Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
Diabetes Care. 2022 Aug 1;45(8):1841-1851. doi: 10.2337/dc22-0110.
In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT).
Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling.
Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity.
We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.
在一项大型、多种族的肥胖青少年队列中，我们分析了导致口服葡萄糖耐量试验（OGTT）180 分钟时血糖反应变化的病理生理和遗传机制。
采用潜在类别轨迹分析方法，在耶鲁青少年 2 型糖尿病发病机制研究（Yale Pathogenesis of Youth-Onset T2D study）的 2378 名参与者中，根据九点 OGTT 的血糖反应，识别出各种不同的血糖反应谱，其中 1190 人有 TCF7L2 基因分型，358 人在 5 年随访期间进行了多次 OGTT。通过葡萄糖、胰岛素和 C 肽模型估计胰岛素敏感性、清除率和β细胞功能。
根据曲线下面积（AUC）的增加，确定了 4 个潜在类别（1 至 4）。类别 3 和 4 的参与者具有最差的代谢和遗传风险特征，表现为胰岛素敏感性、清除率和β细胞功能受损。通过模型预测，被归类为类别 1 和 4 的概率随着年龄的增长而增加，而胰岛素敏感性和清除率则呈短暂下降，β细胞功能逐渐下降。胰岛素敏感性是在招募时进行类别分配和从类别 1 和 2 向更高类别转变的最主要决定因素。在类别 3 和 4 之间的转变仅由β细胞葡萄糖敏感性的变化来解释。
我们在肥胖青少年中发现了 4 种血糖反应类型，它们具有不同的遗传风险特征和胰岛素动力学及作用的进行性损伤。胰岛素敏感性是各年龄段在较低和较高血糖类别之间转变的主要决定因素。相比之下，两个最差的血糖类别之间的转变仅由β细胞葡萄糖敏感性驱动。
