Robert Graves Institute of Endocrinology, Tallaght University Hospital, Dublin, Ireland.
Diabetes Complications Research Centre, School of Medicine, University College Dublin, Belfield, Dublin, Ireland.
Diabetologia. 2021 Mar;64(3):656-667. doi: 10.1007/s00125-020-05320-3. Epub 2020 Nov 9.
AIMS/HYPOTHESIS: The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes.
We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima-media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2 years; BMI 26.9 ± 0.5 kg/m) and 100 non-diabetic participants (37.7 ± 1.1 years; 27.1 ± 0.5 kg/m).
Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04 μmol/l [mean difference (MD) -3.32 μmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05 μmol/l [MD +2.37 μmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56 nm [MD +0.38 nm]) (p < 0.05 for all). Total CEC (14.57 ± 2.47%CEC/4 h vs 12.26 ± 3.81%CEC/4 h [MD +2.31%CEC/4 h]) was greater in participants with type 1 diabetes relative to non-diabetic participants. Increased HDL particle size was independently associated with increased total CEC; however, following adjustment for this in multivariable analysis, CEC remained greater in participants with type 1 diabetes. Both components of CEC, ABCA1-dependent (6.10 ± 2.41%CEC/4 h vs 5.22 ± 2.57%CEC/4 h [MD +0.88%CEC/4 h]) and ABCA1-independent (8.47 ± 1.79% CEC/4 h vs 7.05 ± 1.76% CEC/4 h [MD +1.42% CEC/4 h]) CEC, were greater in type 1 diabetes but the increase in ABCA1-dependent CEC was less marked and not statistically significant in multivariable analysis. CIMT was increased in participants with type 1 diabetes but in multivariable analysis it was only associated negatively with age and BMI.
CONCLUSIONS/INTERPRETATION: HDL particle size but not HDL-cholesterol level is independently associated with enhanced total CEC. HDL particle size is greater in individuals with type 1 diabetes but even after adjusting for this, total and ABCA1-independent CEC are enhanced in type 1 diabetes. Further studies are needed to understand the mechanisms underlying these effects, and whether they help attenuate progression of atherosclerosis in this high-risk group. Graphical abstract.
目的/假设：尽管 HDL-胆固醇水平正常至偏高，1 型糖尿病患者的动脉粥样硬化患病率仍增加。HDL 的胆固醇外排能力（CEC）比静态 HDL-胆固醇更能预测心血管事件。本横断面研究旨在假设 HDL 功能受损导致 1 型糖尿病患者的 CVD 风险增加。
我们比较了 100 名 1 型糖尿病患者（37.6±1.2 岁；BMI 26.9±0.5kg/m）和 100 名非糖尿病参与者（37.7±1.1 岁；27.1±0.5kg/m）的 HDL 颗粒大小和浓度（通过 NMR 测定）、总 CEC、载脂蛋白 B 缺失血清中 ABCA1 依赖性 CEC 和 ABCA1 非依赖性 CEC（通过测定 [H]胆固醇从 J774 巨噬细胞外排到载脂蛋白 B 缺失血清）和颈动脉内膜中层厚度（CIMT）。
与非糖尿病参与者相比，1 型糖尿病患者的总 HDL 颗粒浓度较低（平均值±标准差 31.01±8.66 对 34.33±8.04μmol/l [平均差异（MD）-3.32μmol/l]）。然而，大 HDL 颗粒浓度更大（9.36±3.98 对 6.99±4.05μmol/l [MD+2.37μmol/l]），导致平均 HDL 颗粒大小增加（9.82±0.57 对 9.44±0.56nm [MD+0.38nm]）（所有 p 值均<0.05）。1 型糖尿病患者的总 CEC（14.57±2.47%CEC/4h 对 12.26±3.81%CEC/4h [MD+2.31%CEC/4h]）大于非糖尿病患者。增加的 HDL 颗粒大小与增加的总 CEC 独立相关；然而，在多变量分析中对此进行调整后，1 型糖尿病患者的 CEC 仍然更高。CEC 的两个组成部分，ABCA1 依赖性（6.10±2.41%CEC/4h 对 5.22±2.57%CEC/4h [MD+0.88%CEC/4h]）和 ABCA1 非依赖性（8.47±1.79%CEC/4h 对 7.05±1.76%CEC/4h [MD+1.42%CEC/4h]）在 1 型糖尿病中更高，但 ABCA1 依赖性 CEC 的增加在多变量分析中并不明显且无统计学意义。1 型糖尿病患者的 CIMT 增加，但在多变量分析中，它仅与年龄和 BMI 呈负相关。
结论/解释：HDL 颗粒大小而非 HDL-胆固醇水平与增强的总 CEC 独立相关。1 型糖尿病患者的 HDL 颗粒大小较大，但即使对此进行调整，1 型糖尿病患者的总 CEC 和 ABCA1 非依赖性 CEC 仍增强。需要进一步研究以了解这些影响的机制，以及它们是否有助于减轻该高风险人群的动脉粥样硬化进展。
