Hyperinsulinemic hypoglycemia due to pathogenic INSR variants: metabolic signature, phenotypic overlap, and semidominant inheritance.

OBJECTIVE

Familial hyperinsulinemic hypoglycemia type 5 (HHF5) and type A insulin resistance syndrome (TAIRS) are autosomal dominant disorders caused by heterozygous pathogenic variants in the insulin receptor gene (INSR), whereas Rabson-Mendenhall syndrome (RMS) and Donohue syndrome (DS) result from recessive inheritance. We aimed to characterize the metabolic, phenotypic, and genotypic spectrum of individuals with PGV-INSR presenting with hyperinsulinemic hypoglycemia (HH) and insulin resistance (IR).

METHODS

Normal-weight probands with HH and IR underwent exome sequencing with familial segregation confirmed by Sanger sequencing. Metabolic evaluation included prolonged fasting, mixed-meal, and oral glucose tolerance tests. A published insulinoma cohort served as a comparator.

RESULTS

Five unrelated families (F1-F5) harbored four heterozygous and one homozygous PGV-INSR. Eighteen carriers were identified. HH occurred in 78% (18/23), predominantly postprandial, whereas 22% had diabetes; IR was present in all carriers and 60% of women had PCOS. Marked intrafamilial variability and phenotypic overlap among HHF5, TAIRS, and RMS were observed, including the coexistence of dominant and recessive inheritance within one family. A distinct metabolic signature was identified, characterized by normal BMI, variable degrees of IR (with or without acanthosis), inappropriately elevated fasting and stimulated insulin concentrations, normal triglycerides, and predominantly postprandial hypoglycemia paradoxically associated with ketonemia.

CONCLUSION

PGV-INSR defines a paradoxical metabolic phenotype combining hypoglycemia with ketonemia and insulin resistance, accompanied by broad intrafamilial variability. Recognition of this pattern may support targeted INSR testing, refine genetic counseling, and improve clinical management.