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(Stroke. 1996;27:1986-1992.)
© 1996 American Heart Association, Inc.

Articles

Carotid Artery Intima-Media Thickness in Elderly Patients With NIDDM and in Nondiabetic Subjects

Leo Niskanen, MD; Rainer Rauramaa, MD; Heikki Miettinen, MD; Steven M. Haffner, MD; Michele Mercuri, MD Matti Uusitupa, MD

the Departments of Clinical Nutrition (L.N., M.U.) and Medicine (L.N., H.M.) and the Kuopio Research Institute of Exercise Medicine and Department of Physiology (R.R.), University of Kuopio (Finland); the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio (H.M., S.M.H.); and the Division of Vascular Ultrasound Research, Bowman Gray School of Medicine, Winston-Salem, NC (M.M.).

Correspondence to Steven M. Haffner, MD, University of Texas Health Science Center at San Antonio, Department of Medicine, Division of Clinical Epidemiology, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873. E-mail haffner@uthscsa.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The risk of atherosclerotic vascular disease is increased both in subjects with non–insulin-dependent diabetes mellitus (NIDDM) and in those with impaired glucose tolerance compared with nondiabetic subjects. Although classic cardiovascular risk factors are operative in subjects with NIDDM, other factors closely related to insulin resistance syndrome such as diabetic dyslipidemia and hyperglycemia itself may contribute to an excessive cardiovascular disease risk in subjects with NIDDM. The purpose of this study was to investigate the carotid intimal-medial thicknesses (IMTs) and their determinants in elderly patients with NIDDM and in control subjects.

Methods We investigated the common carotid and carotid bifurcation IMTs and their determinants in groups of elderly patients (n=84, age 67.2±0.6 years) with NIDDM and in 119 control subjects (21 with impaired and 98 with normal glucose tolerance; ages 67.5±1.0 and 65.1±0.6 years, respectively).

Results Common carotid and carotid bifurcation IMTs were greater in the NIDDM group than in control subjects (P<.05 to .01). In NIDDM patients, the mean carotid IMT correlated with postglucose 1-hour plasma insulin (r=.305, P=.01, adjusted for age and sex), serum LDL triglyceride (r=.237, P<.05), and apolipoprotein B concentrations (r=.263, P<.05). Fasting plasma immunoreactive insulin, proinsulin, or specific insulin levels were not significantly associated with carotid IMT. Both diabetic status (P<.05) and the presence of clinical macrovascular disease (P<.01) contributed independently to carotid IMT.

Conclusions Carotid IMT was greater in NIDDM patients than in control subjects. The main determinants of IMT in NIDDM patients were related to both postglucose insulin levels and abnormal lipoprotein profiles characteristic of NIDDM and insulin resistance syndrome. Treatment of these factors is likely to reduce the atherosclerotic burden in NIDDM.

Key Words: aged • apolipoproteins • carotid artery diseases • diabetes mellitus • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The frequency of atherosclerotic vascular disease is markedly increased in subjects with NIDDM compared with nondiabetic subjects. Furthermore, subjects with IGT, a precursor of NIDDM, have an increased risk of macrovascular disease compared with those with NGT.¹ Although classic cardiovascular risk factors are also operative in subjects with NIDDM, there are other factors closely related to insulin resistance syndrome such as diabetic dyslipidemia and hyperglycemia itself^{2 3} that may contribute to an excessive cardiovascular mortality in patients with NIDDM.

