
==== Front
Diabetes Metab Syndr Obes
Diabetes Metab Syndr Obes
dmso
Diabetes, Metabolic Syndrome and Obesity
1178-7007
Dove

456466
10.2147/DMSO.S456466
Review
HLA Alleles Associate with Insulin Autoimmune Syndrome
Yao et al
Yao et al
Yao Dan 1
http://orcid.org/0009-0002-4829-4143
Jiang Jiefeng 1
Zhou Qianyun 1
Feng Caiyun 1
Chu Jianping 2
Chen Zhiyan 1
Yang Jie 1
http://orcid.org/0000-0002-7551-0879
Xia Jinying 3
Chen Yujia 1
1 Department of Endocrinology, Xiangshan Hospital of TCM Medical and Health Group, Xiangshan, Ningbo, People’s Republic of China
2 Department of Endocrinology, Ningbo First Hospital, Ningbo, People’s Republic of China
3 Department of Endocrinology, Ningbo No. 2 Hospital, Ningbo, People’s Republic of China
Correspondence: Jiefeng Jiang, Department of Endocrinology, Xiangshan Hospital of TCM Medical and Health Group, Ningbo, 315799, People’s Republic of China, Tel +86-13606781301,, Email xszyyjjf@126.com
Dan Yao, Department of Endocrinology, Xiangshan Hospital of TCM Medical and Health Group, Xiangshan, Ningbo, 315799, People’s Republic of China, Tel +86-13777191528, Email 3299048@qq.com
16 9 2024
2024
17 34633475
12 3 2024
27 8 2024
© 2024 Yao et al.
2024
Yao et al.
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Abstract

In recent years, there have been hundreds of reports on insulin autoimmune syndrome (IAS) globally; however, fewer than a hundred patients have undergone genetic testing. Our objective is to examine the background of IAS and the variations in drugs that trigger it among patients who have been genetically tested, aiming to deepen our understanding of this condition. HLA Analysis of 68 cases showed that DR4 is predominant, especially in individuals of East Asian descent, notably in DRB1 *0406. Methimazole was the primary drug associated with IAS in these populations, while in Caucasian individuals, the emphasis was on DRB1 *0403, with lipoic acid being the common inducer. The key factor determining disease risk is the combination of chromosomal allele variations, with HLA class II allele DR4 positive patients showing a strong association with DQA1 *0301/DQB1 *0302.

Keywords

insulin autoimmune syndrome
HLA
methimazole
α-lipoic acid
==== Body
pmcIntroduction

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia, elevated endogenous insulin, and positive insulin autoantibodies (IAA). It is often triggered by thiol-containing drugs (including non-thiol drugs like gold thioglucose and albumin) or viral infections, with some cases being idiopathic. IAS was first reported in 1970 by Yukimasa Hirata and colleagues.1 The pathogenesis of IAS is closely linked to specific HLA typing susceptibility gene loci.2

The major histocompatibility complex (MHC) is a genetic locus containing encompassing genes that encode class I and II MHC molecules. In humans, this complex is termed HLA (human leukocyte antigen), and is governed by genes on the short arm of chromosome 6. Class I MHC molecules typically load and present CD8 T cell peptides produced within cells, rather than presenting exogenous peptides, with the second chain remaining unchanged. Class II genes exhibit extensive polymorphism, which influences immune system recognition. Each unique human sequence assigned a four-digit number plus the gene name, such as DRB1 *0401, with an optional fifth number for nucleotide variations that do not affect amino acids. Class II DQ MHC molecules consist of two polymorphic chains (A and B), thus requiring definition, eg, DQA1 *0301/DQB1 *0302. Conversely, DR molecules are mainly polymorphic in the DRB chain, with less variability in the DRA chain, often denoting only the DRB chain, eg, DRB1 *03012 (Figure 1). Figure 1 MHC class II gene composition.

Previous literature on IAS has mainly focused on Japan, with pathogenic factors including thiol containing drugs and viruses.3 Our aim is to explore whether there is a correlation between different regional distributions and the pathogenicity of different drugs and HLA typing.

Methods

We searched the English literature published in PubMed from 1970 to December 2023 using IAS as the keyword, excluding duplicate cases, literature with incomplete data, and articles with only abstracts or lacking full texts. We extracted, summarized, and analyzed factors such as country of origin, pathogenic drug, gender, age, etc. from the HLA typing test patients reported in the IAS literature. We aimed to explore different HLA subtypes and differences in countries and regions; the association between HLA typing and different pathogenic drugs; and differences in HLA subtypes and gender.

