Impaired glucose metabolism in subjects with the Williams-Beuren syndrome: A five-year follow-up cohort study

Objective
The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of β-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults.
Methods
This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity.
Results
IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM.
Conclusions
IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and β-cell dysfunction contribute, in this sequence, to progression to IGM and DM.

研究目标
威廉姆斯-比伦综合征（Williams-Beuren syndrome, WS）与成年早期糖耐量受损（impaired glucose metabolism, IGM）密切相关。但由于缺乏探讨β细胞功能障碍（β-cell dysfunction）与胰岛素敏感性受损（impaired insulin sensitivity）对IGM影响的纵向研究，IGM的病理生理机制仍未明确。本研究旨在评估成年WS患者中IGM的发病率及其潜在发病机制。

研究方法
本项为期5年的观察性纵向队列研究纳入了就诊于三级转诊中心的31例连续入组WS患者。研究每年为受试者行口服葡萄糖耐量试验（oral glucose tolerance test, OGTT），以此将患者分为糖耐量正常与IGM两类，IGM涵盖空腹血糖受损（impaired fasting glucose, IFG）和/或糖耐量减低（impaired glucose tolerance, IGT）及糖尿病（diabetes mellitus, DM），同时计算胰岛素分泌与/或敏感性的替代指标。

研究结果
基线时，18例（58.1%，其中3例为DM）患者存在IGM；随访结束时，该比例升至61.3%（19例，其中5例为DM）。随访期间，共有13例患者的糖代谢稳态分类发生双向改变（其中8例为进展者，5例为逆转者），剩余18例未发生改变（8例未进展者，10例未逆转者）。IGM与DM的年发病率分别为每100人年11.1例与2.53例，所有新发患者均接受非药物治疗。在全队列人群中，且在进展者亚组中更为显著，从基线至随访结束时，早期胰岛素分泌指数与胰岛素敏感性指数均显著下降，伴随口服葡萄糖处置指数与胰岛素分泌敏感性指数2（insulin secretion-sensitivity index-2, ISSI-2）同步降低，尽管机体代偿性增加胰岛素分泌以对抗胰岛素抵抗水平。基线时无任何指标可独立预测病情进展，而病情进展与ISSI-2的基线变化呈显著相关。与糖代谢稳态正常的患者相比，IGT患者存在胰岛素敏感性受损，而胰岛素分泌降低仅见于IFG合并IGT或DM患者。

研究结论
WS年轻成年患者的IGM发病率较高，提示需对该人群开展早期筛查并适时进行干预。与经典2型糖尿病类似，胰岛素敏感性受损与β细胞功能障碍依次参与了IGM及DM的进展过程。