High-resolution B-mode imaging of the carotid artery IMT has been shown to reflect histopathologically verified atherosclerosis ^{4 5} and therefore is widely used to detect and quantify surrogate noninvasive measurements of atherosclerosis.^{6 7} Studies have shown a fair correlation of carotid IMT with angiographically verified coronary artery disease,^{8 9} but a recent comparison of carotid IMT with coronary angiography emphasized that although the correlation is statistically significant, it may not be a strong one.¹⁰ Previous studies have given evidence that patients with NIDDM^{11 12} and even those with IGT¹³ may have greater carotid IMT than nondiabetic subjects, but the extent and the determinants of carotid IMT in NIDDM are still vaguely described, especially in elderly subjects. In this study we measured carotid IMT and its determinants in a well-characterized group of subjects with NIDDM and in control subjects with either NGT or IGT.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Design
This study was a cross-sectional analysis from the 10-year examination of a cohort of patients with NIDDM and nondiabetic control subjects followed up from the time of diagnosis.^{3 14 15} In brief, the original study population comprised 133 patients with newly diagnosed NIDDM, aged 45 to 64 years, and 144 age-matched nondiabetic control subjects randomly selected from the general register. The data collection for the original study group was carried out during the years 1979 through 1981. Both groups were recruited from a defined area of 180 000 inhabitants in the county of Kuopio in Eastern Finland.¹⁴ Approval for the study had been given by the ethics committee of Kuopio University and Kuopio University Hospital. Informed consent was obtained from all the subjects studied.

The original cohort of diabetic patients (70 men and 63 women) from which the present study population was selected was referred to the study by general practitioners working in the community health centers of the survey area. The diagnosis of diabetes was made in the clinical setting,¹⁴ and it was confirmed with an oral glucose tolerance test according to the diagnostic criteria of the World Health Organization Expert Committee on Diabetes Mellitus.¹⁶ Subjects whose fasting blood glucose had exceeded 7.0 mmol/L for more than 6 months, as well as subjects with secondary diabetes, thyroid diseases, alcoholism, renal insufficiency, overt carcinoma, or those in institutional care, were not eligible for the study. All diabetic patients were nonketotic at the time of diagnosis, and none needed insulin treatment during the follow-up period of at least 3 months. The subjects were invited for the 5- and 10-year follow-up studies during the periods between August 1985 and February 1986 and September 1991 and May 1992. At the 10-year examination, carotid ultrasonography measurements were performed for 84 (63%) of the diabetic and 119 (83%) of the nondiabetic subjects of the original study population.

Detailed Methods
This study was based on the data from the 10-year follow-up examination performed in 1991 through 1992. The history of cardiovascular and other diseases and the use of drugs were registered. "Myocardial infarction" refers to hospital-verified myocardial infarction or major Q-QS abnormalities as determined according to the Minnesota code (Mc 1.1 to 2).¹⁷ "Subjects with coronary heart disease" refers to those with myocardial infarction or angina pectoris determined according to Rose's cardiovascular questionnaire.¹⁷ Likewise, intermittent claudication was assessed with Rose's questionnaire,¹⁷ and stroke was defined as a clinical syndrome consisting of neurological findings persisting >24 hours and verified at a hospital.¹⁷ The predictors and radiological imaging of stroke in this population have been reported earlier.¹⁸ The group "any macrovascular disease" refers to the subjects with any previously defined evidence of myocardial infarction, stroke, angina pectoris, or intermittent claudication. Body mass index was calculated as weight in kilograms divided by height in meters squared. Blood pressure was measured with subjects in the sitting position after a 5-minute rest, and the mean of the three readings was used. Hypertension was diagnosed as a predetermined blood pressure level (systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg) and/or history of antihypertensive drug treatment.

An oral glucose tolerance test was performed using a glucose dose of 75 g. Blood samples for glucose and insulin were drawn before the glucose dose and at 1 and 2 hours afterwards.

An oral glucose tolerance test was not performed for those diabetic patients receiving insulin treatment. Glucose determinations were conducted using a glucose oxidase method (Glucose Auto & Stat HGA-1120 analyzer, Daiichi Co) from plasma samples. In this study the control subjects were divided into those with NGT and those with IGT.