Results

Search Results

We included a total of 168 articles and 501 cases, with 68 cases having completed HLA sequencing (Figure 2 and Table 1). China reported the highest number of cases, followed by Japan; Japan had the highest number of HLA sequencing cases (Figure 3). Table 1 Basic Information of 68 IAS Patients

DRB1	DRB1’	DQB1	DQB1’	DQA1	DQA1’	HLA class I	Country	Inducing Drugs	M/F	Age	Year	References	
0405	1302	0402	0604	NA	NA	A23(9)/68, B44/55, Cw2/9(3.1)	Japan	Insulin	M	75	2006	[4]	
0406	1502	0302	0601	NA	NA	NA	China	α-lipoic acid	M	48	2017	[5]	
0403	0701	0202	0202	NA	NA	NA	China	Clopidogrel	M	66	2021	[6]	
04	07	0401	0402	0301	0201	NA	Caucasian	Piritinol	F	3.5	2015	[7]	
0403	NA	NA	NA	NA	NA	NA	Japan	NA	M	84	2015	[8]	
0401	1201	NA	NA	NA	NA	A24/11, B35/62, Cw3/4	Korea	α-lipoic acid	F	71	2009	[9]	
1104	NA	NA	NA	NA	NA	NA	America	Ceftriaxone+ oxacillin	F	7	2013	[10]	
0301	0401	NA	NA	NA	NA	NA	America	NA	M	67	2009	[11]	
0403	1147	0301	0302	NA	NA	NA	China	Clopidogrel	M	82	2023	[12]	
0404	NA	NA	NA	NA	NA	NA	America	Clopidogrel	M	79	2017	[13]	
0301	0901	0302	0501	NA	NA	NA	Korea	NA	F	31	2012	[14]	
0406	NA	0301	NA	NA	NA	NA	China	NA	NA	NA	1992	[15]	
0406	NA	0302	NA	NA	NA	NA	Korea	NA	NA	NA	1992	[15]	
0406	NA	0302	NA	NA	NA	NA	Korea	NA	NA	NA	1992	[15]	
0406	NA	0302	NA	NA	NA	NA	Japan	NA	NA	NA	1992	[15]	
0406	NA	NA	NA	NA	NA	NA	Japan	Albumin	F	80	2016	[16]	
0406	NA	NA	NA	NA	NA	NA	Portugal	Penicillin G	F	24	2001	[17]	
0403	NA	NA	NA	NA	NA	A23/66, B49/51, Cw2/7	Portugal	NA	F	19	2001	[17]	
0406	0901	NA	NA	NA	NA	NA	China	Methimazole	F	17	2014	[18]	
0403	15	0302	05	0301	0103	NA	Italy	NA	M	25	2012	[19]	
0404	NA	NA	NA	NA	NA	NA	Japan	NA	F	53	2006	[20]	
0406	NA	NA	NA	NA	NA	NA	America	α-lipoic acid	NA	NA	2014	[21]	
0403	NA	NA	NA	NA	NA	NA	America	α-lipoic acid	NA	NA	2014	[21]	
0403	NA	NA	NA	NA	NA	NA	America	α-lipoic acid	NA	NA	2014	[21]	
0403	NA	NA	NA	NA	NA	NA	America	α-lipoic acid	NA	NA	2014	[21]	
0403	NA	NA	NA	NA	NA	NA	America	α-lipoic acid	NA	NA	2014	[21]	
0403	NA	NA	NA	NA	NA	NA	America	α-lipoic acid	NA	NA	2014	[21]	
0406	1601	0302	0502	0102	0301	NA	China	Methimazole	F	44	2005	[22]	
0405	0407	NA	NA	NA	NA	NA	China	Methimazole	M	23	2011	[23]	
03	14	NA	NA	NA	NA	NA	America	Omeprazole	F	65	2016	[24]	
0406	090102	030201	030302	030101	0302	NA	Japan	Loxoprofen-sodium	F	62	2013	[25]	
0701	0901	0202	0303	NA	NA	NA	Brazilian	Captopril	F	63	2018	[26]	
0406	NA	NA	NA	NA	NA	NA	Japan	Health supplements	F	70	2013	[27]	
0403	NA	NA	NA	NA	NA	NA	Italy	α-lipoic acid	F	66	2018	[28]	
0406	NA	NA	NA	NA	NA	NA	Italy	α-lipoic acid	F	70	2011	[29]	
0406	NA	NA	NA	NA	NA	NA	Korea	methimazole	F	15	2013	[30]	
0403	NA	NA	NA	NA	NA	NA	Italy	α-lipoic acid	F	71	2021	[31]	
04	15	NA	NA	NA	NA	NA	Japan	Coenzyme Q10	F	52	2019	[32]	
0406	1502	NA	NA	NA	NA	NA	Japan	α-lipoic acid	M	55	2007	[33]	
0406	NA	0302	NA	0301	NA	NA	Japan	Gold thioglucose	F	56	1994	[34]	
0406	NA	NA	NA	NA	NA	NA	Japan	NA	M	84	2011	[35]	
0406	090102	NA	NA	NA	NA	NA	China	Methimazole	F	44	2023	[36]	
0406	NA	NA	NA	NA	NA	NA	China	Methimazole	F	39	2023	[36]	
0406	NA	NA	NA	NA	NA	NA	China	Methimazole	F	50	2023	[36]	
0401	0803	0301	0601	0103	0303	NA	Japan	NA	F	88	2000	[37]	
1301	0802	NA	NA	NA	NA	NA	Brazilian	NA	M	6	2019	[38]	
0406	NA	NA	NA	NA	NA	NA	China	Methimazole	M	31	2022	[39]	
0403	NA	NA	NA	NA	NA	NA	Japan	α-lipoic acid	F	45	2007	[40]	
0403	NA	NA	NA	NA	NA	NA	Italy	α-lipoic acid	F	66	2019	[41]	
0403	NA	NA	NA	NA	NA	NA	Italy	α-lipoic acid	F	82	2019	[41]	
0407	NA	NA	NA	NA	NA	NA	Italy	NA	F	78	2015	[42]	
0406	NA	NA	NA	NA	NA	NA	Poland	Methimazole+ captopril	F	39	2012	[43]	
0404	0301	0302	0201	03	0501	NA	Netherlands	NA	F	45	1996	[44]	
0406	NA	NA	NA	NA	NA	NA	Korea	α-lipoic acid	F	67	2013	[45]	
0403	NA	NA	NA	NA	NA	NA	Italy	α-lipoic acid	NA	NA	2021	[46]	
0403	NA	0302	NA	NA	NA	NA	Germany	Quinapril+α-lipoic acid	F	69	2001	[47]	
0403	09	NA	NA	NA	NA	NA	France	Clopidogrel	M	88	2006	[48]	
04	15	NA	NA	NA	NA	NA	Italy	α-lipoic acid	F	35	2018	[49]	
0406	1501	NA	NA	NA	NA	NA	Korea	Methimazole	F	53	2013	[50]	
0406	0405	NA	NA	NA	NA	NA	Japan	Methimazole	F	26	2016	[51]	
0406	090102	NA	NA	NA	NA	NA	Japan	Methimazole	F	29	2016	[51]	
0410	140,501	0402	050301	0104	0303	NA	Japan	NA	F	80	2011	[52]	
0405	0803	0401	0601	0301	0103	NA	Japan	NA	M	62	1995	[53]	
0401	NA	0301	NA	0301	NA	NA	Norwegian	NA	M	42	1995	[53]	
0101	1601	0501	0502	0101	0102	NA	Swiss	NA	F	55	1995	[53]	
1501	1502	0601	0602	0102	0103	NA	Italy	NA	F	57	1995	[53]	
0701	1501	0201	0602	0201	0102	NA	Italy	NA	M	5	1995	[53]	
0402	1101	0301	0302	0301	0501	NA	Italy	NA	M	79	1995	[53]	

