Clinical features and search for genetic determinants of postprandial hypoglycaemia

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

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.

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.

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.