Immunoreactive insulin samples were drawn into chilled tubes. After separation of plasma, samples were immediately frozen at -70°C until the determination. Determination was carried out with a double-antibody radioimmunoassay (Phadeseph, Pharmacia). Specific insulin was measured with a commercial double-antibody radioimmunoassay (human insulin-specific radioimmunoassay method, LINCO Research) in which proinsulin cross-reactivity is less than 0.2%.¹⁹ Immunoreactive and specific insulin levels were not analyzed for samples from those diabetic patients with insulin treatment. Proinsulin and specific insulin concentrations were measured in the laboratory of Dr Steven M. Haffner (University of Texas Health Science Center, San Antonio, Tex) with a nonequilibrium radioimmunoassay method.²⁰ The polyclonal antibody used for the proinsulin assay (168AB) recognizes a proinsulin-specific epitope formed by the intact A-chain–C-peptide junction.^{19 20}

Glycosylated hemoglobin A1_c was measured with liquid cation exchange liquid chromatography with a reference range of 4.0% to 6.0% (Pharmacia). Serum lipoproteins from 12-hour fasting samples were separated by ultracentrifugation for 12 hours at d<1.006 g/mL to remove VLDL. HDL in the infranatant was separated from LDL by precipitation of LDL, using dextran sulfate and magnesium chloride. LDL cholesterol was calculated as the difference between the mass of cholesterol in the infranatant and in the HDL.²¹ Serum apoA₁ and apoB were determined using a commercial immunochemical method (Kone Diagnostics) that is based on the measurement of immunoprecipitation at 340 nm.²² Urinary albumin excretion was measured from timed overnight samples by kinetic rate nephelometry on a Beckman array protein analyzer using microalbumin reagent.

Carotid Ultrasonographic Measurements
The high-resolution B-mode ultrasonographic imaging protocol was designed to ensure the valid and reliable identification of arterial carotid references and the definition of near-wall and far-wall interfaces. The carotid artery was divided into two segments on the basis of arterial anatomy and geometry (ie, distal common carotid artery) and the carotid bifurcation (bulb). The key anatomic features defining these segments were the proximal origin of the bulb and the tip of the flow divider, which separates internal from external carotid arteries. In longitudinal arterial images, the adventitia-media and the intima-lumen interfaces on the near wall and the lumen-intima and media-adventitia interfaces on the far wall were the specific anatomic boundaries defining the IMT. The scanning protocol has been described in detail elsewhere.²³ Two certified sonographers performed the carotid ultrasound examinations. A Biosound Phase Two ultrasound device equipped with a 10-MHz annular array probe was used. Video-recorded examinations were quantitatively analyzed at a central laboratory using a computer-assisted reading procedure.⁷ The mean maximum of the far wall bilaterally was used as the measure of the common carotid and carotid bifurcation IMT.

Statistical Analysis
The differences between the group means of continuous variables were tested for significance by Student's t test, ANOVA, and ANCOVA. Multiple stepwise (forward) regression analyses were performed to determine statistically independent associates of carotid IMT. The ² test, Fisher's test, and Mantel-Haenszel test for linear trend were used to analyze the differences between the groups for frequency data. Pearson and adjusted (partial) correlation coefficients were calculated between variables of interest. Variables with skewed distribution (eg, insulin and triglycerides) were analyzed after logarithmic transformation to correct for skewness and kurtosis. Values of P<.05 (two-tailed) were considered statistically significant. All the data were analyzed using SPSS for Unix (SPSS Inc).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical and biochemical characteristics of the study population according to glucose tolerance status are shown in Table 1. Fasting immunoreactive and specific insulin levels were highest in IGT subjects, whereas fasting proinsulin levels were highest among patients with NIDDM. No differences in serum total or LDL cholesterol levels were observed between the groups, but HDL cholesterol and apoA1 levels were decreased, and total, VLDL, and LDL triglyceride levels increased with worsening of glucose tolerance status. Likewise, the frequencies of myocardial infarction, coronary heart disease, stroke, and any macrovascular disease increased with worsening glucose tolerance status. The mode of treatment of NIDDM was diet only in 15 patients (17.9%), oral drugs in 49 (58.3%), and insulin in 20 (23.8%); 10 patients received oral hypoglycemic drugs (combination therapy) in addition to insulin.