Figure 2 Literature search flowchart.

Figure 3 Excluding HLA sequencing and including HLA sequencing in various countries.

Regional Distribution and Linkage of Different HLA Subtypes

Among the 68 patients (Table 1), the HLA-DRB1 sequence revealed that 59 cases were DRB1 *04 (DR40, and 2 cases were DRB1 *03 (DR3), with DR4 being predominant. All cases reported in Japan and China had DRB1 as DR4; Out of the 12 reported cases in Italy, 10 were DR4; Out of the 10 reported cases in the America, 7 were DR4; and out of the 7 reported cases in Korea, 6 were DR4 (Figure 4). Although there are 14 subtypes of DR4,54 only 8 subtypes were observed in 68 patients. DRB1 *0406 (26 cases, mainly in East Asian countries) (Figure 5) and DRB1 *0403 (18 cases, mainly in non-East Asian countries) (Figure 6) were the most reported, followed by DRB1 *0404 (3 cases) and DRB1 *0405 (3 cases). Figure 4 Distribution of DRB1 in different countries.

Figure 5 Distribution of IAS patients in different countries and the proportion of DRB1 *0406.

Figure 6 Distribution of IAS patients in different countries and the proportion of DRB1 *0403.

Out of 68 patients, 25 underwent HLA-DQB1 sequencing, with the dominant subtypes being DQB1 *0302 (10 cases) and DQB1 *0301 (5 cases), mainly distributed in Japan, China, and Korea (Figure 7). There were 6 cases of association between DRB1 *0406 and DQB1 *0302, accounting for 6/13, and 4 cases of association between DRB1 *0406 and DQB1 *0901, accounting for 4/13, all found in China, Korea, and Japan. Among the 14 patients sequenced for HLA-DQA1, DQA1 *0301 was mainly identified in Japan and Italy (Figure 8). Figure 7 Distribution of DQB1 in different countries.

Figure 8 Distribution of DQA1 in different countries.

Drug Correlation Induced by Different HLA- DRB1 Subtypes

In a cohort of 26 DRB1 *0406 patients, 11 were induced by methimazole, 5 by α-lipoic acid, 4 by clopidogrel, and 5 cases had unspecified inducing drugs. Other inducers included 1 case each of penicillin G, albumin, gold thioglucose granulomas, health supplements, and lipoprotein sodium, each with 1 case. Among 18 DRB1 *0403 patients, 12 were induced by α-lipoic acid, 3 by clopidogrel, and 3 had no clear inducing drug. In the DRB1 *0405 group, three patients had different triggers: one by exogenous insulin, one by methimazole, and one unspecified. Of the 3 DRB1 *0401 patients, 2 had unclear inducing drugs, and 1 was induced by α-lipoic acid.

