help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Larsson, H.
Right arrow Articles by Ahrén, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Larsson, H.
Right arrow Articles by Ahrén, B.
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4791-4797
Copyright © 2003 by The Endocrine Society

Insulin Sensitivity, Insulin Secretion, and Glucose Tolerance Versus Intima-Media Thickness in Nondiabetic Postmenopausal Women

Hillevi Larsson, Göran Berglund and Bo Ahrén

Department of Medicine, Lund University (H.L., G.B.), Malmö, Sweden; and Department of Medicine, Lund University (B.A.), SE-221 84 Lund, Sweden

Address all correspondence and requests for reprints to: Dr. Bo Ahrén, Department of Medicine, Lund University, B11 BMC, SE-221 84 Lund, Sweden. E-mail: bo.ahren{at}med.lu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To study the association between insulin sensitivity and secretion vs. early manifestations of atherosclerosis, we performed a 5-yr prospective study in 84 nondiabetic, postmenopausal women, aged 58.7 ± 0.4 yr (mean ± SD). Insulin sensitivity was measured with the euglycemic, hyperinsulinemic clamp, and insulin secretion was measured as the acute response to iv arginine (5 g). Early atherosclerosis was studied by ultrasonography of the right carotid artery. Mean intima-media thickness (IMT), determined 1 cm proximal to the bifurcation, was 0.81 ± 0.14 mm at baseline and increased by 0.012 ± 0.014 mm/yr over the 5 yr (P < 0.001). The maximal IMT, determined in the carotid bifurcation, was 1.42 ± 0.42 mm at baseline and increased by 0.035 ± 0.049 mm/yr (P < 0.001). Neither basal IMT nor the increase in mean or maximal IMT correlated to insulin sensitivity or secretion. In contrast, both baseline IMT and the progression in IMT over the 5-yr follow-up (both mean common carotid artery IMT and maximal bifurcation IMT) correlated with systolic blood pressure and low-density lipoprotein cholesterol. We conclude that carotid intima-media thickness is not related to insulin sensitivity or secretion in nondiabetic, postmenopausal women. Instead, the strongest association is seen with systolic blood pressure and low-density lipoprotein cholesterol levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS KNOWN that atherosclerotic vascular disease is a severe complication to impaired glucose tolerance (IGT) and type 2 diabetes (1, 2, 3, 4). Although this has been associated with high glucose levels, particularly after meal ingestion (5, 6), the underlying cause of the association remains unknown. This is partially due to the complex pathophysiology of type 2 diabetes, which involves several processes, and is characterized by both insulin resistance and defective insulin secretion (7). Insulin resistance is thus an important risk factor for the development of diabetes, but insulin resistance has also been suggested to be involved in the atherosclerosis process (8, 9, 10). Such an assumption is supported by indirect studies reporting that insulin resistance correlates with measures of coronary artery disease evaluated using coronary angiography (11). Furthermore, insulin resistance is an independent predictor of future cardiovascular events (12). Whether insulin resistance is also an independent predictor of early manifestations of atherosclerosis in conjunction with well known risk factors such as hypertension and hyperlipidemia is not known.

The contribution of insulin resistance to cardiovascular disease has been inferred from a study using the euglycemic, hyperinsulinemic clamp test for evaluating insulin sensitivity, showing that subjects with fully developed carotid plaques have lower insulin sensitivity than subjects without plaques (13). Fully developed plaques are, however, late manifestations of the atherosclerotic process, and this study can therefore not establish any causal relationship. Recent technological development has made it possible to determine early signs of atherosclerosis by B-mode ultrasonography of the carotid arteries for assessing the intima-media thickness (IMT) (14, 15, 16, 17, 18, 19). This technique has been validated against histological specimens of carotid artery (14, 15, 16), and several studies have reported that IMT is associated with known risk factors for coronary atherosclerosis (17, 18, 19). This technique has been used for studies of the potential association between insulin resistance and early development of atherosclerosis. Such studies have, however, been conflicting. This is partially explained by the methodology of determining insulin resistance or by the heterogeneous populations studied, also including subjects with type 2 diabetes. Thus, only indirect measurements of insulin resistance have been undertaken, such as fasting or postchallenge insulin levels, or indexes based on glucose-insulin relationships in plasma, such as quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment method (HOMA). Some of these studies have shown an association between insulin resistance and cardiovascular diseases (20, 21, 22), whereas others have failed to observed any association between insulin resistance and IMT (23, 24, 25). Yet another study, using the insulin sensitivity index obtained during an iv glucose tolerance test as a measure of insulin sensitivity, found a correlation between insulin resistance and IMT in Hispanics and non-Hispanic whites, but not in blacks, although the association was partially mediated by traditional cardiovascular risk factors (26).