View this table: [in this window] [in a new window]   Table 1. Clinical and Biochemical Characteristics of the Study Population in Relation to Glucose Tolerance Status

Table 2 shows the IMTs of the common carotid and carotid bifurcation and their mean according to glucose tolerance status and sex. In all groups, carotid bifurcation IMTs were greater than common carotid IMTs (P<.001). NIDDM subjects had in general the thickest IMT of the carotid arteries, but subjects with IGT had only modestly increased IMT compared with subjects with NGT. Furthermore, although IMTs were thicker in male than in female subjects, the differences between sexes were not statistically significant in any of the groups.

View this table: [in this window] [in a new window]   Table 2. Common Carotid, Carotid Bifurcation Artery, and Mean IMT in Subjects According to Glucose Tolerance Status and by Sex

Table 3 shows the partial correlations between the mean carotid IMT (adjusted for age and sex) and various risk factors in patients with NIDDM and in control subjects (subjects with IGT and NGT combined). In patients with NIDDM, carotid IMT showed a statistically significant association with LDL triglycerides, apoB, and 1-hour postglucose insulin and an association of borderline significance with diastolic blood pressure, serum total and VLDL cholesterol, and total triglycerides, as well as HDL cholesterol (inversely). No significant association with fasting plasma glucose, glycosylated hemoglobin A1_c, plasma insulin, specific insulin, or proinsulin, as well as apo(a), was observed in diabetic patients. We further divided these parameters into tertiles to find any possible curvilinear association with carotid IMT, but this analysis did not give any further information. In control subjects, none of the measured parameters showed a statistically significant association with carotid IMT. The results regarding control subjects were similar whether or not IGT subjects were included in the analysis (data not shown). Moreover, because we had the data for most of these risk factors for 5 and 10 years earlier in this study population, we analyzed their impact on the carotid IMT, and the results in terms of lipoprotein correlates remained essentially the same (data not shown).

View this table: [in this window] [in a new window]   Table 3. Partial Correlation Coefficients Adjusted for Age and Sex Between Cardiovascular Risk Factors and Mean Carotid IMT in Subjects With NIDDM and in Control Subjects

The impact of smoking on carotid IMT was not significant in this study population (data not shown), but most of the subjects with a history of smoking actually had stopped smoking a long time ago. Table 4 shows the carotid IMT in relation to hypertension, coronary heart disease, and any macrovascular disease in the whole study population and in diabetic and control subjects separately. The impact of hypertension on carotid IMT was not seen in diabetic patients and did not reach statistical significance in control subjects alone nor when both groups were combined. Carotid IMT tended to be greater in subjects with coronary heart disease or any macrovascular disease in the NIDDM and control groups, but the differences were statistically significant only when both groups were combined. When analyzed by ANCOVA, both diabetic status per se (P=.030) and the presence of macrovascular disease (P=.005; Table 4) were independent explanatory factors for the mean carotid IMT.

View this table: [in this window] [in a new window]   Table 4. Mean Carotid IMT in Patients With NIDDM and in Control Subjects in Relation to Symptomatic Coronary Heart Disease, Macrovascular Disease, and Hypertension*

Finally, we explored the determinants of severe carotid atherosclerosis in diabetic patients. An arbitrary cutoff point of 1.94 mm for the mean common and bifurcation IMT was chosen as the criterion because it corresponds to mean±1 SD of the control subjects and is close to 50% stenosis, since the ID of the internal carotid artery is about 4 mm in normal adults.²⁴ The frequency of severe carotid atherosclerosis (ie, IMT 1.94 mm) was markedly higher in patients with NIDDM (25.0%) than in control subjects (10.4%, P=.006). The selected risk factors according to the presence of severe carotid atherosclerosis in diabetic patients are outlined in Table 5. The statistically significant univariate associations were observed with systolic and diastolic blood pressure levels; serum total cholesterol; VLDL cholesterol; serum total, VLDL, and LDL triglycerides; apoB; and postglucose plasma insulin levels. In stepwise logistic regression analyses, LDL triglycerides, apoB, and 1-hour plasma insulin (all after logarithmic transformation) showed independent associations with severe carotid atherosclerosis, whereas diastolic blood pressure was of borderline significance (Table 6).

