to be associated with insulin resistance and metabolic syndrome (4, 9, 40). However, previous studies aimed at investigating the association between major inflammatory markers and subclinical carotid atherosclerosis have led to conflicting results (5, 12, 47, 48).

Nondiabetic offspring of type 2 diabetic patients have become a valuable model for studying the pathogenic mechanism(s) responsible for the susceptibility of the metabolic syndrome, without the confounding effect of hyperglycemia. In fact, family history of type 2 diabetes is associated with both increased cardiovascular risk factors, including increased abdominal fat content, higher plasma levels of insulin, triglyceride and cholesterol, insulin resistance, elevated systolic BP (SBP), and lower HDL cholesterol, and increased risk of developing metabolic syndrome (16, 41).

To determine whether insulin resistance vs. hyperinsulinemia is independently associated with the early manifestation of atherosclerosis, we have measured carotid IMT by ultrasonography in nondiabetic normotensive offspring of type 2 diabetic patients in whom insulin sensitivity was assessed by using the gold standard technique, the euglycemic hyperinsulinemic clamp, and applied a stepwise multiple regression analysis to evaluate the independent influence on carotid IMT variability.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. The study group consisted of 176 unrelated offspring of type 2 diabetic patients participating in the EUGENE2 project (http://www.eugene2.com). Inclusion criteria were the eldest offspring in each family with only one parent affected by type 2 diabetes, absence of diabetes mellitus (fasting plasma glucose <126 mg/dl and/or 2 h post-oral glucose tolerance test <200 mg/dl), absence of circulating anti-GAD antibody, and absence of diseases able to modify glucose metabolism. On the first day, after 12 h of fasting, all subjects underwent anthropometrical evaluation, including body mass index (BMI), waist circumference, and body composition evaluated by bioelectrical impedance. Readings of clinic BP were obtained in the left arm of the supine patients, after 5 min of quiet rest, with a mercury sphygmomanometer. Values were calculated as the average of the last two of three consecutive measurements obtained at 3-min intervals. A 75-g oral glucose tolerance test was performed with 0, 30, 60, 90, and 120 min of sampling for plasma glucose. Normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) were diagnosed according to American Diabetes Association criteria (14a). On the second day, after a 12-h overnight fast, subjects underwent an euglycemic hyperinsulinemic clamp study. Insulin (Humulin; Eli Lilly, Indianapolis, IN) was given as a primed continuous infusion targeted to produce plasma insulin levels of ~80 µU/ml. Thereafter, the insulin infusion rate was fixed at 40 mU·m2·min–1. The blood glucose level was maintained constantly, at about 90 mg/dl for the next 120 min, by infusing 20% glucose at varying rates according to blood glucose measurements performed at 5-min intervals (mean coefficient of variation of blood glucose was <4%). The glucose disposal during the clamp was expressed as the amount of glucose infused per kilogram body weight per minute during the last 60 min of the clamp examination. The protocol was approved by the Ethics Committee of the University Magna Græcia of Catanzaro, Catanzaro, Italy, and informed written consent was obtained from all participants. All the investigations were performed in accordance with the principles of the Declaration of Helsinki.

Ultrasound measurement of IMT of the common carotid artery. High-resolution B-mode ultrasound was used to measure IMT of the common carotid artery by using an ATL HDI 3000 ultrasound system (Advanced Technology Laboratories, Bothell, WA) equipped with a 5-MHz linear array transducer. This system provides high-resolution ultrasonic images with 0.3 mm axial resolution. The patients were examined in the supine position. The thickness of the intima-media complex was assessed as described by Pignoli et al. (34). To avoid variability during the cardiac cycle, the images were frozen in the end-diastolic phase. IMT was determined only from the far wall of the artery because it is known to have a higher precision than the near arterial wall. Measurements were conducted in portions of the 10-mm linear segment proximal to the carotid bulb. For each patient, two measurements were performed bilaterally and the values were averaged, which presented the mean of IMT of the common carotid artery. Ultrasound study was performed by an experienced examiner who was unaware of the subjects' clinical and laboratory findings.

