Worldwide Differences in the Incidence of Insulin Autoimmune Syndrome (Hirata Disease) with Respect to the Evolution of HLA-DR4 Alleles
Abstract
The relationship between the geographic distribution of susceptibility genes to insulin autoimmune syndrome (IAS) and the incidence of insulin autoimmune syndrome was investigated in order to examine the distribution of the genetic background to susceptibility to certain diseases. The HLA-DR4 allele, DRB1*0406, is associated with increased susceptibility to IAS among Japanese, while the DRB1*0403 and DRB1*0407 alleles are not (the odds ratio of which are 1.6 and 1.1, respectively). The worldwide geographic distribution of the three DR*04 alleles showed that the distribution of DRB1*0403 encompassed that of DRB1*0406 and DRB1*0407. Taken together with the findings that Glu at position 74 in the DRB1 molecule is shared by the three DRB1*04 alleles, there are only a few differences between the DRB1 molecule-nucleotide sequences of DRB1*0403, DRB1*0406 and DRB1*0407, and that all the three DRB1*04 alleles are carried by the same class II haplotype, DQA1*0301/DQB1*0302, it may be considered that DRB1*0403 is the ancestral allele of DRB1*0406 and DRB1*0407. Therefore, populations with a higher prevalence of DRB1*0406 have a higher risk of developing IAS. The extremely low prevalence of IAS among Caucasians can be explained by the low prevalence of DRB1*0406 in this population. This is a good example of the association between the predisposition to risk of development of certain diseases and the evolution of susceptibility genes.
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Insulin autoimmune syndrome (IAS) is the third leading cause of hypoglycemia in Japan and is associated with HLA DRB1*0406, which is more prevalent in Asian populations.
“Insulin autoimmune syndrome (IAS) is the third leading cause of hypoglycemia in Japan and has been associated with the presence of Human Leukocyte Antigen (HLA) DRB1*0406, which is more prevalent in Asian populations [72].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [72]
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Eisenbarth, G. S. (2010) · Diabetes · doi:10.2337/db09-1855 · Cited by 107 · see citing works
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“Although the development of IAS is convinced to be more frequent in Japanese than Caucasians with respect to the evolution of HLA-DR4 alleles [10], it is conceivable that those who carry DRB1*0403 or DRB1*0407 which are more frequent in Caucasians could develop IAS when they take drugs such as alpha lipoic acid even t…”
Self-citationCapece, U., Moffa, S., Improta, I., Giuseppe, G. D., Nista, E. C., CEFALO, C. M. A., Cinti, F., Pontecorvi, A., Gasbarrini, A., Giaccari, A., et al. (2022) · Nutrients · doi:10.3390/nu15010018 · Cited by 96 · see citing works
“HLA- DRB1*0403 is closely related to HLA-DRB1*04:06 and it has been suggested that HLA-DRB1*04:03 is an evolutionary predecessor of HLA-DRB1*04:06 [129].”
BackgroundInsulin Autoimmune Syndrome (Hirata Disease) in European Caucasians Taking α-Lipoic Acid
Gullo, D., Evans, J. L., Sortino, G., Goldfine, I. D., & Vigneri, R. (2014) · Clinical Endocrinology · doi:10.1111/cen.12334 · Cited by 71 · see citing works
Autoantibodies in Human Diabetes
Pietropaolo, M., & Eisenbarth, G. S. (2001) · KARGER eBooks · doi:10.1159/000060541 · Cited by 66 · see citing works
Hypoglycemia due to an insulin binding antibody in a patient with an IgA-κ myeloma.
Halsall, D. J., Mangi, M., Soos, M., Fahie-Wilson, M. N., Wark, G., Mainwaring-Burton, R., & O’Rahilly, S. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0075 · Cited by 56 · see citing works
A Current Update on the Use of Alpha Lipoic Acid in the Management of Type 2 Diabetes Mellitus
Poh, Z., & Goh, K. (2009) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/187153009789839147 · Cited by 38 · see citing works
“Finally, the risk is also higher in East Asians and certain North American natives, among whom the prevalence of HLA alleles that confer predisposition to this syndrome is relatively high [86].”
BackgroundAnnals of the New York Academy of Sciences: Preface
Mehra, N., Kaur, G., Kanga, U., & Tandon, N. (1998) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1998.tb09903.x · Cited by 41
Lipoic acid in animal models and clinical use in diabetic retinopathy
Nebbioso, M., Pranno, F., & Pescosolido, N. (2013) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2013.813483 · Cited by 34 · see citing works
“This disease is relatively common in Japan, where it is the third leading cause of hyperinsulinemic hypoglycemia-probably due to the high prevalence of HLA alleles that confer predisposition to this syndrome [51].”