To establish whether insulin sensitivity is associated with IMT, i.e. the early manifestation of atherosclerosis, by using adequate technology and avoiding the confounding factor of fully developed type 2 diabetes, we have assessed carotid IMT by ultrasonography in nondiabetic postmenopausal women in whom we also determined insulin sensitivity by the euglycemic hyperinsulinemic clamp test. Furthermore, we have established insulin secretion in these women by an iv arginine challenge and glucose tolerance by a standardized 75-g oral glucose tolerance test (OGTT). Finally, to examine whether insulin sensitivity, insulin secretion, and glucose tolerance would predict future development of atherosclerosis, we performed a follow-up after 5 yr and related the change in IMT to the baseline measurements of these variables.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

In 1993–1994 a prospective 5-yr study in postmenopausal women was initiated, using ultrasound of the right and common carotid arteries to quantify early signs of atherosclerosis (IMT). The ultrasound findings were related to glucose tolerance, insulin sensitivity, insulin secretion, and clinical characteristics of the study subjects. Glucose tolerance was determined by an OGTT, and insulin sensitivity was measured using the euglycemic, hyperinsulinemic clamp. Insulin secretion was evaluated as the acute (2–5 min) insulin response to iv arginine. Follow-up examinations of ultrasound measurements were performed after 5 yr. Studies were performed in the morning after an overnight fast. The study was approved by the ethics committee at Lund University. The nature and purpose of the study were explained in detail to all participants, and written informed consent was obtained from all subjects before the study.

Subjects

One hundred and eight nondiabetic women were enrolled in the prospective study. The women were randomly selected from a larger cohort of 841 postmenopausal women born in 1935 living in the city of Malmö, Sweden, who had previously participated in a health screening (1990–1991), which included an OGTT (27). The selection procedure was based on the 2-h blood glucose (BG) value after a standard WHO 75-g OGTT. Women with 2-h BG below 11.1 mmol/liter were stratified so that all degrees of glucose tolerance from normal glucose tolerance (NGT; 2-h BG, <7.8 mmol/liter) to IGT (2-h BG, >=7.8 and <11.1 mmol/liter) were represented, whereas no case of diabetes was included. None of the women included in the study was taking any medication known to affect carbohydrate metabolism. There were nine subjects taking lipid-lowering statins. Subjects with known cardiovascular disease, such as previous myocardial infarction, angina, or stroke, were excluded from the study. Of the 108 women, 84 participated in the 5-yr follow-up. The 24 women who did not participate in the follow-up did not differ from the 84 participants in baseline body weight or body mass index (BMI), glucose tolerance, insulin sensitivity, insulin secretion, or ultrasound-determined variables. This paper presents data on the 84 women who participated in both baseline and follow-up examinations.

Anthropometric measurements

All measurements were performed with the subjects in light clothing without shoes. Body weight was measured to the nearest 0.1 kg in the morning before breakfast. Height was measured to the nearest centimeter. Both body weight and height were measured on two separate occasions. BMI was then calculated as the weight (kilograms) divided by height (meters) squared for each separate measurement, and the mean BMI was calculated.

Glucose tolerance

Oral glucose tolerance was determined with a standard WHO 75-g glucose load, with samples taken before and 2 h after the glucose load. The subjects spent the 2 h in a semirecumbent position.

Insulin sensitivity

Insulin sensitivity was determined with the euglycemic, hyperinsulinemic clamp, performed according to DeFronzo et al. (28). Intravenous catheters were inserted into antecubital veins in both arms. One arm was used for infusion of glucose and insulin. The contralateral arm was used for intermittent sampling, and the catheter was kept patent with a slow infusion of 0.9% saline. Baseline samples of glucose and insulin were taken. A primed constant infusion of insulin (100 U/ml; Actrapid, Novo Nordisk, Bagsvaerd, Denmark) with a constant infusion rate of 0.28 nmol/m2 body surface area·min was started. After 4 min, a variable rate 20% glucose infusion was added, and its infusion rate was adjusted manually throughout the clamp procedure to maintain the blood glucose level at 5.0 mmol/liter. Blood glucose was determined at the bedside every 5 min. Samples for analysis of the achieved insulin concentration were taken at 60 and 120 min.