Analytical determinations. Plasma glucose was measured in duplicate by the glucose oxidation method (Beckman Glucose Analyzer II; Beckman Instruments, Milan, Italy). Total and HDL cholesterol concentrations and triglycerides were measured by enzymatic methods (Roche Diagnostics, Mannheim, Germany). Plasma insulin concentration was determined by a chemiluminescence-based assay (Roche). IL-6 concentration was measured by an enzymatic assay (Quantikine kit; R&D Systems, Minneapolis, MN). Intra-assay and interassay coefficients of variation for IL-6 were 3.9 and 4.9%, respectively. Plasma fibrinogen concentration and total white blood cell count were determined by routine laboratory tests using Sysmex CA-7000 Automated Coagulation Analyzer and Sysmex SE9500 (DASIT SpA, Milan, Italy), respectively. LDL cholesterol level was calculated by the Friedewald formula.

Statistical analysis. The Kolmogorov-Smirnov test was used to test the normality of distribution, and non-normally distributed variables were naturally log transformed. Relationships between variables were determined by Pearson's correlation coefficient (r). Relationships between variables were sought by stepwise multivariate linear regression analysis with forward selection to assess the magnitude of their individual effect on IMT. Continuous data are expressed as means ± SD and median. A P value <0.05 was considered statistically significant. All analyses were performed using SPSS software program version 12.0 for Windows.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The clinical characteristics and laboratory data for the study group are shown in Table 1. Among the study subjects, 145 subjects (82.4%) had NGT, 18 subjects (10.2%) had IFG, and 13 subjects (7.4%) had IGT. Univariate correlations between carotid IMT and metabolic and anthropometric risk factors of atherosclerosis showed that age, BMI, waist circumference, fat mass, SBP, diastolic blood pressure (DBP), 2-h postchallenge glucose, fasting plasma insulin, triglyceride levels, plasma IL-6, fibrinogen, and white blood cell count were all significantly correlated with carotid IMT, whereas HDL cholesterol and insulin-stimulated glucose disposal, as measures of insulin sensitivity, were negatively correlated with IMT (Table 2 and Fig. 1). These correlations remained significant after adjustments for gender and age were made (Table 2). No correlation with carotid IMT was noted for other factors, such as total and LDL cholesterol and fasting plasma glucose (Table 2). Plasma IL-6 concentrations significantly correlated with both white blood cell count (r = 0.32, P = 0.001) and fibrinogen levels (r = 0.24, P = 0.009), even after adjustments for gender and age were made. BMI was significantly correlated with plasma IL-6 concentrations (r = 0.38, P < 0.0001), white blood cell count (r = 0.36, P < 0.0001), and fibrinogen levels (r = 0.38, P < 0.0001), even after adjustments for gender and age were made. Waist circumference was significantly correlated with insulin-stimulated glucose disposal (r = –0.62, P < 0.0001), plasma IL-6 concentrations (r = 0.35, P < 0.0001), white blood cell count (r = 0.31, P < 0.0001), and fibrinogen levels (r = 0.33, P < 0.0001), even after adjustments for gender and age were made. Insulin-stimulated glucose disposal was significantly correlated with plasma IL-6 concentrations (r = –0.34, P < 0.0001), white blood cell count (r = –0.30, P < 0.0001), and fibrinogen levels (r =–0.30, P < 0.0001), even after adjustments for gender and age were made. Fasting plasma insulin was strongly correlated with insulin-stimulated glucose disposal (r = –0.56, P < 0.0001), even after adjustmetns for gender and age (r = –0.51, P < 0.0001) were made. To estimate the independent contribution of insulin sensitivity vs. hyperinsulinemia as risk factors to carotid IMT, we carried out a stepwise forward multivariate regression analysis in a model including, in addition to fasting plasma insulin and insulin-stimulated glucose disposal, the components of the metabolic syndrome as defined by NCEP-ATP III, which were associated with carotid IMT in univariate analysis, i.e., waist circumference, SBP, DBP, triglyceride levels, and HDL cholesterol and other confounder variables such as age, gender, smoking status, 2-h postchallenge glucose, IL-6, fibrinogen, and white blood cell count. The four variables that remained significantly associated with carotid IMT were waist circumference, insulin-stimulated glucose disposal, white blood cell count, and DBP, accounting for 33.7% of its variation (Table 3).


