{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T13:12:43Z","timestamp":1778159563894,"version":"3.51.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      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 (\n                      <jats:italic>INSR<\/jats:italic>\n                      ), whereas Rabson\u2013Mendenhall syndrome (RMS) and Donohue syndrome (DS) result from recessive inheritance. We aimed to characterize the metabolic, phenotypic, and genotypic spectrum of individuals with PGV-\n                      <jats:italic>INSR<\/jats:italic>\n                      presenting with hyperinsulinemic hypoglycemia (HH) and insulin resistance (IR).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five unrelated families (F1\u2013F5) harbored four heterozygous and one homozygous PGV-\n                      <jats:italic>INSR<\/jats:italic>\n                      . 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      PGV-\n                      <jats:italic>INSR<\/jats:italic>\n                      defines a paradoxical metabolic phenotype combining hypoglycemia with ketonemia and insulin resistance, accompanied by broad intrafamilial variability. Recognition of this pattern may support targeted\n                      <jats:italic>INSR<\/jats:italic>\n                      testing, refine genetic counseling, and improve clinical management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1716020","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T12:33:12Z","timestamp":1778157192000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyperinsulinemic hypoglycemia due to pathogenic INSR variants: metabolic signature, phenotypic overlap, and semidominant inheritance"],"prefix":"10.3389","volume":"17","author":[{"given":"Ramon","family":"Marcelino do Nascimento","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of S\u00e3o Paulo School of Medicine (FMUSP)","place":["S\u00e3o Paulo, 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