The HLA-DRB1 alleles related to methimazole induction include DRB1 *0406 (11 cases) and DRB1 *0405 (1 case), mainly in China, Japan, and Korea (Table 2). α-lipoic acid-related HLA-DRB1 alleles are DRB1 *0403 (12 cases), predominantly in the America and Italy; DRB1 *0406 (5 cases), sporadically; and DRB1 *0401 (1 case) in Korea (Table 3). The HLA-DRB1 alleles linked to clopidogrel induction are DRB1 *0403 (3 cases) in China and France, and DRB1 *0404 (1 case) in the America (Table 4). Other drugs have been associated with sporadic reports. Table 2 Methimazole and HLA Typing

	Methimazole	Methimazole & Captopril	Total	
DRB1 * 0405	1	0	1	
 China	1	0	–	
DRB1 * 0406	10	1	11	
 China	6	0	–	
 Japan	2	0	–	
 Korea	2	0	–	
 Poland	0	1	–	
Total	11	1	12	

Table 3 α-Lipoic Acid and HLA Typing

	Quinapril+α-Lipoic Acid	α-Lipoic Acid	Total	
DRB1 * 04	0	1	1	
 Italy	0	1	–	
DRB1 * 0401	0	1	1	
 Korea	0	1	–	
DRB1 * 0403	1	11	12	
 America	0	5	–	
 Germany	1	0	–	
 Italy	0	5	–	
 Japan	0	1	–	
DRB1 * 0406	0	5	5	
 America	0	1	–	
 China	0	1	–	
 Italy	0	1	–	
 Korea	0	1	–	
 Japan	0	1	–	
Total	1	18	19	

Table 4 Clopidogrel and HLA Typing

	Clopidogrel	
DRB1 * 0403	–	
 China	2	
 France	1	
DRB1 * 0404	–	
 America	1	
Total	4	

The Association Between Different HLA Subtypes and Gender

Among the 26 DRB1 *0406 patients, gender was not reported in 5 cases. Of the remaining cases, 17 were female, and 4 were male. All 3 cases with DRB1 *0405 were male. For the three DRB1 *0401 patients, one did not report gender, and two were female. Although there is a higher prevalence of females in DRB1 *0406 patients and all DRB1 *0405 patients are male, suggesting some gender bias, the small sample size limits the accuracy of these observations. Further research with larger sample sizes is necessary to better understand the relationship between genetic differences and gender.

Discussion

IAA is detected in individuals or animals who have not been given exogenous insulin. The presence of both IAA positivity and hypoglycemia characterizes IAS. However, IAA is also found in type 1 diabetes patients treated with exogenous insulin. Scatchard analysis indicates that the IA detected in patients differs from the IA associated with exogenous insulin injection in diabetes patients, but matches the insulin autoantibodies found in IAS patients.4 This syndrome can occur spontaneously or after exposure to drugs such as methimazole, penicillamine, and α-mercaptopropionyl ester, all of which contains thiol group. However, cases of IAS induced by drugs without thiol groups, such as albumin, have also been reported (albumin).16

A survey on DR4 allele prevalence revealed that DRB1 *0406 is more prevalent common among the Han and Manchu populations in Japan, Korea, and northern China, while DRB1 *0403 is more prevalent in Europe, America, the Pacific islands, and other regions, with a lower occurrence of DRB1 *0406. This partially explains the regional differences in IAS incidence.55 The influence of HLA-II genes is highly polymorphic and related to immune system recognition. The high polymorphism of DRB1, which encodes the DR β chain, accounts for the variations in immune responses of different individuals to different antigens.54 The combination of allele variations ultimately determines the risk of disease.2 Among the 14 patients tested by DQA1 in this study, 8 were DQA1 *0301, all of whom were linked to DR4; 5 cases showed a DQA1 *0301/DQB1 *0302 linkage, indicating a strong correlation between DRB1 *04/DQA1 *0301/DQB1 *0302 and IAS. However, DQA1 *0301 may not be essential, as it is also associated with the DRB1 *0405 and DQB1 *0401 combination. Despite its high prevalence among Japanese DR4 positive individuals, no IAS cases with this haplotype have been reported. Therefore, DQB1 *0302 remains a potential factor influencing IAS development.3

The microenvironment can also impact the imbalanced expression of HLA-DQA1 alleles.56 IAS can be induced by exposure to viruses and drugs, with the proposed mechanism suggesting that viral infection acts as a superantigen, triggering the production of IAA, which leads to IAS. Theoretically, drugs with thiol groups can interact with insulin’s disulfide bonds, potentially forming cysteine or causing structural changes in insulin molecules, making them immunogenic.57 In this study of 68 patients, 22 did not report any specific triggering drugs. The spontaneous occurrence of IAS is mainly observed in Japan and appears to be rare in Western countries. It is suggested that cases labeled as spontaneous may actually result from unrecognized triggering factors.3

