Pre-β1-HDL is a minor HDL subfraction that stimulates cholesterol efflux from cell membranes (1,2). However, the fasting preβ1-HDL concentration is elevated in patients with coronary artery disease (CAD), hyperlipidemia, and obesity and in hemodialysis patients (3–7). We examined whether the preβ1-HDL concentration is elevated in type 2 diabetic patients and whether elevated preβ1-HDL concentration is a predictor of carotid atherosclerosis.

We measured the preβ1-HDL concentration in 30 patients with type 2 diabetes (mean ± SD age 58.5 ± 12.3 years, 13 men and 17 women) and in 30 age- and sex-matched healthy control subjects. We excluded patients receiving hypolipidemic agents and those with renal dysfunction. The diabetic group had a long duration of disease (9.9 ± 8.6 years), high A1C levels (10.4 ± 2.0%), and high BMI (26.1 ± 6.5 kg/m2). The preβ1-HDL in frozen plasma, pretreated with sucrose solution for stabilization, was measured using an immunoassay (8). In the diabetic group, we evaluated the severity of carotid atherosclerosis using ultrasonography with a 7.5-MHz probe. The greatest intima-media thickness (max IMT) and plaque score were determined as previously reported (9).

The diabetic group had higher triglyceride concentrations than the control subjects (166.9 ± 138.4 vs. 90.9 ± 28.6 mg/dl, P < 0.01), while the two groups did not differ significantly in total cholesterol (215.1 ± 49.9 vs. 201.0 ± 20.9 mg/dl), LDL cholesterol (135.9 ± 37.1 vs. 125.3 ± 17.9 mg/dl), or HDL cholesterol (55.5 ± 18.7 vs. 58.3 ± 16.6 mg/dl) concentrations. Although the diabetic group had lower apoliopoprotein (apo)AI (the only protein component of preβ1-HDL) levels than the control subjects (124.6 ± 20.8 vs. 137.8 ± 27.1 mg/dl, P < 0.05), the former had higher absolute and relative preβ1-HDL concentrations than the latter (24.5 ± 6.0 vs. 20.3 ± 5.7 mg/l apoAI, respectively, P < 0.01; 1.99 ± 0.51 vs. 1.49 ± 0.36% apoAI, P < 0.001). In the diabetic group, the absolute preβ1-HDL concentration was not correlated with HDL cholesterol or apoAI, while the relative preβ1-HDL concentration was negatively correlated with HDL cholesterol and apoAI (r = −0.49, P < 0.01; r = −0.43, P < 0.05). In comparisons using nonsmokers only, the diabetic group (n = 18) had greater absolute and relative preβ1-HDL concentrations than control subjects (n = 28) (24.3 ± 6.7 vs. 20.0 ± 5.7 mg/l apoAI, respectively, P < 0.05; 1.86 ± 0.58 vs. 1.46 ± 0.36% apoAI, P < 0.05).

B-mode ultrasound imaging revealed that carotid atherosclerosis was more severe in the diabetic group than in the control subjects. The mean max IMT in the diabetic group was nearly twice that in the control subjects (1.20 ± 0.70 vs. 0.64 ± 0.12 mm, P < 0.001). A higher max IMT, defined as >1.0 mm or at least one carotid plaque, was detected in 80% of the diabetic patients.

In the diabetic group, the max IMT had significant correlations with the absolute and relative preβ1-HDL (Fig. 1) and LDL cholesterol concentrations (r = 0.373, P = 0.043). The plaque score had positive correlations with age (r = 0.540, P = 0.002), duration of diabetes (r = 0.472, P = 0.008), and both the absolute and relative preβ1-HDL concentrations (Fig. 1). Stepwise multiple regression analysis was performed using the max IMT or plaque score as the dependent variable, and preβ1-HDL (model 1, absolute concentration; model 2, relative concentration) together with other risk factors (age, sex, duration of diabetes, triglycerides, LDL cholesterol, A1C, systolic blood pressure, and Brinkman index [cigarettes per day multiplied by years smoked]) as the independent variables. The preβ1-HDL concentration was selected as an independent risk factor for the max IMT (model 1, R = 0.382, P = 0.037, B = 0.382, F = 4.776; model 2, R = 0.563, P = 0.006, B = 0.454, F = 7.024) and plaque score (model 1, R = 0.630, P = 0.001, B = 0.473, F = 7.773; model 2, R = 0.681, P = 0.0002, B = 0.493, F = 8.668 [R, multiple correlation coefficient; B, partial correlation coefficient]). Of the other variables, LDL cholesterol was also selected for the max IMT and the duration of diabetes and age for plaque score.