Insulin secretion

Insulin secretion was determined as the acute (2–5 min) insulin response to iv arginine (5 g) after an overnight fast. Intravenous catheters were inserted into antecubital veins in both arms. After obtaining two baseline samples at -5 and -2 min, a maximally stimulating dose of arginine hydrochloride (5 g) was injected iv over 45 sec, and new samples were taken at 2, 3, 4, and 5 min.

Carotid artery ultrasound

The right carotid artery was investigated using a 128 Computed Sonography System (Acuson, Mountain View, CA) with a 7-MHz transducer, for determination of IMT. The methods have been described in detail previously (29). Briefly, the examinations and image analyses were performed by specially trained sonographers who were certified after completion of an extensive training program. The extent of early atherosclerotic lesions was determined off-line in the far wall of the distal common carotid artery (CCA) using the leading edge principle to determine the IMT, with a specially designed computer-assisted image analyzing system. The mean CCA IMT was measured 1 cm proximal to the bifurcation, and the maximal IMT was measured in the carotid bifurcation. The measurement of IMT included plaque, if it was localized to the defined area. The presence of late atherosclerotic lesions was determined by scanning the artery with a window consisting of 3 cm of the distal CCA, the carotid bulb, and 1 cm each of the internal and external carotid arteries. A plaque was defined as a discernable focal thickening of the artery wall exceeding 1.2 mm. When a plaque was present, the degree of CCA stenosis was determined after measuring the blood flow velocity at the location of maximum lumen reduction. Furthermore, in each subject a plaque score was calculated: 0, no plaques; 1, one plaque less than 10 mm2; 2, one plaque 10 mm2 or more; 3, one circumferential or two plaques; and 4, more than two plaques (30). In the case of unaltered blood flow velocity, the degree of stenosis was estimated by "eye-balling" the plaque protrusion into the lumen (maximum, 30%). The intra- and interobserver variability of this method in our laboratory is less than 10% (16).

Biochemical analyses

The BG concentration was determined at the bedside by the glucose dehydrogenase technique with a Hemocue (Hemocue AB, Ängelholm, Sweden) during the hyperinsulinemic, euglycemic clamp. Blood samples for analysis of insulin and glucose from the arginine studies, of insulin from the clamp studies, and of glucose from the OGTT were immediately centrifuged at 5 C, and serum or plasma was frozen at -20 C until analysis in duplicate. Serum insulin concentrations were analyzed using a double-antibody RIA technique with guinea pig antihuman insulin antibodies, human insulin standard, and mono-[125I-Tyr]human insulin (Linco Research, Inc., St. Charles, MO). The assay was specific for insulin, with no cross-reactivity (<0.2%) with intact proinsulin or des-31,32-proinsulin. The intra- and interassay coefficients of variation of the insulin assay were less than 3%.

