Department of Endocrinology, Metabolism and Genetics, Vietnam National Children's Hospital, Hanoi, Vietnam.
Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.
Front Endocrinol (Lausanne). 2021 Sep 9;12:727083. doi: 10.3389/fendo.2021.727083. eCollection 2021.
Neonatal diabetes mellitus (NDM) is defined as insulin-requiring persistent hyperglycemia occurring within the first 6 months of life, which can result from mutations in at least 25 different genes. Activating heterozygous mutations in genes encoding either of the subunits of the ATP-sensitive K channel (K channel; or ) of the pancreatic beta cell are the most common cause of permanent NDM and the second most common cause of transient NDM. Patients with NDM caused by K channel mutations are sensitive to sulfonylurea (SU) treatment; therefore, their clinical management can be improved by replacing insulin with oral agents.
Seventy patients were diagnosed with NDM between May 2008 and May 2021 at Vietnam National Children's Hospital, and molecular genetic testing for all genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Patients with or mutations were transferred from insulin to oral SU. Clinical characteristics, molecular genetics, and annual data relating to glycemic control, SU dose, severe hypoglycemia, and side effects were collected. The main outcomes of interest were SU dose, SU failure (defined as permanent reintroduction of daily insulin), and glycemic control (HbA1c).
Fifty-four of 70 patients (77%) with NDM harbored a genetic mutation and of these; 27 (50%) had activating heterozygous mutations in or . A total of 21 pathogenic mutations were identified in the 27 patients, including 13 mutations in and 8 mutations in . Overall, 51% had low birth weight (below 3rd percentile), 23 (85%) were diagnosed before 3 months of age, and 23 (85%) presented with diabetic ketoacidosis. At diagnosis, clinical and biochemical findings (mean ± SD) were pH 7.16 ± 0.16; , 7.9 ± 7.4 mmol/L; BE, -17.9 ± 9.1 mmol/L; HbA1C, 7.98% ± 2.93%; blood glucose, 36.2 ± 12.3 mmol/L; and C-peptide median, 0.09 (range, 0-1.61 nmol/l). Twenty-six patients were successfully transferred from insulin to SU therapy. In the remaining case, remission of diabetes occurred prior to transfer. Glycemic control on SU treatment was better than on insulin treatment: HbA1c and blood glucose level decreased from 7.58% ± 4.63% and 19.04 ± 14.09 mmol/L when treated with insulin to 5.8 ± 0.94% and 6.87 ± 3.46 mmol/L when treated with SU, respectively.
This is the first case series of NDM patients with mutations reported in Vietnam. SU is safe in the short term for these patients and more effective than insulin therapy, consistent with all studies to date. This is relevant for populations where access to and cost of insulin are problematic, reinforcing the importance of genetic testing for NDM.
新生儿糖尿病（NDM）定义为在生命的前 6 个月内发生的需要胰岛素治疗的持续性高血糖症，其可由至少 25 种不同基因的突变引起。胰腺β细胞中 ATP 敏感性钾通道（K 通道； 或 ）的亚单位编码基因的杂合激活突变是永久性 NDM 的最常见原因，也是暂时性 NDM 的第二大常见原因。由 K 通道突变引起的 NDM 患者对磺酰脲类（SU）治疗敏感；因此，用口服药物替代胰岛素可以改善他们的临床管理。
2008 年 5 月至 2021 年 5 月，越南国家儿童医院诊断出 70 例 NDM 患者，在英国埃克塞特基因组实验室对所有已知导致 NDM 的基因进行了分子遗传学检测。将 或 突变患者从胰岛素转为口服 SU。收集临床特征、分子遗传学和与血糖控制、SU 剂量、严重低血糖和副作用相关的年度数据。主要观察终点是 SU 剂量、SU 失败（定义为每日胰岛素的永久性重新引入）和血糖控制（HbA1c）。
70 例 NDM 患者中有 54 例（77%）存在基因突变，其中 27 例（50%）在 或 中存在杂合激活突变。在 27 例患者中总共发现了 21 种致病性突变，包括 13 种 突变和 8 种 突变。总体而言，51%的患者出生体重低（低于第 3 百分位），23 例（85%）在 3 个月前被诊断出，23 例（85%）表现为糖尿病酮症酸中毒。在诊断时，临床和生化指标（平均值 ± 标准差）为 pH 值 7.16 ± 0.16； ，7.9 ± 7.4 mmol/L；BE，-17.9 ± 9.1 mmol/L；HbA1C，7.98% ± 2.93%；血糖，36.2 ± 12.3 mmol/L；C 肽中位数，0.09（范围，0-1.61 nmol/L）。26 例患者成功从胰岛素转为 SU 治疗。在其余病例中，糖尿病在转为 SU 治疗前得到缓解。SU 治疗的血糖控制优于胰岛素治疗：HbA1c 和血糖水平分别从胰岛素治疗时的 7.58% ± 4.63%和 19.04 ± 14.09 mmol/L 降至 SU 治疗时的 5.8 ± 0.94%和 6.87 ± 3.46 mmol/L。
这是越南首例报告的 突变 NDM 患者的病例系列。SU 在短期内对这些患者是安全的，并且比胰岛素治疗更有效，与迄今为止所有研究一致。这对于胰岛素获取和成本存在问题的人群具有重要意义，这进一步强调了进行 NDM 基因检测的重要性。