We observed distinct differences in IAS induction by various drugs. Reports indicate that all Japanese IAS patients exposed to methimazole carry DRB1 *0406.58 In our study, among 12 methimazole-induced IAS cases, 11 were DRB1 *0406 and 1 was DRB1 *0405, showing a significant genetic bias. Although there are instances of alleles other than DRB1 *0406, when Graves disease patients with the Bw62/Cw4/DR4 haplotype carry DRB1 *0406, there is a high likelihood of developing IAS following methimazole treatment.58 Only 3 out of these 12 patients underwent HLA class I classification testing, showing no notable link with the inducing drug. The HLA-DRB1 alleles linked to α-lipoic acid induction are predominantly DRB1 *0403 and DRB1 *0406. Therefore, individuals with DRB1 *0403 who consume α-lipoic acid may face higher risk of IAS compared to those not exposed to α-lipoic acid,59 Most DRB1 *0403 carriers are found in non-Asian countries. HLA-DRB1 alleles related to clopidogrel induction are mainly DRB1 *0403*0. Despite clopidogrel-induced HLA-DRB1 alleles being the same as those induced by lipoic acid, there is no apparent clustering in their national distribution. It can be inferred that methimazole, associated with the DRB1 *0406 gene, is the predominant IAS-inducing drug in Asian countries. In non-Asian countries, α-lipoic acid is the main IAS-inducing drug, related to DRB1 *0403.

Among the 68 IAS patients, one case, induced by exogenous insulin necessitates careful distinction: anti-insulin antibodies are classified into two types those associated with exogenous insulin (insulin antibodies, IA) and those linked with the autoimmune system (insulin autoantibodies, IAA). The latter can sometimes be observed in type 1 diabetes patients before and/or shortly after onset and in IAS patients. Differentiating between IAA and IA subtypes using phage display technology60 remains limited in clinical application and cannot be reliably used for distinction. Clinically, inferences are primarily made based on medical history and clinical manifestations. Patients with Exogenous Insulin-Induced Endogenous Insulin Antibody Syndrome (EIAS) have a history of insulin exposure, characterized mainly by hyperinsulinemia, significant blood sugar fluctuations, and less hypoglycemia due to affinity antibodies. The genetic background common to both EIAS and IAS cases, and the mechanism differentiating endogenously induced IAA from exogenously induced IA, remains unclear. Alleles such as DR7, DR4, and/or B15 predispose individuals to produce IA in response to exogenous insulin, while B8 and/or DR3 exhibit a protective effect.61,62 The case under discussion presents one of the IAA formation and IAS susceptibility phenotypes, HLA-DR4. However, its molecular type is not DRB1 *0406 but DRB1 *0405, with molecular alleles DRB1 *0405/1302 and DQB1 *0401/*0604. DRB1 *0405 is typically seen in type 1 diabetes patients and appears to confer some protection against IAS.54 Further research is necessary to verify the regulation mechanisms of IA or IAA, including the DRB1 molecule and other HLA-related factors.4 The assertion that exogenous insulin induces IAS is subject to investigation.

The article also notes a gender disparity: female patients dominate in the DRB1 *0406 group, while all DRB1 *0405 patients are male. Whether this gender bias holds significant meaning requires further investigation.

Conclusion

In IAS patients, HLA typing indicates that the majority are DRB1 *04 (59/68), with DRB1 *0406 and DRB1 *0403 being the most common. DRB1 *0406 is prevalent in the East Asian population, where methimazole is the main inducing drug, while DRB1 *0403 is found in the Caucasian population, with α-lipoic acid and clopidogrel being the primary inducing drugs. The combination of these allele variants ultimately determines the disease risk, with DRB1 *04/DQA1 *0301/DQB1 *0302 showing the strongest correlation with IAS occurrence. It is essential to differentiate the diagnosis of IAS patients who have undergone insulin therapy from exogenous insulin antibody syndrome.

Ethics Approval and Consent to Participate

This study was approved by the Ethics Committee of the Medical Health Group of Xiangshan County Traditional Chinese Medicine Hospital (No. P2024-SL-603).