Calculations and statistics

Data are presented as the mean ± SD unless otherwise noted. For calculation of insulin sensitivity, a steady state condition was assumed during the second hour of the clamp, and insulin sensitivity (nanomoles of glucose per kilogram of body weight per minute/picomoles of insulin per liter) was taken as the glucose infusion rate during the second hour of the clamp divided by the measured mean insulin concentration during the second hour of the clamp. For calculation of insulin secretion, the acute insulin response to arginine was calculated as the mean of the 2- to 5-min samples minus the mean prestimulus hormone concentration. Statistical analyses were performed with the SPSS for Windows system (SPSS, Inc., Chicago, IL), and differences between groups were tested with t test for unrelated samples, whereas differences between baseline and follow-up within groups were tested with t test for related samples. The difference in frequency of a condition between baseline and follow-up was assessed using the {chi}2 test. Two-sided tests were used, and P <0.05 was considered statistically significant. Pearson’s product-moment correlation coefficients were obtained to estimate linear correlation between variables. Linear multiple regression was used to assess the independent effect of several variables on mean CCA IMT and maximal bifurcation IMT. The stepwise forward method was used. Finally, the Kolmogorov-Smirnov test was used to test for normality of distribution.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics of the 84 study subjects at baseline are shown in Table 1Go, results from the ultrasound examinations at baseline and follow-up are shown in Table 2Go, and the distribution of insulin sensitivity in this population is shown in Fig. 1Go. It is seen that measures of carotid atherosclerosis increased over the 5 yr in this population. Mean CCA IMT thus increased by 0.012 ± 0.014 mm or 1.48 ± 2.0%/yr (P < 0.001), and maximal bifurcation IMT increased by 0.035 ± 0.049 mm or 30.01 ± 4.39%/yr (P < 0.001). Furthermore, the number of subjects with CCA plaque and stenosis also increased significantly from baseline to follow-up. Moreover, insulin sensitivity in this population showed a normal distribution with a wide range (Table 1Go and Fig. 1Go; P = 0.964, by Kolmogorov-Smirnov test). Also, mean CCA IMT and maximal bifurcation IMT were normally distributed at both baseline and follow-up. Of the 84 subjects, 57 (67%) had NGT, and 27 (33%) had IGT, as defined by the WHO, i.e. below or above 7.8 mmol/liter at the 120 min value in the OGTT. There was no difference in the relation between the various risk factors and IMT in those with IGT vs. those with NGT; thus, the analysis of relations was performed in the entire study group. The nine subjects taking lipid-lowering statins did not differ from the 75 subjects not taking statins in regard to mean CCA IMT (0.81 ± 0.08 vs. 0.81 ± 0.14 mm; P = 0.93), maximal bifurcation IMT (1.40 ± 0.37 vs. 1.43 ± 0.47 mm; P = 0.83), or insulin sensitivity [66.5 ± 30.1 vs. 72.2 ± 26.6 (nmol glucose/kg/min)/(pmol insulin/liter); P = 0.54].


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical characteristics at baseline in the 84 postmenopausal women studied

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Variables obtained from the ultrasonography of the carotid artery in the 84 women at baseline and at the 5-yr follow-up

 


View larger version (17K):
[in this window]
[in a new window]
  		FIG. 1. Distribution of insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp technique in 84 women. Each bar represents the number of individuals within each range of 20 (nmol glucose/kg·min)/(pmol insulin/liter).

 
Correlation coefficients were obtained to study the univariate association of IMT with various risk factors, using both mean CCA IMT (Table 3Go) and maximal bifurcation IMT as measures (Table 4Go). Both mean CCA IMT and maximal bifurcation IMT at baseline were significantly related to systolic blood pressure and low-density lipoprotein (LDL) cholesterol. In contrast, no associations were noted between the IMT measures and BMI, fasting or 2-h glucose or insulin, insulin sensitivity, glucose tolerance, or the insulin response to arginine. The regression between insulin sensitivity and mean CCA IMT at baseline is illustrated in Fig. 2Go. A stepwise forward multivariate regression analysis was performed to identify independent predictors of baseline mean CCA IMT (Table 5Go). Both systolic blood pressure and LDL cholesterol independently predicted mean CCA IMT. Similar associations were seen for maximal bifurcation IMT (data not shown).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Correlations between baseline or the 5-yr change in mean CCA IMT and clinical characteristics at the baseline examination

 

View this table:
[in this window]
[in a new window]
  		TABLE 4. Correlations between baseline or the 5-yr change in maximal bifurcation IMT and clinical characteristics at the baseline examination

 


View larger version (18K):
[in this window]
[in a new window]
  		FIG. 2. Linear regression between insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp technique and mean CCA IMT as determined by ultrasonography in 84 women. The regression was not significant (r = 0.057; P = 0.60).

 

View this table:
[in this window]
[in a new window]
  		TABLE 5. Stepwise forward multiple linear regression model to determine independent predictors for baseline mean CCA IMT in the 84 postmenopausal women

 
To further study whether insulin resistance is associated with measures of carotid atherosclerosis, we compared these measures in the 10 subjects with the highest insulin sensitivity [118.2 ± 11.3 (nmol glucose/kg·min)/(pmol insulin/liter)] vs. in the 10 subjects with the lowest insulin sensitivity [27.2 ± 10.8 (nmol glucose/kg·min)/(pmol insulin/liter)]. Mean CCA IMT (0.84 ± 0.12 vs. 0.79 ± 0.09 mm; P = 0.25), maximal bifurcation IMT (1.52 ± 0.28 vs. 1.35 ± 0.12 mm; P = 0.60), and CCA lumen diameter (5.73 ± 0.24 vs. 5.57 ± 0.20 mm; P = 0.52) did not differ between these groups.

