Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan

Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects.

The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations.

We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m²) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ≥15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia.

The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11).

To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.