Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China.
Department of Endocrinology, Beijing Pinggu District Hospital, Beijing, China.
Front Endocrinol (Lausanne). 2021 Oct 26;12:677130. doi: 10.3389/fendo.2021.677130. eCollection 2021.
variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.
exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by assays. Additionally, a review of the literature was performed to obtain all reported cases with rare variants to evaluate the characteristics of variants in different functional domains.
Six (0.6%) patients had variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare variants in AF1 of had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.
The prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients genetic testing and suggest that thiazolidinediones might be a good choice for these patients.
变体导致脂肪营养不良、胰岛素抵抗和糖尿病。本研究旨在确定基因型与表型之间的关系，并探讨超越这种关系的糖尿病发病机制。
对 1002 名早发性 2 型糖尿病（诊断年龄<40 岁）中国患者的外显子进行测序。通过测定评估变体的功能。此外，还进行了文献复习，以获得所有报道的罕见变体病例，以评估不同功能域变体的特征。
在早发性 2 型糖尿病组中，有 6 名（0.6%）患者存在变体诱导的糖尿病（PPARG-DM），其中 3 名存在激活功能 1 域（AF1）中的 p.Tyr95Cys 变体，其中 5 名患者（83%）患有糖尿病肾病（DKD）。功能实验表明，p.Tyr95Cys 抑制 3T3-L1 前体脂肪细胞分化。先前共报道了 64 例具有破坏性罕见变体的病例。与其他域变体相比，AF1 中具有罕见变体的患者发生脂肪营养不良的风险较低，肥胖率较高，本研究中鉴定的患者也证实了这一点。
PPARG-DM 在白种人和中国人中的患病率相似，这些患者常伴有 DKD。与其他域变体相比，AF1 中的变体患者的临床表型较轻，缺乏典型的脂肪营养不良特征。我们的研究结果强调了对这些患者进行基因筛查和遗传检测的重要性，并表明噻唑烷二酮类药物可能是这些患者的一个不错选择。