Our results indicate that the preβ1-HDL concentration is elevated in the diabetic group and that a high preβ1-HDL concentration is a predictor of carotid atherosclerosis. Many prospective studies have reported positive correlations between the severity of carotid atherosclerosis and cardiovascular risks in general populations and diabetic patients (9,10). Accelerated atherosclerosis in diabetic patients may be explained by insulin resistance, chronic inflammation, hyperglycemia, and dyslipidemia (11,12).

Interestingly, the absolute preβ1-HDL concentration was associated with carotid atherosclerosis but not with glycemic control or other HDL markers. In the group combining hypertriglyceridemics and normolipidemics, the absolute preβ1-HDL concentration did not significantly correlate with either HDL cholesterol or apoAI levels (5). Furthermore, patients with CAD or hemodialysis patients (high-risk patients for CAD) had an elevated preβ1-HDL concentration despite low HDL cholesterol or apoAI (3,4,7). These data correspond well with our study.

An increased preβ1-HDL concentration in atherosclerotic disorders may result either from the impaired maturation of preβ1-HDL into α-HDL (3,6,7,13) or from enhanced production of preβ1-HDL (5,14). Previously, we found that low lecithin-cholesterol acyltransferase (LCAT) activity was closely related to a high preβ1-HDL concentration (3,7). In diabetic patients, the relationship between LCAT activity and atherosclerosis was inconsistent (15,16). In healthy Japanese control subjects, the most important determinant of the preβ1-HDL concentration was not the LCAT mass but the rate of LCAT-dependent conversion of preβ1-HDL into α-HDL (17). Therefore, we need to determine the LCAT-dependent conversion rate of preβ1-HDL in diabetic patients in a future study.

Another possible explanation for the high preβ1-HDL concentration in diabetic patients is the enhanced production of preβ1-HDL from α-HDL. The rates of preβ1-HDL synthesis and recycling of α-HDL to preβ1-HDL were elevated in diabetic patients (14). The PLTP (phospholipid transfer protein) activity enhances preβ1-HDL synthesis and is positively associated with carotid atherosclerosis in type 2 diabetes (18,19). As measuring PLTP activity is quite difficult, it might be more useful to measure the preβ1-HDL concentration when evaluating carotid atherosclerosis.

In conclusion, the preβ1-HDL concentration is elevated in type 2 diabetic patients, and an elevated preβ1-HDL concentration is a predictor of carotid atherosclerosis. A prospective study would confirm the clinical significance of preβ1-HDL in type 2 diabetic patients.

Figure 1—
Figure 1—. Positive correlation between the preβ1-HDL concentration and the indexes of carotid atherosclerosis defined as the max IMT and plaque score (PS) in type 2 diabetic patients. The preβ1-HDL concentration is expressed as absolute (•) or relative (○) concentrations. In the diabetic group (n = 30), the max IMT and plaque score had significant positive correlations with both the absolute and relative preβ1-HDL concentrations.
View largeDownload slide

Positive correlation between the preβ1-HDL concentration and the indexes of carotid atherosclerosis defined as the max IMT and plaque score (PS) in type 2 diabetic patients. The preβ1-HDL concentration is expressed as absolute (•) or relative (○) concentrations. In the diabetic group (n = 30), the max IMT and plaque score had significant positive correlations with both the absolute and relative preβ1-HDL concentrations.

Figure 1—
Figure 1—. Positive correlation between the preβ1-HDL concentration and the indexes of carotid atherosclerosis defined as the max IMT and plaque score (PS) in type 2 diabetic patients. The preβ1-HDL concentration is expressed as absolute (•) or relative (○) concentrations. In the diabetic group (n = 30), the max IMT and plaque score had significant positive correlations with both the absolute and relative preβ1-HDL concentrations.
View largeDownload slide

Positive correlation between the preβ1-HDL concentration and the indexes of carotid atherosclerosis defined as the max IMT and plaque score (PS) in type 2 diabetic patients. The preβ1-HDL concentration is expressed as absolute (•) or relative (○) concentrations. In the diabetic group (n = 30), the max IMT and plaque score had significant positive correlations with both the absolute and relative preβ1-HDL concentrations.

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Published ahead of print at http://care.diabetesjournals.org on 15 February 2007. DOI: 10.2337/dc06-1948.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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

DIABETES CARE
2007