Associations of Plasma Glucose Levels and Traits of Metabolic Syndrome with Carotid Intima Media Thickness in Nondiabetic Elderly Subjects: Are They Mediated by Insulin Resistance?

Abstract

Background:

The independent role of insulin resistance (IR) and high fasting blood glucose (FBG) levels within the normal range on vascular diseases is still under debate. This study was designed to explore whether IR, FBG levels, and the traits of metabolic syndrome are associated with increased carotid intima media thickness (IMT), the early marker of subclinical atherosclerosis, independently of each other in nondiabetic elderly subjects.

Methods:

Blood analytes and anthropometric measurements were obtained. Carotid IMT was measured by ultrasonography; metabolic syndrome was diagnosed according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. IR was assessed through homeostasis model assessment of insulin resistance (HOMA-IR).

Results:

At total of 207 subjects aged 68.2±3.6 years were enrolled. Subjects with increased carotid IMT (50.7%) were older (P=0.001), had a higher prevalence of metabolic syndrome (P<0.0001) and all its traits, impaired fasting glucose (IFG) (P<0.0001), and values of HOMA-IR (P<0.0001) than normal subjects. Increased carotid IMT significantly correlated with metabolic syndrome, its traits, IFG, and HOMA-IR. When multivariable regression models were constructed, central obesity [B=0.392; 95% confidence interval (CI) 0.280–0.505; P<0.0001], high-density lipoprotein cholesterol (HDL-C) (B=−0.007; 95% CI −0.013–0.000; P=0.042], hypertension (B=0.475; 95% CI 0.363–0.587; P<0.0001), and IFG (B=0.230; 95% CI 0.092–0.367; P=0.001) were found to be the independent determinants of increased carotid IMT independently of HOMA-IR, but not FBG (B=0.013; 95% CI 0.000–0.026; P=0.050) and HOMA-IR itself.

Conclusions:

Our results suggest that hypertension, low HDL-C, and central obesity are independently associated with increased carotid IMT in nondiabetic elderly subjects. These associations seem to be not affected by IR. The associations of FBG levels within the normal range and IR with carotid IMT should be investigated further.

Introduction

M etabolic syndrome is a cluster of cardiovascular (CV) risk factors that includes central obesity, hypertension, low plasma levels of high-density lipoprotein cholesterol (HDL-C), high levels of triglycerides, and raised concentrations of fasting blood glucose (FBG).^1,2 In Western countries, it is estimated that 25% of adults have the condition according to the Third Adult Treatment Panel (ATP III) criteria.^3,4 In subjects aged 65 years and older, metabolic syndrome reaches a prevalence of 40%.^4,5 Several pieces of evidence suggest that early atherosclerosis is more frequent in the patients with metabolic syndrome.^6
–8 Insulin resistance is thought to play a pivotal role in the genesis of almost all of the single components of metabolic syndrome. Currently, it remains uncertain whether IR itself plays a role on atherosclerotic vascular disease independently of FBG concentrations. Data on this are mixed,^8
–10 perhaps because of methodological differences across the investigations. Impaired fasting glucose (IFG) is a common finding in the patients with metabolic syndrome, and it is widely accepted as an independent CV risk factor.^2,11 Some authors suggested that normal-high FBG levels, even within the normal range, could be independently associated with vascular damage, but data on this topic are mixed.^12,13

Detection of atherosclerosis at early stages allows prevention of severe outcomes overall in the patients with metabolic derangements. The measurement of carotid intima media thickness (IMT) is accepted worldwide as a marker of subclinical atherosclerosis. Increased carotid IMT precedes the development of artery plaques and stenosis,^6,8 and it positively correlates with the severity of coronary atherosclerotic burden. Carotid IMT represents a noninvasive and useful tool to screen subjects at high risk.^1,8 The aims of the present study were to evaluate: (1) Whether FBG levels and the single features of metabolic syndrome were independently associated with increased carotid IMT in nondiabetic elderly subjects and (2) whether such an association was independent of IR.

Material and Methods

Study population

Patients who visited the ambulatory of our Department in the period between January, 2012, and June, 2012, were considered for this study. Our ambulatory specifically serves older outpatients referred by their primary care provider for a specialist evaluation of CV risk factors, overall hypertension, dyslipidemia, and obesity.

Elderly subjects were considered for recruitment. We excluded subjects with diabetes or those who were on antidiabetic treatment; subjects with chronic diseases, except blood hypertension, obesity, dyslipidemia, IFG; and those who reported a history of coronary heart disease, stroke, transient ischemic attack or other symptomatic cardiovascular events. Patients aged 65 years and more who did not meet any of the aforementioned exclusion criteria were consecutively enrolled at the present study.