Disclosure

The authors report no conflicts of interest in this work.
==== Refs
References

1. Hirata Y. Insulin autoimmunity in a case with spontaneous hypoglycemia. Tounyoubyou. 1970;13 :312–320. doi:10.11213/tonyobyo1958.13.312
2. Eisenbarth GS. Immunoendocrinology: Scientific and Clinical Aspects. Springer Science & Business Media; 2010. doi:10.1007/978-1-60327-478-4
3. Cappellani D, Macchia E, Falorni A, et al. Insulin autoimmune syndrome (Hirata disease): a comprehensive review fifty years after its first description. Diabet Metabc Syndr Obes. 2020;Volume 13 :963–978. doi:10.2147/DMSO.S219438
4. Matsuyoshi A, Shimoda S, Tsuruzoe K, et al. A case of slowly progressive type 1 diabetes with unstable glycemic control caused by unusual insulin antibody and successfully treated with steroid therapy. Diabet Res Clin Pract. 2006;72 (3 ):238–243. doi:10.1016/j.diabres.2005.10.018
5. Wu LL, Kong XM, Li SX, et al. Used by patients with diabetes α- A case of insulin autoim-mune syndrome induced by lipoic acid. Chin J Diabet. 2017;9 (8 ):3. doi:10.3760/cma.j.issn.1674-5809.2017.08.012
6. Yang CC, Gu WJ, Lyu ZH, et al. One case report of insulin autoimmune syndrome induced by clopidogrel. Chinese J Int Med. 2021;60 (1 ):55–57. doi:10.3760/cma.j.cn112138-20200221-00109
7. Kuznetsova E, Melikyan M, Trkova M. A case of hyperinsulinemic hypoglycemia, associated with insulin autoimmune syndrome (IAS) in 3.5 year old girl. Hormone Res Paediatrics. 2016;86 (5 ):349. doi:10.3760/cma.j.cn112138-20200221-00109
8. Yoshino H, Kawakami K, Watanabe T, et al. A case of insulin autoimmune syndrome in an elder patient. Eur Geriatric Med. 2015;1 (6 ):85–86. doi:10.1016/j.eurger.2014.04.009
9. Chang HJ, Choi HS, Park MY, et al. A case of insulin autoimmune syndrome related to alpha-lipoic acid. Korean J Med. 2009;76 (5 ):600–604. doi:10.1136/bmj.b600
10. Alves C, Constança J, De León DD, et al. A novel atypical presentation of insulin autoimmune syndrome (Hirata’s disease) in a child. J Pediatr Endocrinol Metab. 2013;26 (11–12 ):1163–1166. doi:10.1515/jpem-2013-0215 23843578
11. Lupsa BC, Chong AY, Cochran EK, et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore). 2009;88 (3 ):141–153. doi:10.1097/MD.0b013e3181a5b42e 19440117
12. Chen S, Qiang J, Zhao B, et al. Clopidogrel as a distinctive cause of insulin autoimmune syndrome: a systematic case review. Diabet Metab Syndr Obes. 2023;Volume 16 :2583–2592. doi:10.2147/DMSO.S418845
13. Rajpal A, Kassem LS, Moscoso-Cordero M, et al. Clopidogrel-induced insulin autoimmune syndrome: a newly recognized cause of hypoglycemia in a patient without diabetes. J Endocrin Soc. 2017;1 (9 ):1217–1223. doi:10.1210/js.2017-00316
14. Kim H, Lee TY, Kim E, et al. Fulminant Type 1 diabetes in a pregnant woman as an initial manifestation of the insulin autoimmune syndrome. Diabetic Med. 2012;29 (10 ):1335–1338. doi:10.1111/j.1464-5491.2012.03623.x 22356444
15. Uchigata Y, Omori Y, Nieda M, et al. HLA-DR4 genotype and insulin-processing in insulin autoimmune syndrome. Lancet. 1992;340 (8833 ):1467. doi:10.1016/0140-6736(92)92654-X 1360579
16. Kamei S, Kaneto H, Shigemoto R, et al. Human serum albumin: possible cause of insulin autoimmune syndrome. J Diabetes Invest. 2016;7 (6 ):919–920. doi:10.1111/jdi.12515
17. Cavaco B, Uchigata Y, Porto T, et al. Hypoglycaemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies. Eur J Endocrinol. 2001;145 (3 ):311–316. doi:10.1530/eje.0.1450311 11517012
18. Zhang Y, Zhao T. Hypoglycemic coma due to insulin autoimmune syndrome induced by methimazole: a rare case report. Exp Ther Med. 2014;8 (5 ):1581–1584. doi:10.3892/etm.2014.1964 25289063
19. Sudano M, Turchi F, Sossai P. Insulin autoimmune syndrome (Hirata Disease): case report in a Caucasian patient with new-onset diabetes. Clin Med Diag. 2012;2 (5 ):51–53. doi:10.5923/j.cmd.20120205.02
20. Miyamura N, Murata Y, Taketa K, et al. A case of insulin autoimmune syndrome with HLA DRB1*0404: impact on the hypothesis for the molecular pathogenesis involving DRB1 molecules. Diabetic Med. 2006;23 (1 ):104–105. doi:10.1111/j.1464-5491.2006.01775.x 16409576
21. Gullo D, Evans JL, Sortino G, et al. Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking α‐lipoic acid. Clin. Endocrinol. 2014;81 (2 ):204–209. doi:10.1111/cen.12334
22. Masjhur JS. Insulin autoimmune syndrome (Hirata’s disease): severe hypoglycemic episodes in Graves’ hyperthyroidism patient treated with methimazole. Acta Med Indones. 2005;37 (4 ):214–217.16377854
23. Zhang Q, Chen S-G, Sheng C-J, et al. Insulin autoimmune syndrome: a case associated with HLA-DRB1 polymorphism. J Endocrinol Invest. 2011;34 (7 ):568–569. doi:10.1007/BF03345394 21897108
24. Sahni P, Trivedi N, Omer A. Insulin Autoimmune Syndrome: a rare cause of postprandial hypoglycemia. Endocrinol Diabet Metab Case Rep. 2016;2016 (1 ). doi:10.1530/EDM-16-0064
25. Okazaki-Sakai S, Yoshimoto S, Yagi K, et al. Insulin autoimmune syndrome caused by an adhesive skin patch containing loxoprofen-sodium. Internal Medicine. 2013;52 (21 ):2447–2451. doi:10.2169/internalmedicine.52.0570 24190150
26. Reis MZR, Fernandes VO, Fontenele EGP, et al. Insulin autoimmune syndrome in an occidental woman: a case report and literature review. Archiv Endocrinol Metab. 2018;62 (5 ):566–570. doi:10.20945/2359-3997000000078
27. Deguchi A, Okauchi Y, Suehara S, et al. Insulin autoimmune syndrome in a health supplement user: the effectiveness of cornstarch therapy for treating hypoglycemia. Internal Medicine. 2013;52 (3 ):369–372. doi:10.2169/internalmedicine.52.7844 23370747
28. Izzo V, Greco C, Corradini D, et al. Insulin autoimmune syndrome in an Argentine woman taking α-lipoic acid: a case report and review of the literature. SAGE Open Med Case Rep. 2018;6 :2050313X18819601. doi:10.1177/2050313X18819601
29. Bresciani E, Bussi A, Bazzigaluppi E, et al. Insulin autoimmune syndrome induced by α–lipoic acid in a Caucasian woman: case report. Diabetes Care. 2011;34 (9 ):e146–e146. doi:10.2337/dc11-0600 21868770
30. Lee SH, Oh SH, Chung WY. Insulin autoimmune syndrome induced by methimazole in a Korean girl with Graves’ disease. Ann Pediatr Endocrinol Metab. 2013;18 (1 ):32. doi:10.6065/apem.2013.18.1.32 24904848
31. Gullo D, Magliozzo M, Strano A, et al. Insulin autoimmune syndrome misdiagnosed as an insulinoma in a woman presenting with a pancreatic cystic lesion and taking alpha lipoic acid: a lesson to be learned. Hormones. 2021;20 (3 ):593–595. doi:10.1007/s42000-020-00261-3 33175361
32. Kusano Y. Insulin autoimmune syndrome possibly caused by coenzyme Q10. J Rural Med. 2019;14 (1 ):132–137. doi:10.2185/jrm.2975 31191778
33. Takeuchi Y, Miyamoto T, Kakizawa T, et al. Insulin autoimmune syndrome possibly caused by alpha lipoic acid. Internal Medicine. 2007;46 (5 ):237–239. doi:10.2169/internalmedicine.46.1893 17329919
34. Eguchi Y, Uchigata Y, Yao K, et al. Longitudinal changes of serum insulin concentration and insulin antibody features in persistent insulin autoimmune syndrome (Hirata’s disease). Autoimmunity. 1994;19 (4 ):279–284. doi:10.3109/08916939409071354 7578855
35. Nasu T, Suzuki R, Okamoto Y, et al. Late postprandial hypoglycemia due to bioactive insulin dissociation from autoantibody leading to unconsciousness in a patient with insulin autoimmune syndrome. Internal Medicine. 2011;50 (4 ):339–343. doi:10.2169/internalmedicine.50.4145 21325768
36. Zhao L, He J, Ye S, et al. Long-term follow-up after discharge witnesses a slow decline of insulin autoantibodies in patients with insulin autoimmune syndrome complicated with Grave’s disease: a report of two cases. BMC Endocr Disord. 2023;23 (1 ):177. doi:10.1186/s12902-023-01410-6 37587407
37. Murakami M, Mizuide M, Kashima K, et al. Identification of monoclonal insulin autoantibodies in insulin autoimmune syndrome associated with HLA-DRB1*0401. Hormone Res. 2000;54 (1 ):49–52. doi:10.1159/000063437 11182636
38. Dos Santos TJ, Passone CGB, Ybarra M, et al. Pitfalls in the diagnosis of insulin autoimmune syndrome (Hirata’s disease) in a hypoglycemic child: a case report and review of the literature. J Pediatr Endocrinol Metab. 2019;32 (4 ):421–428. doi:10.1515/jpem-2018-0441 30862762
39. Zeng Y, Li G, Song H. Polyethylene glycol precipitation to avoid misdiagnosis of insulin autoimmune syndrome: a case report and testing pathway in medical laboratories. Ann Lab Med. 2022;42 (5 ):609–611. doi:10.3343/alm.2022.42.5.609 35470281
40. Yamada T, Imai J, Ishigaki Y, et al. Possible relevance of HLA-DRB1*0403 haplotype in insulin autoimmune syndrome induced by α-lipoic acid, used as a dietary supplement. Diabetes Care. 2007;30 (12 ):e131–e131. doi:10.2337/dc07-1636 18042740
41. Moffa S, Improta I, Rocchetti S, et al. Potential cause-effect relationship between insulin autoimmune syndrome and alpha lipoic acid: two case reports. Nutrition. 2019;57 :1–4. doi:10.1016/j.nut.2018.04.010 30086435
42. Balestrieri A, Magnani E, Ragazzini C, et al. Primary insulin autoimmune syndrome in an Italian woman: a case report. Ital J Aerosp Med. 2015;9 (2 ):169–172. doi:10.1016/j.nut.2018.04.010
43. Bae SM, Bae MN, Kim EY, et al. Recurrent insulin autoimmune syndrome caused by α-lipoic acid in type 2 diabetes. Endocrinol Metab. 2013;28 (4 ):326–330. doi:10.3803/enm.2013.28.4.326
44. Schlemper R, Uchigata Y, Frölich M, et al. Recurrent hypoglycaemia caused by the insulin autoimmune syndrome: the first Dutch case. Neth J med. 1996;48 (5 ):188–192. doi:10.1016/0300-2977(95)00085-2 8710037
45. Krysiak R, Okopien B. Recurrent drug-induced insulin autoimmune syndrome in a patient with premature ovarian failure. Eur J Inflammation. 2012;10 (1 ):121–125. doi:10.1016/0300-2977(95)00085-2
46. Rossini A, Cassibba S, Scaranna C, et al. Severe fasting hypoglycemia mimicking insulinoma in three patients with insulin autoimmune syndrome. J Endocrin Soc. 2021;5 (Suppl 1 ):A399. doi:10.1210/jendso/bvab048.812
47. Lohmann T, Kratzsch J, Kellner K, et al. Severe hypoglycemia due to insulin autoimmune syndrome with insulin autoantibodies cross reactive to proinsulin. Exp Clin Endocrinol Diabetes. 2001;109 (04 ):245–248. doi:10.1055/s-2001-15113 11453038
48. Bortolotti D, Mothe-Satney I, Ferrari P, et al. Spontaneous hypoglycaemia in the presence of both anti-insulin antibody and anti-insulin receptor antibody. Diabetes Metabolism. 2006;32 (6 ):598–603. doi:10.1016/S1262-3636(07)70314-2 17296513
49. Cappellani D, Sardella C, Campopiano M, et al. Spontaneously remitting insulin autoimmune syndrome in a patient taking alpha-lipoic acid. Endocrinol Diabet Metab Case Rep. 2018;2018 (1 ). doi:10.1530/edm-18-0122
50. Roh E, Kim YA, Ku EJ, et al. Two cases of methimazole-induced insulin autoimmune syndrome in graves’ disease. Endocrinol Metab. 2013;28 (1 ):55–60. doi:10.3803/EnM.2013.28.1.55
51. Torimoto K, Okada Y, Mori H, et al. Two sisters with Graves’ disease and similar clinical features who tested positive for anti-insulin antibodies after thiamazole treatment. Internal Medicine. 2016;55 (9 ):1125–1129. doi:10.2169/internalmedicine.55.6024 27150866
52. Caudal rigidity, Kenji H, Satsuki N, Niitsuma S, et al. A case of insulin autoimmune syndrome with frequent hypoglycemia. J Japanese Soc Int Med. 2011;100 (8 ):2263–2265. doi:10.2169/naika.100.2263.
53. Uchigata Y, Tokunaga K, Nepom G, et al. Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata’s disease) and monoclonal insulin autoimmune syndrome. Diabetes. 1995;44 (10 ):1227–1232. doi:10.2337/diabetes.44.10.1227 7556962
54. Matsushita S, Takahashi K, Motoki M, et al. Allele specificity of structural requirement for peptides bound to HLA-DRB1*0405 and-DRB1*0406 complexes: implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndrome. J Exp Med. 1994;180 (3 ):873–883. doi:10.1084/jem.180.3.873 8064238
55. Uchigata Y, Hirata Y, Omori Y, et al. Worldwide differences in the incidence of insulin autoimmune syndrome (Hirata disease) with respect to the evolution of HLA-DR4 alleles. Hum Immunol. 2000;61 (2 ):154–157. doi:10.1016/S0198-8859(99)00144-5 10717808
56. Maffei A, Harris PE, Reed EF, et al. Differential expression of insulin-dependent diabetes mellitus-associated HLA-DQA1 alleles in vivo. Eur J Immunol. 1997;27 (6 ):1549–1556. doi:10.1002/eji.1830270634 9209509
57. Palmer JP. Insulin autoantibodies: their role in the pathogenesis of IDDM. Diabetes/Metabolism Rev. 1987;3 (4 ):1005–1015. doi:10.1002/eji.1830270634
58. Uchigata Y, Kuwata S, Tsushima T, et al. Patients with Graves’ disease who developed insulin autoimmune syndrome (Hirata disease) possess HLA-Bw62/Cw4/DR4 carrying DRB1*0406. J Clin Endocrinol Metab. 1993;77 (1 ):249–254. doi:10.1210/jc.77.1.249 8325948
59. Uchigata Y, Hirata Y, Iwamoto Y. Insulin autoimmune syndrome (Hirata disease): epidemiology in Asia, including Japan. Diabetol int. 2010;1 (1 ):21–25. doi:10.1007/s13340-010-0001-z
60. Devendra D, Galloway T, Horton S, et al. The use of phage display to distinguish insulin autoantibody (IAA) from insulin antibody (IA) idiotypes. Diabetologia. 2003;46 (6 ):802–809. doi:10.1007/s00125-003-1107-7 12783163
61. Dahl-Jørgensen K, Torjesen P, Hanssen KF, et al. Increase in insulin antibodies during continuous subcutaneous insulin infusion and multiple-injection therapy in contrast to conventional treatment. Diabetes. 1987;36 (1 ):1–5. doi:10.2337/diabetes.36.1.1 3539672
62. Reeves WG, Barr D, Douglas CA, et al. Factors governing the human immune response to injected insulin. Diabetologia. 1984;26 (4 ):266–271. doi:10.1007/BF00283648 6376234
