Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA.
Genet Med. 2018 Jun;20(6):583-590. doi: 10.1038/gim.2017.150. Epub 2017 Oct 12.
PurposeMonogenic diabetes accounts for 1-2% of diabetes cases. It is often undiagnosed, which may lead to inappropriate treatment. This study was performed to estimate the prevalence of monogenic diabetes in a cohort of overweight/obese adolescents diagnosed with type 2 diabetes (T2D).MethodsSequencing using a custom monogenic diabetes gene panel was performed on a racially/ethnically diverse cohort of 488 overweight/obese adolescents with T2D in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed.ResultsMore than 4% (22/488) had genetic variants causing monogenic diabetes (seven GCK, seven HNF4A, five HNF1A, two INS, and one KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower body mass index (BMI) z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.
目的
单基因糖尿病占糖尿病病例的 1-2%。由于其常常未被诊断，可能导致治疗不当。本研究旨在评估超重/肥胖 2 型糖尿病（T2D）青少年患者中单基因糖尿病的患病率。
方法
在治疗青少年和儿童 2 型糖尿病的选项（TODAY）临床试验中，对一个种族/民族多样化的 488 名超重/肥胖 T2D 青少年队列进行了使用定制单基因糖尿病基因panel 的测序。分析了携带单基因糖尿病变异与临床特征和治疗失败时间之间的关联。
结果
超过 4%（22/488）的患者存在导致单基因糖尿病的基因突变（七个 GCK、七个 HNF4A、五个 HNF1A、两个 INS 和一个 KLF11）。单基因糖尿病患者的体重指数（BMI）z 评分、空腹胰岛素和空腹血糖均有统计学上但无临床意义的降低。大多数（6/7）携带 HNF4A 变异的患者在研究臂中迅速出现 TODAY 治疗失败（风险比=5.03，P=0.0002），而 GCK 变异患者无一例治疗失败。
结论
在超重/肥胖的 T2D 青少年队列中，有 4.5%的患者存在单基因糖尿病，这表明即使在无糖尿病相关自身抗体和维持 C 肽的情况下，无论 BMI 如何，都应考虑对儿童和青少年进行单基因糖尿病诊断，因为这可能有助于进行适当的临床管理。