Measurements

On the same morning of the visit, each subject completed all elements of the study assessment. After an overnight fast, each patient underwent venous blood sampling. FBG, triglycerides, HDL, and total cholesterol were assessed through enzymatic assay; low-density lipoprotein cholesterol (LDL-C) was assessed through the Friedewald formula, as follows: LDL-C=Total cholesterol−(HDL-C – Triglycerides/5). Fasting insulin was determined through an enzyme-linked immunosorbent assay (ELISA) kit.

A clinical interview investigated medical history, home therapy, and general habits of the patients. Waist circumference (WC) was measured at the level of the iliac crest with the patients standing; body mass index (BMI) was calculated by dividing the weight (kilograms) by the square of the height (meters).

Each patient underwent three blood pressure measurements during the same morning of the visit. Blood pressure was measured by the same physician using a mercury sphygmomanometer. All measurements were obtained after the subjects had rested for 10 min. The average value of the three measurements was considered: subjects were classified as hypertensive if they were on antihypertensive therapy or if they had systolic blood pressure (SBP) ≥130 mmHg and/or diastolic blood pressure (DBP) ≥85 mmHg.

IFG was defined by FBG concentrations within 110–125 mg/dL.¹ Insulin resistance (IR) was estimated by using the homeostasis model assessment index of IR (HOMA-IR). HOMA-IR was calculated with the following formula: Fasting insulin (U/mL)×fasting glucose (mmol/L)/22.5.

Metabolic syndrome was diagnosed according to the National Cholesterol Education Program (NCEP) ATP III 2001 criteria by the presence of three or more of the following features: Central obesity defined by WC≥88 cm in women and ≥102 cm in men; HDL-C<50 mg/dL in women and <40 mg/dL in men; FBG>110 mg/dL or antidiabetic treatment; fasting triglycerides ≥150 mg/dL; SBP≥130 mmHg and/or DBP≥85 mmHg or antihypertensive medication.¹

Carotid IMT was measured by the same operator using a high-resolution echo-Doppler device with a 7-MHz linear probe. The patients were examined in a supine position. The head was extended and turned 45 degrees in the opposite direction of the examined side. Carotid IMT was measured at the distal artery wall, at the level of the common carotid artery (10 mm from the bifurcation) and internal carotid arteries, using the best images. The value of carotid IMT assigned to each patient resulted from the average of right and left carotid IMT. Carotid IMT values up to 0.9 mm were considered normal.^6,7 Both internal and common carotid arteries and their bifurcations were examined for the presence of atherosclerotic plaques. A plaque was defined as a focal wall thickening area more than 50% greater than surrounding wall thickness.^6,7

Statistical analysis

All analyses were performed via Statistical Package for Social Sciences (SPSS) software, version 17.0 for Windows. Data are presented according to carotid IMT values. Continuous variables are presented as means±standard deviation; categorical variables as frequencies. The chi-squared test was used to compare categorical variables. The Student t-test was adopted to compare continuous variables. Bivariate regression analysis was performed to investigate the correlations between increased carotid IMT and the other variables. Multivariable regression models were constructed to identify the variables independently associated with increased carotid IMT. A P value of <0.05 was considered statistically significant.

Results

The study population was composed of 207 subjects (57% women), mean age 68.2±3.6 years. All subjects were able to complete all elements of the study assessment. In all, metabolic syndrome was diagnosed in 49.7% of the subjects; carotid IMT>0.9 mm was observed in 50.7%; 13.5% of the patients were found to have at least one carotid plaque.

As shown in Table 1, the subjects with increased carotid IMT had significantly higher prevalence of metabolic syndrome (P<0.0001), central obesity (P<0.0001), hypertension (P=0.002), and IFG (P<0.0001), higher triglycerides (P<0.0001), FBG (P<0.0001), and HOMA-IR (P<0.0001) values and higher prevalence of low HDL-C (P=0.010). Moreover, they were older (P=0.001) and consumed more lipid-lowering drugs when compared to the subjects with normal carotid IMT. No differences were found in sex, current smoking, carotid plaques, BMI, LDL-C cholesterol concentrations, and consumption of antihypertensive and antiplatelet drugs.

Table 1.

