Clinical features and search for genetic determinants of postprandial hypoglycemia

in Endocrine Connections
Authors:
Qian Ren Q Ren, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Xueyao Han X Han, Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China

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Siqian Gong S Gong, 1. Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China

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Simin Zhang S Zhang, Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China

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Tianhao Ba T Ba, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Yilin Zhao Y Zhao, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Yating Li Y Li, Department of Endocrinology and Metabolism, Peking University Diabetes Center, Beijing, China

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Yanai Wang Y Wang, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Xianghai Zhou X Zhou, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Yufeng Li Y Li, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Linong Ji L Ji, Endocrinology and metabolism department, Peking University People's Hospital, Beijing, China

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Correspondence: Linong Ji, Email: jiln@bjmu.edu.cn
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Objective: To test whether postprandial hypoglycaemia is an extreme and repeatable phenotype of glucose metabolism. Secondly, we explored the genetic determinants of this phenotype.

Design and methods: We conducted this study using data from Pinggu Metabolic Disease Study database (n = 3,345). We selected subjects after an oral glucose tolerance test (OGTT) (2 h, glucose <3 mmol/L_ and compared clinical features with those of normal glucose tolerance (NGT). We additionally selected 75 subjects as super-healthy control group. Whole-exome sequencing (WES) was performed on postprandial hypoglycaemic and super-healthy controls. We also evaluated several candidate genes believed to be important in pancreatic hypoglycaemia.

Results: We found 13 participants (0.39%) had an OGTT 2 h glucose <3 mmol/L. Ten patients were men (76.9%). All 13 participants had insulin > 3 uU/mL when postprandial blood glucose levels were <3 mmol/L. WES analysis identified one gene, paternally expressed 3 (PEG3), which had three rare mutations in four patients (30.8%). Minor allele frequencies (MAF) of rare PEG3 mutations were significantly higher in subjects with postprandial hypoglycaemia than in super-healthy controls. Among all four subjects with PEG3 gene mutations, 71.4% were men, and their body mass index (BMI) was significantly lower than that of the NGT.

Conclusions: Postprandial hypoglycaemia is an extreme and reproducible phenotype in the general population. PEG3 mutations may represent a potential genetic aetiology for postprandial hypoglycaemia. Further research with larger and more diverse populations and a broader genetic focus is needed to understand the genetic basis of postprandial hypoglycaemia.