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  		Table 1. Anthropometric and biochemical characteristics of the study subjects

 

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  		Table 2. Univariate correlations between IMT and anthropometric and biochemical variables

 

Figure 1
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  		Fig. 1. Correlation between intima-media thickness and insulin-stimulated glucose disposal measured by euglycemic hyperinsulinemic clamp (r = –0.46, P < 0.0001).

 

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  		Table 3. Stepwise forward multivariate regression analysis

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The role of hyperinsulinemia vs. insulin resistance as an independent risk factor for cardiovascular disease in nondiabetic subjects remains unsettled. In the recent joint statement from the American Diabetes Association and the European Association for the Study of Diabetes, authors observed that they "could find no study that has compared insulin resistance, as measured by sensitive and specific methods (e.g., euglycemic insulin clamp), with fasting insulin levels to determine which variable is a better predictor of cardiovascular events in nondiabetic individuals (22)." In this study, we investigated the association between insulin resistance, assessed by the gold standard euglycemic hyperinsulinemic clamp, and carotid IMT, a validated measure of the early stage of atherosclerosis (31), in a Caucasian cohort of nondiabetic normotensive offspring of type 2 diabetic patients. These subjects are at a high risk for atherosclerosis because they showed decreased endothelial-dependent vasodilation (2) and increased carotid IMT (32) compared with control subjects with no family history of diabetes. We found that, in univariate analysis, both insulin sensitivity and fasting insulin levels were associated with carotid IMT. A multivariate regression analysis in a model including the NCEP-ATP III-defined components of the metabolic syndrome, smoking status, 2-h postchallenge glucose levels, and inflammatory markers such as IL-6, fibrinogen, and white blood cell count demonstrated that insulin sensitivity, but not fasting insulin levels, was independently associated with carotid IMT. This was also confirmed in a stepwise forward multivariate regression analysis in a model including age, gender, fasting insulin level, and insulin-stimulated glucose disposal, which showed that the only variable that remained significantly associated with carotid IMT was insulin-stimulated glucose disposal, accounting for 26.9% of its variation. Only a few studies have addressed the potential association between insulin resistance and IMT by using direct measurements of insulin sensitivity in nondiabetic subjects. Some of these studies have shown an association between insulin resistance and IMT (1, 18, 24, 44), whereas others have failed to do so (25). A Finnish study (24) carried out in 43 asymptomatic normoglycemic subjects has shown an association between insulin resistance and early atherosclerosis. However, the authors did not adjust for cardiovascular risk factors, adiposity, or insulin levels by multivariate analysis, thus making it impossible to compare the role of hyperinsulinemia vs. insulin resistance as an independent risk factor for increased IMT. An association between carotid IMT and insulin sensitivity was also observed in 25 Swedish nondiabetic men considered to be at high risk of atherosclerosis and 23 Swedish nondiabetic men considered to be at low risk of atherosclerosis (1). In a multivariate analysis, the relationship between carotid IMT and insulin sensitivity remained significant after adjustment for the confounding effect of BMI in the low-risk group but not in the high-risk group. However, authors did not include age, BP, lipoprotein analysis, plasma glucose levels, or insulin levels in the regression model. A Japanese study carried out in 72 nondiabetic subjects with essential hypertension demonstrated that reduced insulin sensitivity, as assessed by steady-state plasma glucose method, was the strongest risk factor associated with IMT in a multiple regression model including age, sex, BMI, smoking, systolic and diastolic BP, triglycerides, LDL cholesterol, HDL cholesterol, LDL apoB, fasting plasma glucose, fasting plasma insulin, and hemoglobin A1c as independent variables (44). In the Insulin Resistance Atherosclerosis Study (IRAS) comprised of 637 NGT subjects, 315 individuals with IGT, and 445 subjects with type 2 diabetes, it has been shown that low insulin sensitivity, as evaluated by the frequently sampled intravenous glucose tolerance test with minimal model analysis, was independently associated with carotid IMT (18). The association was reduced, but not completely eliminated, after adjustments were made for confounding factors, including age, sex, HDL cholesterol, LDL cholesterol, smoking status, hypertension, glucose tolerance status, BMI, waist-to-hip ratio, fasting insulin level, and 2-h insulin level. The results of these reports are consistent with the present study, which used the gold standard technique for assessment of insulin sensitivity, i.e., the euglycemic hyperinsulinemic clamp. By contrast, a study carried out in 84 nondiabetic postmenopausal Swedish women did not show any association between IMT and insulin sensitivity, as assessed by euglycemic hyperinsulinemic clamp (25). It is possible that differences in age, gender, and BMI might explain the divergent results between the present study and the Swedish study.

