Frontiers in endocrinology · 2026
Hyperinsulinemic hypoglycemia due to pathogenic INSR variants: metabolic signature, phenotypic overlap, and semidominant inheritance.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Marcelino do Nascimento Ramon, Dos Santos Andrey, Guadagnini Dioze, de Santana Lucas Santos, Santomauro Augusto Cezar Junior, Gouveia Buff Passone Caroline, Gurgel Teles Bezerra Milena, Gomes Larissa Garcia, Corrêa-Giannella Maria Lucia, Nery Marcia, Abdalla Saad Mario José, Lourenço Delmar Muniz Junior, Albergaria Pereira Maria Adelaide
Аннотация
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.
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.