Characteristics of the Sample According to Carotid IMT

	Normal IMT (n=102)	Increased IMT (n=105)	P
Age (years)	67.4±2.5	69.0±4.3	0.001
Female sex (%)	57.8	55.1	NS
Current smokers (%)	17.6	23.4	NS
Carotid IMT (mm)	0.80±0.08	1.13±0.12	<0.0001
Carotid plaques (%)	8.8	17.7	NS
BMI (kg/m²)	28.4±3.6	29.3±3.8	NS
Metabolic syndrome (%)	19.6	77.6	<0.0001
Central obesity (%)	31.2	62.3	<0.0001
Low HDL-C (%)	18.6	35.5	0.010
Hypertension (%)	50.0	72.8	0.002
Triglycerides (mg/dL)	125.3±50.0	157.1±71.7	<0.0001
FBG (mg/dL)	93.7±9.6	103.2±12.0	<0.0001
IFG (%)	4.9	36.2	<0.0001
HOMA-IR (n)	2.25±0.92	3.77±1.53	<0.0001
LDL-C (mg/dL)	134.4±36.0	136.0±35.0	NS
Antihypertensive drugs (%)	36.3	50.5	NS
Lipid-lowering drugs (%)	22.5	36.2	0.049
Antiplatelet drugs (%)	14.7	26.7	NS

IMT, intima-media thickness; NS, not significant; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; FBG, fasting blood glucose; IFG, impaired fasting glucose; HOMA-IR, homeostasis model assessment index of insulin resistance; LDL-C, low-density lipoprotein cholesterol.

As shown in Table 2, in the bivariate analysis, the presence of increased carotid IMT showed a strong linear correlation (P<0.0001) with metabolic syndrome (r=0.350), hypertension (r=0.797), central obesity (r=0.683), FBG (r=0.402), IFG (r=0.345), and HOMA-IR (r=0.347). In addition, increased carotid IMT correlated with age (r=0.243; p=0.005), BMI (r=0.184; P=0.023), HDL-C (r=− 0.295; P=0.001) and triglycerides (r=0.273; P=0.005). No further correlations were observed. As shown in Table 3, in the multivariable model that included age, sex, BMI, metabolic syndrome and its single components, IFG, adjusted for LDL-C, current smoking, and medications, we found that central obesity [B=0.390; 95% confidence interval (CI) 0.278–0.501; P<0.0001], HDL-C (B=−0.006; 95% CI −0.013–0.000; P=0.047], hypertension (B=0.475; 95% CI 0.364–0.586; P<0.0001), FBG (B=0.015; 95% CI 0.004–0.026; P=0.008), and IFG (B=0.228; 95% CI 0.091–0.365; P=0.001] were independently associated with increased carotid IMT. When HOMA-IR was added to the model, the strength of the associations of central obesity (B=0.392; 95% CI 0.280–0.505; P<0.0001], HDL-C (B=−0.007; 95% CI −0.013–0.000; P=0.042), hypertension (B=0.475; 95% CI 0.363–0.587; P<0.0001), and IFG (B=0.230; 95% CI 0.092–0.367; P=0.001) persisted unchanged. Conversely, the independent association of FBG was less (B=0.013; 95% CI 0.000–0.026; P=0.050). HOMA-IR was not found to be independently associated with increased carotid IMT.

Table 2.

Bivariate Regression Analysis Between Increased cIMT and the Other Variables

	r	P
Age	0.243	0.005
BMI	0.184	0.023
Metabolic syndrome	0.350	<0.0001
Hypertension	0.797	<0.0001
Central obesity	0.683	<0.0001
HDL-C	−0.295	0.001
Triglycerides	0.273	0.005
FBG	0.402	<0.0001
IFG	0.354	<0.0001
HOMA-IR	0.347	<0.0001

cIMT, carotid intima media thickness; r, Pearson correlation coefficient; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; FBG, fasting blood glucose; IFG, impaired fasting glucose; HOMA-IR, homeostasis model assessment of insulin resistance.

Table 3.

Multivariable Logistic Regression: Predictors of Increased Carotid IMT

Covariates	B	95% CI	P	B	95% CI	P
Age	−0.002	−0.014 0.011	NS	−0.002	−0.015 0.011	NS
Sex	0.045	−0.054 0.144	NS	0.046	−0.054 0.146	NS
BMI	−0.015	−0.033 0.003	NS	−0.015	−0.033 0.003	NS
Metabolic syndrome	−0.065	−0.142 0.012	NS	−0.064	−0.141 0.013	NS
Central obesity	0.390	0.278 0.501	<0.0001	0.392	0.280 0.505	<0.0001
HDL-C	−0.006	−0.013 0.000	0.047	−0.007	−0.013 0.000	0.042
Hypertension	0.475	0.364 0.586	<0.0001	0.475	0.363 0.587	<0.0001
Triglycerides	0.032	−0.109 0.173	NS	0.033	−0.108 0.174	NS
FBG	0.015	0.004 0.026	0.008	0.013	0.000 0.026	0.050
IFG	0.228	0.091 0.365	0.001	0.230	0.092 0.367	0.001
HOMA-IR	—	— —	—	−0.053	−0.248 0.141	NS

Dependent variable: carotid IMT>0.9 mm.

Adjusted for LDL-C, currents smoking, antihypertensive, antiplatelet, and lipid-lowering drugs consumption.