We found that waist circumference was the strongest risk factor associated with IMT in the stepwise multivariate regression analysis in a model including all of the components of the metabolic syndrome, as defined by NCEP-ATP III, smoking status, 2-h postchallenge glucose levels, and inflammatory markers, including IL-6, fibrinogen, and white blood cell count. It is of note that the above-cited studies did not evaluate the influence of abdominal adiposity on IMT in a multivariate regression analysis, with the exception of the IRAS, where waist-to-hip ratio was included in the regression model. Increased abdominal visceral fat has been associated with insulin resistance, type 2 diabetes, and coronary heart disease (3, 15). The main role in the relationship between visceral fat mass and increased cardiovascular risk has been attributed to metabolites, such as free fatty acids (42), and adipokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}), plasminogen activator inhibitor-1, and angiotensinogen, which are predominantly secreted from visceral adipose tissue and affect vasculature (3, 50).

We also found that white blood cell count, but not IL-6 and fibrinogen, was an independent risk factor associated with IMT in the stepwise multivariate regression analysis in a model including all the components of the metabolic syndrome and direct measure of insulin sensitivity. IL-6 is a central stimulus for the hepatic synthesis of several acute-phase proteins and a primary determinant of hepatic production of fibrinogen. The finding that serum IL-6 and fibrinogen levels were not associated with carotid IMT after adjustment for waist circumference is not unexpected, because adipose tissue is an important source of IL-6 production accounting for 15–35% of its circulating levels (29), and adjustment for indexes of adiposity may have masked the relationship of IL-6 with early stage of carotid atherosclerosis. The observation that white blood cell count was independently associated with IMT, even after adjustments for conventional components of the metabolic syndrome were made, is consistent with previous studies (5, 8, 20, 45), although in these studies the influence of direct measure of insulin sensitivity was not evaluated and corroborates the view that inclusion of subclinical inflammation markers into the definition of the metabolic syndrome strengthens prediction of development of atherosclerotic cardiovascular disease.

The present study has some potential limitations. Insulin sensitivity, conventional risk factors, plasma insulin, and inflammatory marker levels were measured only once; therefore, intraindividual variation in levels of these parameters cannot be taken into account. Other inflammatory markers, such as C-reactive protein or TNF-{alpha}, were not measured, although they are important for the total inflammatory status. However, previous studies suggest that C-reactive protein may be a better predictor of more advanced atherosclerosis rather than a predictor of the early stage of atherosclerosis (5, 12, 21, 43, 47). Multivariate analysis included all subjects, although there were minor differences in insulin sensitivity, conventional risk factors, and levels of inflammatory markers between males and females. However, sex differences were adjusted for in the multivariate models. Finally, because this is a cross-sectional study, the present results reflect only an association with prevalent and not incident atherosclerosis. In conclusion, we showed a significant, independent association between insulin sensitivity and IMT, but we failed to document an independent association between fasting insulin levels and IMT. In addition, the finding that high white blood cell count was independently associated with carotid IMT, even after adjustments for conventional components of the metabolic syndrome and direct measure of insulin sensitivity, supports the hypothesis that leukocytes may have an independent role in the early vascular atherogenesis, and their measurements may represent an inexpensive marker for subclinical atherosclerosis.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by the European Community's FP6 EUGENE2 no. LSHM-CT-2004-512013 grant (G. Sesti).


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. Sesti, Dipartimento di Medicina Sperimentale e Clinica, Policlinico Universitario Mater Domini, Via Europa, Campus Germaneto, 88100 - Catanzaro, Italy (e-mail: sesti{at}unicz.it)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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M. A. Marini, E. Succurro, S. Frontoni, M. L. Hribal, F. Andreozzi, R. Lauro, F. Perticone, and G. Sesti
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