An additional analysis of correlation coefficients was carried out to study the relation between baseline variables and the change in IMTs over the 5-yr study period (i.e. IMT at the 5-yr follow-up minus the IMT at baseline divided by the follow-up time), as shown in Tables 3Go and 4Go. It was found that the progression rate of CCA IMT correlated to baseline systolic blood pressure (r = 0.26; P = 0.048) and LDL cholesterol (r = 0.29; P = 0.042), but not to the other variables, including insulin sensitivity (r = 0.062; P = 0.59) or baseline mean CCA IMT (r = 0.10; P = 0.24). Similarly, the 5-yr progression rate of maximal bifurcation IMT correlated significantly to systolic blood pressure (r = 0.21; P = 0.042) and LDL cholesterol (r = 0.29; P = 0.039), but not to the other variables, including insulin sensitivity (r = -0.035; P = 0.78) or baseline maximal bifurcation IMT (r = 0.18; P = 0.074). Furthermore, a multivariate regression analysis showed that both systolic blood pressure and LDL cholesterol at baseline were independent predictors of the progression of IMTs (Table 6Go).


View this table:
[in this window]
[in a new window]
  		TABLE 6. Stepwise forward multiple linear regression model to determine independent baseline predictors for change in mean CCA IMT in the 84 postmenopausal women

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study examined the possible importance of insulin sensitivity (insulin resistance), insulin secretion, and glucose tolerance for early manifestation of atherosclerosis. The study used B-mode ultrasonography of the right carotid artery for measurement of IMT as a sign of early atherosclerosis. This approach has been validated in previous studies. Thus, carotid artery ultrasonography correlates to morphology of the arterial wall (14, 15, 16) and to direct measures of coronary artery disease as reflected by angiography (11). IMT correlates also to known risk factors for coronary atherosclerosis (17, 18, 19) and predicts future cardiovascular events (12). The IMT measure obtained by this technique thus seems to accurately reflect the early manifestation of the disease and the long-term overall risk. Furthermore, we performed the study in a highly standardized population; all 84 subjects were nondiabetic postmenopausal women of the same age, and we repeated the examination after a standardized follow-up period of 5 yr. We found that mean CCA IMT was 0.81 ± 0.14 mm at baseline investigation, when all subjects were 58 yr of age, and increased to 0.86 ± 0.14 mm after 5 yr. The corresponding figures for maximal bifurcation IMT were 1.42 ± 0.42 and 1.60 ± 0.40 mm. These figures are similar to those previously reported in a 5-yr prospective population study (21).

Our main purpose with this study was to examine whether insulin sensitivity, as determined by the gold standard technique, euglycemic, hyperinsulinemic clamp, could predict the changes in IMT in this population of nondiabetic subjects. Previous studies of the relation between insulin resistance and IMT have usually been cross-sectional. Moreover, they have used indirect measures of insulin sensitivity, such as fasting or postchallenge insulin levels, or simple indexes based on glucose and insulin levels at steady state, for example, QUICKI and HOMA. These studies have yielded conflicting results, reporting both a relation between insulin resistance and IMT (20, 21, 22) and no relation in nondiabetic subjects (23, 24, 25). We confirm by the gold standard technique that there is no clear association between insulin sensitivity and IMT in nondiabetic subjects, and furthermore, we establish this both in the cross-sectional study at baseline and in the prospective, follow-up study after 5 yr. We obtained similar results when using both mean CCA IMT and maximal bifurcation IMT as the marker for early atherosclerosis. This suggests that the early atherogenic events are not induced by insulin resistance. This, in turn, suggests that the association between IMT and deterioration of glucose tolerance in type 2 diabetes is caused by other factors associated with the disease, such as other cardiovascular risk factors and hyperglycemia, which is also inferred from previous studies (5, 6, 21, 24, 31). It may be argued that our study population was too small to detect any association with IMT. However, as the range in insulin sensitivity was more than 15-fold, the ranges in the two IMT measurements were more than 3-fold, and all measurers were normally distributed, the probability of missing a significant association is less than 1% when r values of the correlations were less than 0.06. The lack of regression between insulin sensitivity and mean CCA IMT is also evident by plotting the regression, as performed in Fig. 2Go. In our study we measured IMT of the CCA and bifurcation only and not in the internal carotid artery. This was because earlier studies have shown that there is no difference in results when using IMT of the CCA vs. internal carotid artery in relation to insulin sensitivity or type 2 diabetes (32, 33). Hence, it seems sufficient to rely on results from IMT measurements of either CCA or internal carotid artery when studying associations between atherosclerosis and those variables.