BackgroundChen, S.-W., Lv, F., Gao, J., Lin, J.-H., Liu, Z.-H., Fu, Y., Liu, Y., Lin, B., Xie, Y., Ren, X., et al. (2007) · Journal of Alternative and Complementary Medicine · doi:10.1089/acm.2006.6126 · Cited by 40
Insulin autoimmune syndrome (Hirata disease): epidemiology in Asia, including Japan
Uchigata, Y., Hirata, Y., & Iwamoto, Y. (2010) · Diabetology International · doi:10.1007/s13340-010-0001-z · Cited by 36
Self-citationGomez Cruz, M. J., Jabbar, M., Saini, N., Eng, D., Crawford, B., Vazquez, D. M., Menon, R., & Chen, M. (2012) · Pediatric Diabetes · doi:10.1111/j.1399-5448.2012.00884.x · Cited by 34 · see citing works
Censi, S., Albergoni, M., Gallo, N., Plebani, M., Boscaro, M., & Betterle, C. (2017) · Clinical Chemistry and Laboratory Medicine · doi:10.1515/cclm-2017-0392 · Cited by 34 · see citing works
“…with antigen DR4 of the HLA [23], but subsequent studies have shown that in Japanese patients it is associated with DRB1*0406 (odds ratio 56.6), and less frequently with DRB1*0403 and 0407 (odds ratios 1.6 and 1.0, respectively), whereas Caucasian patients more frequently carry HLA-DRB1*0403 [24].”
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“We report on the first case of IAS likely induced byALA in aCaucasian patient.”
BackgroundInfluentialGatti, M., Ippoliti, I., Poluzzi, E., Antonazzo, I., Moro, P., Moretti, U., Menniti-Ippolito, F., Mazzanti, G., de Ponti, F., & Raschi, E. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.07.028 · Cited by 31 · see citing works
Kokaraki, G., Daniilidis, M., Yiangou, M., Arsenakis, M., Karyotis, N., Tsilipakou, M., Fleva, A., Gerofotis, A., Karadani, N., & Yovos, J. (2009) · Tissue Antigens · doi:10.1111/j.1399-0039.2008.01182.x · Cited by 31 · see citing works
The double whammy of endogenous insulin antibodies in non-diabetic subjects
Ismail, A. (2008) · Clinical Chemistry and Laboratory Medicine · doi:10.1515/cclm.2008.031 · Cited by 28 · see citing works
Deguchi, A., Okauchi, Y., Suehara, S., & Mineo, I. (2013) · Internal Medicine · doi:10.2169/internalmedicine.52.7844 · Cited by 27 · see citing works
“The DRB1*0406 genotype is more common in East Asian, including Japanese, patients than in Western populations (9) and most likely accounts for the large number of reported cases of IAS in Japan.”
BackgroundNasu, T., Suzuki, R., Okamoto, Y., Miyata, K., Uno, A., Nakao, R., Kawashima, A., Nakao, T., & Kondo, M. (2011) · Internal medicine · doi:10.2169/internalmedicine.50.4145 · Cited by 27
“Most HLA-DR4 positive patients with IAS have HLA-DRB10406, DRB10403, DRB10407 or DR9 alleles (5-8).”
BackgroundMoffa, S., Improta, I., Rocchetti, S., Mezza, T., & Giaccari, A. (2018) · Nutrition · doi:10.1016/j.nut.2018.04.010 · Cited by 25 · see citing works
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Roh, E., Kim, Y. A., Ku, E. J., Bae, J. H., Kim, H. M., Cho, Y. M., Park, Y. J., Park, K. S., Kim, S. Y., & Kwak, S. H. (2013) · Endocrinology and Metabolism · doi:10.3803/enm.2013.28.1.55 · Cited by 24 · see citing works
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“Furthermore, in contrast to the very low prevalence of DRB1*0406 in ethnic groups other than East Asians, DRB1*0403 was found to be widely distributed across various populations (5).”
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Huynh, T. (2020) · Clinical Biochemist Reviews · doi:10.33176/aacb-20-00008 · Cited by 17 · see citing works
Turck, D., Castenmiller, J., de Henauw, S., Hirsch-Ernst, K., Kearney, J., Knutsen, H., Mangelsdorf, I., Mcardle, H., Naska, A., Pélaez, C., et al. (2021) · EFSA journal. European Food Safety Authority · doi:10.2903/j.efsa.2021.6577 · Cited by 14 · see citing works
“(Uchigata et al., 2000)).”
InfluentialPatel, M., Shah, R., Ramteke-Jadhav, S., Patil, V. A., Patel, S., Lila, A., Shah, N., & Bandgar, T. (2020) · Clinical Endocrinology · doi:10.1111/cen.14174 · Cited by 14 · see citing works
Oest, L., Roden, M., & Müssig, K. (2021) · Clinical Endocrinology · doi:10.1111/cen.14634 · Cited by 13 · see citing works
“This is in line with a previous study showing that non‐East Asian populations, compared to East Asian populations, have a lower prevalence of DRB1*0406, assuming that non‐East Asian populations, therefore have a lower incidence of IAS.(45) The frequency of DRB1*0406, the most common HLA allele in East Asian IAS patien…”
BackgroundResultInfluentialMangarov, I., Voynikov, Y., Petkova, V., Iliev, S., Kostadinova, I., Marinov, L., & Nikolova, I. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47060402 · Cited by 12 · see citing works
“Individuals with HLA-DRB1*04:03 and HLA-DRB1*04:06 who consume ALA might have a higher risk of developing IAS [284,286,287].”
InfluentialBalas, A., Vilches, C., Rodriguez, M.-A., Fernandez, B., Martínez, M., de Pablo, R., García-Sánchez, F., & Vicario, J. (2006) · Human Immunology · doi:10.1016/j.humimm.2006.09.002 · Cited by 12
Insulin autoimmune syndrome caused by an adhesive skin patch containing loxoprofen-sodium.
Okazaki-Sakai, S., Yoshimoto, S., Yagi, K., