A novel presentation of a His1157Arg INSR mutation in male half-siblings with type A insulin resistance: A case report
Type A insulin resistance, a rare disorder resulting from mutations in the INSR gene, exhibits a wide range of clinical presentations. We report two male half-siblings with a His1157Arg missense mutation in exon 19 of the INSR gene. Patient 1 presented with hyperglycemia and features resembling type 1 diabetes, without acanthosis nigricans. In contrast, patient 2 exhibited characteristics typically seen in children diagnosed with type 2 diabetes, including obesity and acanthosis. Genetic testing confirmed the shared pathogenic mutation. Their divergent phenotypes underscore the heterogeneity of type A insulin resistance and highlight the critical role of genetic testing in atypical diabetes cases. Targeted therapy with metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose co-transporter 2 inhibitors improved glycemic control in both patients.
- Ogawa W, Araki E, Ishigaki Y, et al. New classification and diagnostic criteria for insulin resistance syndrome. Diabetol Int. 2022;13(2):337-343. doi: 10.1007/s13340-022-00570-5
- Angelidi AM, Filippaios A, Mantzoros CS. Severe insulin resistance syndromes. J Clin Invest. 2021;131(4):e142245. doi: 10.1172/JCI142245
- Ardon O, Procter M, Tvrdik T, Longo N, Mao R. Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene. Mol Genet Metab Rep. 2014;1:71-84. doi: 10.1016/j.ymgmr.2013.12.006
- Vambergue A, Lautier C, Valat AS, Cortet-Rudelli C, Grigorescu F, Dewailly D. Follow-up study of two sisters with type A syndrome of severe insulin resistance gives a new insight into PCOS pathogenesis in relation to puberty and pregnancy outcome: A case report. Hum Reprod. 2006;21(5):1274-1278. doi: 10.1093/humrep/dei455
- Sanderson EE, Shah M, Hooper AJ, Bell DA, Choong CS. Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance. Endocrinol Diabetes Metab Case Rep. 2022;2022(1):1-5. doi: 10.1530/EDM-21-0114
- Takahashi I, Yamada Y, Kadowaki H, et al. Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene. Endocr J. 2010;57(6):509-516. doi: 10.1507/endocrj.k09e-339
- Collin-Chavagnac D, Saint-Martin C, Bedidi L, et al. Insulin receptor variants: Extending the traditional Mendelian spectrum. Genet Med. 2025;27(6):101404. doi: 10.1016/j.gim.2025.101404
- Hirota Y, Kakei Y, Imai J, et al. A multicenter, open-label, single-arm trial of the efficacy and safety of empagliflozin treatment for refractory diabetes mellitus with insulin resistance (EMPIRE-01). Diabetes Ther. 2024;15(2):533-545. doi: 10.1007/s13300-023-01526-x
- Martínez-Montoro JI, Pinzón-Martín JL, Damas-Fuentes M, Feràndez-Valero A, Tinahones FJ. Combination therapy with semaglutide and dapagliflozin as an effective approach for the management of type A insulin resistance syndrome: A case report. Front Endocrinol (Lausanne). 2022;13:838887. doi: 10.3389/fendo.2022.838887
- Nagashima S, Wakabayashi T, Saito N, et al. Long-term efficacy of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, in a case of type A insulin resistance syndrome. J Diabetes Investig. 2020;11(5):1363-1365. doi: 10.1111/jdi.13241
- Nishikage S, Hirota Y, Takayoshi T, et al. Utility of the C-peptide/insulin molar ratio for distinguishing type A insulin resistance syndrome from type 2 diabetes. J Clin Endocrinol Metab. 2025;110(10):e3383-e3390. doi: 10.1210/clinem/dgaf043