One recent cross-sectional study found a gender influence on the correlation between insulin resistance and IMT in approximately 200 subjects, as the association was evident in males, but not in females (22). That study used indexes for determination of insulin resistance (QUICKI and HOMA) and also included diabetic subjects in the analyses. Nevertheless, despite these differences between that study and the present, they seem to confirm that in females no association is evident between IMT and insulin resistance. Other previous studies have also shown that gender is associated with IMT (20, 21), and this corroborates the finding that the excess cardiovascular risk for women is more related to mortality from heart disease rather than an increased incidence of atherosclerosis (34). It is thus possible that gender differences may explain differences in results between different studies, although it should also be emphasized that the relation in males was weak, with an r value of only 0.15 (22).

A study using the insulin sensitivity index obtained during an iv glucose tolerance test for measurement of insulin sensitivity has found an association between insulin resistance and IMT in Hispanic and non-Hispanic whites, but not in blacks (26). This association was markedly reduced, however, by including confounding factors in the analysis, such as lipid levels, blood pressure, glucose tolerance, and degree of adiposity. Although the relation remained significant after adjustment for these variables, the independent association between insulin resistance and IMT was weak. This is in line with the findings of the present study that, if anything, insulin resistance only marginally contributes to IMT independently of its association with other factors.

Insulin sensitivity is intimately associated with insulin secretion, such that insulin resistance is compensated by an increased insulin secretion (7, 35, 36), and if this compensation fails, type 2 diabetes develops. Defective insulin secretion is therefore an important contributor to the development of type 2 diabetes. In this study we also evaluated whether insulin secretion relates to IMT by performing an iv arginine challenge after an overnight fast and measuring the insulin response. However, we found no association between insulin secretion and IMT. We also found no association between fasting or 2-h glucose values and baseline IMT or change in IMT in this population of nondiabetic subjects, which supports previous reports that the association between atherosclerosis and glucose intolerance is seen mainly in diabetic subjects (31). Within groups of near-normal glucose tolerance, therefore, factors other than fasting and postprandial glucose are of greater importance for the early atherogenic events. This does not exclude, however, major contribution of glucose levels to the development of atherosclerosis at later stages (37).

As demonstrated in several previous studies (22, 24, 26), we found a strong association between blood pressure and IMT. This association was seen in the baseline study, and the baseline blood pressure also independently predicted the progression of IMT. We thereby confirm the finding by Hedblad et al. (24) that hypertension is the strongest predictor of IMT in nondiabetic subjects. We also found that LDL cholesterol independently predicted at both baseline and follow-up IMT, which also supports previous studies (24). In fact, in our study only blood pressure and LDL cholesterol remained significant in association with IMT after adjustment for other factors. These two factors to date override any influence of insulin resistance for IMT in nondiabetic subjects.

As the measurement of IMT in our study was repeated after 5 yr, we could also estimate the association of the various risk factors for the progression of atherosclerosis over this period of time. We then found that the same risk factors that correlated to baseline IMT also correlated to the progression rate of IMT. Nevertheless, the baseline wall thickness did not significantly correlate to the progression rate, although there was a significant correlation between baseline and follow-up IMT (r = 0.81; P < 0.001 for mean CCA IMT and r = 0.61; P < 0.001 for maximal bifurcation IMT). As insulin sensitivity or secretion did not relate to the progression of IMT in this population of nondiabetic subjects, the results of the follow-up study further emphasize that in the early stages of development of diabetes, events other than insulin resistance or secretion are more important for IMT.

In conclusion, we used the euglycemic hyperinsulinemic clamp technique for evaluating insulin sensitivity and B-mode ultrasonography of the right carotid artery for measuring IMT as a sign of early atherogenic changes in 84 nondiabetic postmenopausal women, all aged 58 yr, and we repeated the ultrasonography after 5 yr. We found no independent relation between insulin sensitivity and IMT, whereas we found strong associations between IMT and blood pressure as well as LDL cholesterol. We also did not find any association between IMT and insulin secretion or glucose intolerance. Our results therefore suggest that blood pressure and LDL cholesterol override insulin resistance as a risk marker for early atherogenic events in nondiabetic subjects.


