Clinical Report: Pathogenic Variants in the Insulin Receptor Gene Linked to Hyperinsulinemic Hypoglycemia
Overview
This study characterizes the metabolic and phenotypic spectrum of individuals with pathogenic variants in the insulin receptor gene (INSR) associated with hyperinsulinemic hypoglycemia (HH) and insulin resistance (IR). The findings highlight a distinct metabolic profile and intrafamilial variability, suggesting a semidominant inheritance pattern.
Background
Hyperinsulinemic hypoglycemia is a rare condition with diverse causes, including genetic factors. Pathogenic germline variants in the INSR gene are among the rarest causes of HH, leading to significant clinical implications. Understanding these variants is crucial for accurate diagnosis, genetic counseling, and management of affected individuals.
Data Highlights
Family
PGV-INSR Type
HH Prevalence
IR Presence
PCOS in Women
F1–F5
4 heterozygous, 1 homozygous
78% (18/23)
100%
60%
Key Findings
78% of individuals with PGV-INSR experienced hyperinsulinemic hypoglycemia, primarily postprandial.
All carriers exhibited insulin resistance, with 60% of women having polycystic ovary syndrome (PCOS).
Marked intrafamilial variability was observed, with both dominant and recessive inheritance patterns present.
A distinct metabolic signature included normal BMI, elevated insulin levels, and postprandial hypoglycemia with ketonemia.
The study supports the concept of semidominant inheritance for INSR-related disorders.
Clinical Implications
Recognition of the metabolic phenotype associated with PGV-INSR can aid in the timely diagnosis and management of hyperinsulinemic hypoglycemia. Clinicians should consider genetic testing for INSR variants in families with a history of hypoglycemia and insulin resistance.
Conclusion
Pathogenic variants in the insulin receptor gene present a unique metabolic profile that necessitates awareness among healthcare providers for improved clinical outcomes. Further research is warranted to explore the implications of semidominant inheritance in these disorders.
by Ramon Marcelino do Nascimento, Andrey dos Santos, Dioze Guadagnini, Lucas Santos de Santana, Augusto Cezar Junior Santomauro, Caroline Gouveia Buff Passone, Milena Gurgel Teles Bezerra, Larissa Garcia Gomes, Maria Lucia Corrêa-Giannella, Marcia Nery, Mario José Abdalla Saad, Delmar Muniz Junior Lourenço, Maria Adelaide Albergaria Pereira