View this table: [in this window] [in a new window]   Table 5. Relationship of Selected Variables to Advanced Carotid Atherosclerosis in Diabetic Patients

View this table: [in this window] [in a new window]   Table 6. Stepwise Logistic Regression Analyses* on the Determinants of Severe Carotid Atherosclerosis (Mean Carotid IMT >1.93 mm) in Diabetic Patients

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study confirms earlier reports showing that mean carotid IMT is greater in patients with NIDDM than in nondiabetic subjects.^{11 12} Furthermore, dyslipidemia characteristic of NIDDM (in particular, elevated serum LDL triglyceride levels) and 1-hour postglucose plasma insulin were the major determinants of mean carotid IMT in diabetic patients, whereas fasting plasma glucose, insulin, and proinsulin concentrations showed no significant association in this respect.

When interpreting these results, it should be borne in mind that this was a cross-sectional analysis performed at the 10th year of follow-up for a cohort consisting of newly diagnosed NIDDM patients and control subjects from an area with a high frequency of coronary heart disease.²⁵ Thus, the mean carotid IMT measurement was markedly higher in our Finnish patients with NIDDM (1.66 mm) than in the Japanese counterparts (1.32 mm) of similar age.¹¹ Hemodynamic factors related to oscillatory and turbulent blood flow at the carotid bifurcation, albeit with relatively low shear stress, favor the formation of an atherosclerotic process at bifurcation sites.²⁶ The carotid IMTs were also greater at the bifurcation in diabetic patients than in control subjects of the present study, indicating that this mechanism is operative in NIDDM also.

In the present study, the Finnish control subjects had increased carotid IMT compared with subjects in other recent studies carried out in other nondiabetic populations.^{12 27 28} In comparison with another Finnish population-based survey²³ in the same geographic area, the men in the present control group had carotid IMTs similar to those in middle-aged men with cardiovascular disease in the other study²³ and increased carotid IMT compared with men without clinical cardiovascular disease. In both studies, the same ultrasonography scanning and reading methodology were used.⁷ A recent study has suggested that the patients with IGT have an increased carotid IMT compared with subjects with NGT,¹³ but this was not the case in the present study, although subjects with IGT showed more signs of clinical vascular disease than subjects with NGT. However, the number of IGT subjects among the controls was rather low in the present report.

During the 10-year follow-up, cardiovascular mortality was strikingly increased in patients with NIDDM compared with control subjects.³ Despite the selection bias associated with incident mortality, the surviving diabetic patients of both sexes had greater carotid IMTs than the respective control subjects. Interestingly, we could not see a significant sex difference regarding carotid IMT in either the diabetic or control group. In diabetic patients this may be expected, since NIDDM has been shown repeatedly to reduce the female protective factor for premature atherosclerosis.¹ Regarding control subjects, the lack of sex difference could be partly ascribed to the rather high age of the subjects in general, since postmenopausal women are not protected from vascular diseases. On the other hand, this finding may be explained by the small number of subjects and low statistical power. Actually, our findings are in accordance with the population-based study by Willeit and Kiechl,²⁹ in which the sex difference found in middle-aged subjects decreased with advancing age.