IMT, intima media thickness; B, regression coefficient; CI, confidence interval; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; FBG, fasting blood glucose; IFG, impaired fasting glucose; LDL-C, low-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment index of insulin resistance.

Discussion

In the present study, we found that hypertension, HDL-C, central obesity, and IFG were associated with increased carotid IMT independently of insulin resistance, in a population of nondiabetic elderly. Conversely, FBG ceased to be an independent predictor of increased carotid IMT when HOMA-IR was added to the regression model.

Interestingly we found that the presence of metabolic syndrome itself was not independently associated with increased carotid IMT. This finding is in contrast with previous reports. In a large longitudinal study, the presence of metabolic syndrome was significantly associated with higher progression of carotid thickening.⁸ However, this study was conducted on a large population not matched for age. Moreover, it remains unclear whether subjects with diabetes and symptomatic atherosclerotic vascular diseases were excluded. The positive association between metabolic syndrome and increased carotid IMT was found by other authors in a cross-sectional investigation.¹³ Similarly, the population of this study was not matched for age. Our study was conducted on a population of relatively healthy, nondiabetic, elderly subjects, free of clinically manifest atherosclerotic diseases. The failure to find an association between metabolic syndrome itself and early atherosclerosis could be attributable to differences in the study population and to the adopted exclusion criteria. However, a longitudinal design would be more suitable for exploring this association. Despite the cross-sectional design of our study, we can hypothesize that the severity of single metabolic derangements could be more important than their clustering in triggering early vascular damage, at least in nondiabetic subjects.

Increased carotid IMT is considered to be part of composite target organ damage in older subjects, particularly in those affected by hypertension. As expected, blood hypertension was found to be the strongest predictor of increased carotid IMT, as reported formerly.^1,6
–8

In accordance with previous results,^6,9 HDL-C concentrations were found to be inversely associated with carotid IMT. Despite the cross-sectional nature of our results, which do not allow implying causality, it is reasonable to assume that derangements in the inverse cholesterol transport pathway could be an independent promoter of atherosclerosis, more important than LDL-C metabolism, in nondiabetic subjects. Further longitudinal investigations are needed to disentangle their specific effects on early atherosclerotic disease.

WC, the accepted surrogate of visceral obesity, has been found to be positively and independently associated with increased carotid IMT, as reported previously.^6,9 In our study, this association was independent of BMI, suggesting that whole body adiposity could not independently affect carotid IMT in nondiabetic subjects. The visceral adipose tissue is more active than the subcutaneous in triggering chronic microinflammation. The inflamed visceral adipose tissue is thought to be the leading cause of insulin resistance. However, we found that the association was independent of HOMA-IR. The metabolic syndrome–related microinflammation could be an important independent promoter of vascular damage, and circulating levels of C-reactive protein, a suitable marker of metabolic-related inflammation, has been proposed as an independent marker of vascular atherosclerotic disease. A certain limitation of our study is that we have not assessed the inflammatory status of the patients. It would be interesting to explore whether inflammation would have been independently associated with increased carotid IMT and whether the adjustment for inflammation would have affected the association between carotid IMT and central obesity. Further investigations are certainly needed.

IFG was confirmed to be independently associated with increased carotid IMT.¹¹ By multivariable regression analysis, we did not observe an independent association of FBG levels with increased carotid IMT in the multivariable model adjusted for HOMA-IR. Likewise, we failed to find an independent association with HOMA-IR itself. Data on the independent role of FBG levels and IR are mixed. Data from a study on nondiabetic offspring of type 2 diabetic parents suggested that increased carotid IMT was positively associated with IR, measured through euglycemic hyperinsulinemic clamp.⁹ Other authors revealed that FBG levels in diabetic and prediabetic (IFG) patients were associated with increased carotid and femoral IMT independently of markers of IR, assessed through an oral glucose tolerance test.¹¹ In a dated longitudinal survey, the authors found that FBG levels, not 2-h postload plasma glucose, were associated with increased carotid IMT.¹² However IR was not assessed. The independent role of IR on early atherosclerosis remains controversial. Even in this case, longitudinal investigations are needed to define this association.

All in all we found that FBG levels within the normal range were not independently associated with increased carotid IMT, in a population of nondiabetic elderly subjects. However, as suggested by our results, it should be emphasized that the association between FBG and increased carotid IMT was found to be close to statistical significance (P=0.05) by the multivariate analysis adjusted for HOMA-IR. Further investigations are needed to explore the significance of this association and to determine the optimal FBG target value to prevent early manifestations of atherosclerosis.

In conclusion, our results support the importance of screening patients with metabolic derangements to detect vascular damage at early stages. A possible limitation of our investigation is that the study population was constituted of “relatively healthy” subjects, so that our results cannot be completely transferred to the entire elderly population. However, these are the typical outpatients coming to medical attention, for which early prevention should always be guaranteed.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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