Comprehensive assessment of alterations in lipid species preceding type 2 diabetes (T2D) is largely unknown. We aimed to identify plasma molecular lipids associated with risk of T2D in American Indians.

Using untargeted liquid chromatography–mass spectrometry, we repeatedly measured 3,907 fasting plasma samples from 1,958 participants who attended two examinations (~5.5 years apart) and were followed up to 16 years in the Strong Heart Family Study. Mixed-effects logistic regression was used to identify lipids associated with risk of T2D, adjusting for traditional risk factors. Repeated measurement analysis was performed to examine the association between change in lipidome and change in continuous measures of T2D, adjusting for baseline lipids. Multiple testing was controlled by false discovery rate at 0.05.

Higher baseline level of 33 lipid species, including triacylglycerols, diacylglycerols, phosphoethanolamines, and phosphocholines, was significantly associated with increased risk of T2D (odds ratio [OR] per SD increase in log2-transformed baseline lipids 1.50–2.85) at 5-year follow-up. Of these, 21 lipids were also associated with risk of T2D at 16-year follow-up. Aberrant lipid profiles were also observed in prediabetes (OR per SD increase in log2-transformed baseline lipids 1.30–2.19 for risk lipids and 0.70–0.78 for protective lipids). Longitudinal changes in 568 lipids were significantly associated with changes in continuous measures of T2D. Multivariate analysis identified distinct lipidomic signatures differentiating high- from low-risk groups.

Lipid dysregulation occurs many years preceding T2D, and novel molecular lipids (both baseline level and longitudinal change over time) are significantly associated with risk of T2D beyond traditional risk factors. Our findings shed light on the mechanisms linking dyslipidemia to T2D and may yield novel therapeutic targets for early intervention tailored to American Indians.

对 2 型糖尿病 (T2D) 之前脂质种类变化的综合评估在很大程度上尚不清楚。我们的目的是确定与美洲印第安人患 T2D 风险相关的血浆分子脂质。

使用非靶向液相色谱-质谱法，我们重复测量了 1,958 名参与者的 3,907 份空腹血浆样本，这些参与者参加了两次检查（相隔约 5.5 年），并在强心脏家族研究中随访了长达 16 年。混合效应逻辑回归用于识别与 T2D 风险相关的血脂，并调整传统风险因素。进行重复测量分析，以检查脂质组变化与 T2D 连续测量变化之间的关联，并调整基线脂质。多次测试的错误发现率控制在 0.05。

5 年随访时，33 种脂质的基线水平较高，包括三酰甘油、二酰甘油、磷酸乙醇胺和磷酸胆碱，与 T2D 风险增加显着相关（比值比 [OR] 每 SD 增加 log2 转换基线脂质 1.50-2.85） -向上。其中，21 种脂质在 16 年随访中也与 T2D 风险相关。在前驱糖尿病中也观察到了异常的脂质谱（风险脂质的 log2 转换基线脂质的 OR 每 SD 增加 1.30-2.19，保护性脂质的 OR 每 SD 增加 0.70-0.78）。 568 种脂质的纵向变化与 T2D 连续测量值的变化显着相关。多变量分析确定了区分高风险人群和低风险人群的不同脂质组学特征。

脂质失调发生在 T2D 之前许多年，新型分子脂质（基线水平和随时间的纵向变化）与传统危险因素之外的 T2D 风险显着相关。我们的研究结果揭示了血脂异常与 T2D 之间的联系机制，并可能为针对美洲印第安人的早期干预提供新的治疗靶点。