The main predictors of cardiovascular mortality in diabetic patients in this study population were smoking, elevated LDL triglyceride levels, and hyperglycemia, in addition to an ischemic electrocardiographic finding at baseline.³ In the present study, smoking history was not associated with carotid IMT, but in diabetic patients smoking was a strong risk factor predicting mortality³ ; actually, only a few current smokers were included, obscuring the well-known effect of smoking on the risk of atherosclerosis. Interestingly, carotid IMT in diabetic patients of the present study showed a strong association with LDL triglyceride and apoB levels. This finding differs from that seen in nondiabetic subjects, in whom LDL cholesterol showed greater proportional impact than apoB.³⁰ It is noticeable that elevated LDL triglyceride, VLDL cholesterol, and apoB levels all reflect the disturbed catabolism of VLDL ("remnant particles") commonly seen in NIDDM and in insulin resistance syndrome.^{2 3 31} Furthermore, content of immunologically detectable apoB in human aortic intima has a positive relation to the serum apoB concentration,³² and these particles can be found even in lesion-free human aortic intima.³³ In fact, the strong predictive value of LDL triglyceride levels in terms of cardiovascular mortality in patients with NIDDM was shown for the first time in the present study population.³ Therefore, the association of these remnant particles with ultrasonography at 10-year examination in diabetic patients strongly supports the fundamental role of these lipoprotein particles in the development of atherosclerotic vascular disease in NIDDM; furthermore, this relationship is not solely mediated by a tendency to thrombosis favored by disturbances in triglyceride metabolism.³⁴

Fasting immunoreactive specific insulin or proinsulin levels did not show statistically significant associations with carotid IMT in either the diabetic or control group, whereas postglucose 1-hour insulin level in diabetic patients was an independent determinant of carotid IMT. Three studies^{35 36 37} have shown that both fasting and postglucose insulin levels are predictive of coronary heart disease in middle-aged nondiabetic men. Folsom et al¹² demonstrated in 14 430 middle-aged asymptomatic subjects that fasting hyperinsulinemia is the significant determinant of carotid IMT. The controversy about the "villain," however, still remains: is it hyperinsulinemia per se or insulin resistance with associated abnormalities that is to be blamed for clogging the arteries? In support of the latter concept, Laakso et al³⁸ demonstrated in a cross-sectional study on clinically healthy subjects that those with plaque in carotid or femoral arteries measured by Doppler ultrasound were more insulin resistant than those without plaques. However, the relationship of hyperinsulinemia with cardiovascular risk seen in middle-aged male subjects seems to vanish in elderly populations.^{39 40} In this study, 1-hour immunoreactive insulin showed an independent association with carotid IMT in diabetic patients. However, our study has two limitations in this respect. First, we were not able to measure proinsulin from 1-hour samples, and second, because of cross-reactivity of immunoreactive insulin with proinsulin, we were unable to clarify the possible independent effect of postglucose plasma proinsulin on carotid IMT. Although there are studies showing that elevated plasma proinsulin levels are associated with dyslipidemia and hypertension in diabetic⁴¹ and nondiabetic subjects,²⁰ there are no previous reports on the relation of proinsulin to direct measures of atherosclerosis, eg, carotid IMT in diabetic or nondiabetic subjects. If elevated plasma proinsulin is, as it is currently held, just a marker of impending ß-cell failure,⁴² the possible relationship of proinsulin with atherosclerotic process is likely to be that of an innocent bystander.

In conclusion, the elderly population patients with NIDDM showed greater carotid IMT than the respective control subjects, which was not explained by the more frequent occurrence of clinical vascular disease in the diabetic group. The main determinants of carotid IMT in diabetic patients were related to the components of insulin resistance syndrome; abnormal triglyceride metabolism and compositional LDL changes (high LDL triglyceride and apoB levels); postglucose plasma insulin; and blood pressure levels. Therefore, it is highly likely, but not yet proved, that treatment of these components reduces the markedly increased cardiovascular burden in patients with NIDDM.

	Selected Abbreviations and Acronyms

 

apo = apolipoprotein IGT = impaired glucose tolerance IMT = intimal-medial thickness NGT = normal glucose tolerance NIDDM = non–insulin-dependent diabetes mellitus

	Acknowledgments

 
This study was financially supported by grants from the Finnish Foundation of Diabetes Research and Academy of Finland.

Received May 28, 1996; revision received July 24, 1996; accepted August 9, 1996.

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