A novel presentation of a His1157Arg INSR mutation in male half-siblings with type A insulin resistance: A case report

Abstract

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.

Keywords

Insulin resistance / Insulin receptor / INSR / Atypical diabetes / Type A insulin resistance

Acknowledgments

The authors acknowledge Kathryn Duvall, a Master of Arts in Health Communication, for her assistance with the Institutional Review Board preparation related to this research.

Funding

None.

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: All authors

Investigation: Evan Los

Writing-original draft: All authors

Writing-review & editing: All authors

Ethics approval and consent to participate

The East Tennessee State University Institutional Review Board and the Ballad Health Institutional Review Board determined that this case report does not constitute “Human Subjects Research.” The patients and guardians provided verbal consent to participate in the study.

Consent for publication

Verbal informed consent was obtained from the patients and their legal guardians for the publication of this report.

Availability of data

Not applicable.

Further disclosure

This case was originally presented in oral form (Type A insulin resistance can be misdiagnosed as type 1 or type 2 diabetes - A cautionary tale) by Kaci Wirthwein at the American Diabetes Association 84^th Scientific Sessions (Orlando, Florida) on [June 21, 2024].

References

[1] 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

[2] Angelidi AM, Filippaios A, Mantzoros CS. Severe insulin resistance syndromes. J Clin Invest. 2021; 131(4):e142245. doi: 10.1172/JCI142245

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] 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

[11] 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