Exogenous insulin-associated autoimmunity and the emergence of double diabetes in type 2 diabetes

doi:10.4239/wjd.v16.i9.109130

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World Journal of Diabetes

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1948-9358

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Diabetes. Sep 15, 2025; 16(9): 109130
Published online Sep 15, 2025. doi: 10.4239/wjd.v16.i9.109130

Exogenous insulin-associated autoimmunity and the emergence of double diabetes in type 2 diabetes

Xin-Gang Li, Meng-Ya Qi, Xiang Li, Fan Ping

Xin-Gang Li, Meng-Ya Qi, Department of Endocrinology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China

Xiang Li, Fan Ping, Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

Co-first authors: Xin-Gang Li and Meng-Ya Qi.

Author contributions: Ping F conceptualized and supervised, and provided critical guidance on clinical interpretation and manuscript development; Li XG, Li X and Qi MY contributed to data collection, analysis, and drafting of the manuscript. All authors read and approved the final version of the manuscript. Li XG prepared the initial draft, which was critically reviewed and revised by all co-authors. Li XG and Qi MY contributed equally to this work as co-first authors.

Supported by CAMS Innovation Fund for Medical Sciences, No. 2021-I2M-1-002; Healthcare Quality and Safety Incubation Programme of the Peking Union Medical Foundation, No. XHFY 2406; and the National High-Level Hospital Clinical Research Funding, No. 2022-PUMCH-B-015.

Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of PUMCH (Approval No. K3260).

Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data sharing statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request, in accordance with institutional ethical and privacy regulations (pingfan6779@163.com).

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Fan Ping, Professor, Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuai Fu Yuan, Dongcheng District, Beijing 100730, China. pingfan6779@163.com

Received: May 7, 2025
Revised: June 18, 2025
Accepted: August 20, 2025
Published online: September 15, 2025
Processing time: 133 Days and 21.6 Hours

Abstract

BACKGROUND

Exogenous insulin may trigger immune-mediated complications, particularly among East Asian populations. Double diabetes, characterized by overlapping features of type 1 diabetes (T1D) and type 2 diabetes (T2D), may arise from insulin-induced autoimmunity. This study aimed to explore the association between high-risk human leukocyte antigen (HLA) class II genotypes and susceptibility to double diabetes in patients initially diagnosed with T2D.

AIM

To investigate clinical and immunogenic features of patients who develop double diabetes following exogenous insulin therapy.

METHODS

We retrospectively analyzed five cases from Peking Union Medical College Hospital and 18 cases identified from published literature. Patients were categorized into two groups: The T2D→T1D group, characterized by autoimmune progression, and the stable T2D (T2D→T2D). Clinical characteristics and HLA class II genotypes were compared descriptively between the two groups.

RESULTS

A total of 23 patients were included in the analysis. Of these, 10 progressed from theT2D→T1D with autoimmune features, while 13 remained in the stable T2D→T2D group. There was no statistically significant difference in age at diagnosis between the two groups (57.10 ± 16.11 years vs 60.31 ± 17.41 years). In the T2D→T1D group, 70% of patients carried the HLA-DRB1 04: 05 allele and 40% carried DRB1 09: 01, both of which are commonly associated with a high risk of T1D. In contrast, the T2D→T2D group showed greater genetic heterogeneity, with a broader distribution of HLA-DRB1 alleles, including DRB1 03: 02 (n = 4), DRB1 09: 01 (n = 4), and several lower frequency alleles such as DRB1*04: 05, *08: 03, *03: 01, *04: 06, *14: 01, *04: 01, *12: 02,*15: 02 and *02: 01.

CONCLUSION

These findings suggest that patients in the T2D→T1D group exhibit a stronger autoimmune genetic predisposition, characterized by an enrichment of high-risk HLA class II alleles. In contrast, individuals with stable T2D demonstrate greater HLA diversity and lack definitive autoimmune-associated markers.

Keywords: Double diabetes; Insulin autoantibodies; Exogenous insulin; β-cell failure; Human leukocyte antigen genotype; Type 1 diabetes; Type 2 diabetes

Core Tip: We report a rare and under-recognized subtype of double diabetes, in which insulin autoantibodies induced by exogenous insulin therapy accelerate β-cell failure in patients with type 2 diabetes. This immune-mediated phenotype-predominantly observed in East Asian populations and associated with high-risk human leukocyte antigen class II alleles highlights a novel immunogenic mechanism underlying diabetes progression.