Clinical features and search for genetic determinants of postprandial hypoglycaemia.

Abstract

Objective: To test whether postprandial hypoglycaemia is an extreme and repeatable phenotype of glucose metabolism. We also explored the genetic determinants of this phenotype.

Design and methods: We conducted this study using data from the 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 their clinical features with those of subjects with normal glucose tolerance (NGT). In addition, we selected 75 subjects as a super-healthy control group. Whole-exome sequencing (WES) was performed on subjects with 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%) who had an OGTT (2 h glucose < 3 mmol/L). Ten of these patients were men (76.9%). All 13 participants had insulin >3 μU/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 of rare PEG3 mutations were significantly higher in subjects with postprandial hypoglycaemia than in super-healthy controls. Among the four subjects with PEG3 gene mutations, 71.4% were men, and their body mass index was significantly lower than that of the NGT group.

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.