   Acknowledgments
 
We are grateful to Gerd Östling for performing and analyzing the ultrasonography; to Margaretha Persson and Kerstin Nilsson for nursing assistance during the euglycemic, hyperinsulinemic clamp, the iv arginine challenge, and the OGTT; and to Lilian Bengtsson for expert technical assistance in the analyses of samples.


   Footnotes
 
This work was supported by grants from the Swedish Research Council (Grant 6834), the Albert Påhlsson Foundation, the Swedish Diabetes Association, and the Faculty of Medicine, Lund University.

Abbreviations: BG, Blood glucose; BMI, body mass index; CCA, common carotid artery; HOMA, homeostasis model assessment method; IGT, impaired glucose tolerance; IMT, intima-media thickness; LDL, low-density lipoprotein; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; QUICK1, quantitative insulin sensitivity check index.

Received February 26, 2003.

Accepted July 14, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Kannel WB, McGee DL 1979 Diabetes and cardiovascular disease. The Framingham study. JAMA 241:2035–2038[Abstract]
  2. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H 1983 Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study. Br Med J 287:867–870
  3. Pan WH, Cedres LB, Liu K, Dyer A, Schoenberger JA, Shekelle RB, Stamler R, Smith D, Collette P, Stamler J 1986 Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women. Am J Epidemiol 123:504–516[Abstract/Free Full Text]
  4. Jarrett RJ 1996 The cardiovascular risk associated with impaired glucose tolerance. Diabet Med 13:S15–S19
  5. Hanefeld M, Koehler C, Henkel E, Fuecker K, Schaper F, Temelkova-Kurktschiev T 2000 Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD study. Diabet Med 17:835–840[CrossRef][Medline]
  6. Hanefeld M 2002 Postprandial hyperglycaemia: noxious effects on the vessel wall. Int J Clin Pract 129:45–50
  7. Kahn SE 2001 The importance of ß-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 86:4047–4058[Free Full Text]
  8. Stout RW 1994 The impact of insulin upon atherosclerosis. Horm Metab Res 26:125–128[Medline]
  9. DeFronzo RA, Ferrannini E 1991 Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14:173–194[Abstract]
  10. Liese AD, Mayer-Davis EJ, Haffner SM 1998 Development of the multiple metabolic syndrome: an epidemiologic perspective. Epidemiol Rev 20:157–172[Free Full Text]
  11. Viscona A, Persavento R, Lusiani L, Bonanome A, Cernetti C, Rossi M, Maiolino P, Pagnan A 1996 Intimal medial thickness of common carotid artery as indicator of coronary artery disease. Angiology 47:61–66
  12. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, Clegg LX 1997 Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) study, 1987–1993. Am J Epidemiol 46:483–494
  13. Laakso M, Sarlund H, Salonen R, Suhonen M, Pyörälä K, Salonen JT, Karhapää P 1991 Asymptomatic atherosclerosis and insulin resistance. Artierioscler Thromb 11:1068–1076
  14. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R 1986 Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 74:1399–1406[Abstract/Free Full Text]
  15. Wong M, Edelstein J, Wollman J, Bond MG 1993 Ultrasonic-pathological comparison of the human arterial wall. Verification of intima-media thickness. Arterioscl Thromb 13:482–486[Abstract/Free Full Text]
  16. Persson J, Formgren J, Israelsson B, Berglund G 1994 Ultrasound-determined intima-media thickness and atherosclerosis. Direct and indirect validation. Arterioscl Thromb 14:261–264[Abstract/Free Full Text]
  17. Heiss G, Sharrett AR, Barnes R, Chamblers LE, Szklo M, Alzola C 1991 Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol 34:250–256
  18. Crouse JR, Toole JF, McKinney WM, Dignan MB, Howard G, Kahl FR, McMahan MR, Harpold GH 1987 Risk factors for extracranial carotid artery atherosclerosis. Stroke 18:990–996[Abstract/Free Full Text]
  19. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK 1999 Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340:14–22[Abstract/Free Full Text]
  20. Folsom AR, Eckfeldt JH, Weizman S, Ma J, Chambless LE, Barnes RW, Cram KB, Hutchinson RG 1994 Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Stroke 25:66–73[Abstract]
