Arya V B, Rahman S, Senniappan S, Flanagan S E, Ellard S, Hussain K
Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS, Trust, London; The Institute of Child Health, University College London, Exeter, UK.
Diabet Med. 2014 Mar;31(3):e11-5. doi: 10.1111/dme.12369.
Hepatocyte nuclear factor 4α (HNF4A) is a member of the nuclear receptor family of ligand-activated transcription factors. HNF4A mutations cause hyperinsulinaemic hypoglycaemia in early life and maturity-onset diabetes of the young. Regular screening of HNF4A mutation carriers using the oral glucose tolerance test has been recommended to diagnose diabetes mellitus at an early stage. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are incretin hormones, responsible for up to 70% of the secreted insulin after a meal in healthy individuals. We describe, for the first time, gradual alteration of glucose homeostasis in a patient with HNF4A mutation after resolution of hyperinsulinaemic hypoglycaemia, on serial oral glucose tolerance testing. We also measured the incretin response to a mixed meal in our patient.
Our patient was born with macrosomia and developed hyperinsulinaemic hypoglycaemia in the neonatal period. Molecular genetic analysis confirmed HNF4A mutation (p.M116I, c.317G>A) as an underlying cause of hyperinsulinaemic hypoglycaemia. Serial oral glucose tolerance testing, after the resolution of hyperinsulinaemic hypoglycaemia, confirmed the diagnosis of maturity-onset diabetes of the young at the age of 10 years. Interestingly, the intravenous glucose tolerance test revealed normal glucose disappearance rate and first-phase insulin secretion. Incretin hormones showed a suboptimal rise in response to the mixed meal, potentially explaining the discrepancy between the oral glucose tolerance test and the intravenous glucose tolerance test.
Maturity-onset diabetes of the young can develop as early as the first decade of life in persons with an HNF4A mutation. Impaired incretin response might be contributory in the early stages of HNF4A maturity-onset diabetes of the young.
肝细胞核因子4α（HNF4A）是配体激活转录因子核受体家族的成员。HNF4A突变会导致早年出现高胰岛素血症性低血糖以及青年发病型糖尿病。已建议对HNF4A突变携带者定期进行口服葡萄糖耐量试验筛查，以便早期诊断糖尿病。胰高血糖素样肽-1和葡萄糖依赖性促胰岛素多肽是肠促胰岛素激素，在健康个体中，它们在餐后分泌的胰岛素中所占比例高达70%。我们首次描述了一名携带HNF4A突变的患者在高胰岛素血症性低血糖症缓解后，通过连续口服葡萄糖耐量试验观察到的葡萄糖稳态的逐渐变化。我们还测量了该患者对混合餐的肠促胰岛素反应。
我们的患者出生时体重巨大，新生儿期出现高胰岛素血症性低血糖。分子遗传学分析证实HNF4A突变（p.M116I，c.317G>A）是高胰岛素血症性低血糖的潜在病因。高胰岛素血症性低血糖症缓解后进行的连续口服葡萄糖耐量试验，在患者10岁时确诊为青年发病型糖尿病。有趣的是，静脉葡萄糖耐量试验显示葡萄糖消失率和第一相胰岛素分泌正常。肠促胰岛素激素对混合餐的反应升高未达最佳水平，这可能解释了口服葡萄糖耐量试验和静脉葡萄糖耐量试验结果之间的差异。
携带HNF4A突变的个体在生命的第一个十年就可能发生青年发病型糖尿病。肠促胰岛素反应受损可能在HNF4A相关青年发病型糖尿病的早期阶段起作用。
