To characterize the metabolic, phenotypic, and genotypic spectrum of individuals with pathogenic germline variants in the insulin receptor gene (INSR) presenting with hyperinsulinemic hypoglycemia (HH) and insulin resistance (IR), specifically focusing on the differences between HHF5, TAIRS, and RMS.
Key Findings:
Five families with pathogenic variants in INSR were identified, including four heterozygous and one homozygous variant.
78% of individuals (18 out of 23) experienced postprandial hyperinsulinemic hypoglycemia, while 22% had diabetes.
All carriers exhibited insulin resistance, with 60% of women having polycystic ovary syndrome (PCOS).
Marked intrafamilial variability and phenotypic overlap were observed among HHF5, TAIRS, and RMS.
Interpretation:
The study highlights a unique metabolic phenotype characterized by hypoglycemia with ketonemia and insulin resistance, suggesting a need for targeted INSR testing and improved genetic counseling to enhance clinical management.
Limitations:
The study is based on a small sample size from a single center.
Potential biases in retrospective data collection.
Lack of diversity in the sample population may limit generalizability.
Conclusion:
Pathogenic variants in INSR lead to a paradoxical metabolic phenotype that warrants recognition for better clinical management and genetic counseling.
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
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