  21. Bonora E, Kiechl S, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M, Willeit J 2000 Impaired glucose tolerance, type II diabetes mellitus and carotid atherosclerosis: prospective results from Bruneck study. Diabetologia 43:156–164[CrossRef][Medline]
  22. Rajala U, Laakso M, Päivänsalo M, Pelkonen O, Suramo I, Keinänen-Kiukaaniemi S 2002 Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima-media thickness of the carotid artery. J Clin Endocrinol Metab 87:5092–5097[Abstract/Free Full Text]
  23. Rantala AO, Päivänsalo M, Kauma H, Lilja M, Savolainen MJ, Reunanen A, Kesäniemi YA 1998 Hyperinsulinemia and carotid atherosclerosis in hypertensive and control subjects. Diabetes Care 21:1188–1193[Abstract]
  24. Hedblad B, Nilsson P, Janzon L, Berglund G 2000 Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmö, Sweden. Diabet Med 17:299–307[CrossRef][Medline]
  25. Bonora E, Tessari R, Micciolo R, Zenere M, Targher G, Padovani R, Falezza G, Muggeo M 1997 Intima-medial thickness of the carotid artery in nondiabetic and NIDDM patients. Diabetes Care 20:627–631[Abstract]
  26. Howard G, O'Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R 1996 Insulin sensitivity and atherosclerosis. Circulation 93:1809–1817[Abstract/Free Full Text]
  27. Larsson H, Ahrén B, Lindgärde F, Berglund G 1995 Fasting blood glucose in determining prevalence of diabetes in a large, homogenous population of Caucasian middle-aged women. J Int Med 237:537–541[Medline]
  28. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
  29. Wendelhag I, Gustavsson T, Suurkula M, Berglund G, Wikstrand J 1991 Ultrasound measurement of wall thickness in the carotid artery. Fundamental principles and description of a computerized image analyzing system. Clin Physiol 11:565–577[Medline]
  30. Persson J, Israelsson B, Stavenow L, Holmström E, Berglund G 1996 Progression of atherosclerosis in middle-aged men: effects of multifactorial intervention. J Intern Med 239:425–433[CrossRef][Medline]
  31. Wagenknecht LE, D'Agostino RB, Haffner SM, Savage PJ, Rewers M 1998 Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness. Diabetes Care 21:1812–1818[Abstract]
  32. Haffner SM, D'Agostino R, Mykkänen L, Tracy R, Howard B, Rewers M, Selby J, Savage PJ, Saad MF 1999 Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the insulin resistance atherosclerosis study. Diabetes Care 22:562–568[Abstract]
  33. Snehalatha C, Vijay V, Suresh Mohan R, Satyavani K, Sivasankari S, Megha T, Radhika S, Ramachandran A 2001 Lack of association of insulin resistance and carotid intimal medial thickness in non-diabetic Asian Indian subjects. Diabet Metab Res Rev 17:444–447
  34. Orchard TJ 1996 The impact of gender and general risk factors on the occurrence of atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Ann Med 28:323–333[Medline]
  35. Larsson H, Ahrén B 2000 Glucose intolerance is predicted by low insulin secretion and high glucagon secretion: outcome of a prospective study in postmenopausal Caucasian women. Diabetologia 43:194–202[CrossRef][Medline]
  36. Ahrén B, Larsson H 2002 Quantification of insulin secretion in relation to insulin sensitivity in non-diabetic post-menopausal women. Diabetes 52(Suppl 1):S202–S211
  37. Qiao Q, Tuomilehto J, Borch-Johnsen K 2003 Post-challenge hyperglycaemia is associated with premature death and macrovascular complications. Diabetologia 46(Suppl 1):M17–M21



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. Cardellini, M. A. Marini, S. Frontoni, M. L. Hribal, F. Andreozzi, F. Perticone, M. Federici, D. Lauro, and G. Sesti
Carotid artery intima-media thickness is associated with insulin-mediated glucose disposal in nondiabetic normotensive offspring of type 2 diabetic patients
Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E347 - E352.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
P. B. Mellen, W. T. Cefalu, and D. M. Herrington
Diabetes, the Metabolic Syndrome, and Angiographic Progression of Coronary Arterial Disease in Postmenopausal Women
Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 189 - 193.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Larsson, H.
Right arrow Articles by Ahrén, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Larsson, H.
Right arrow Articles by Ahrén, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals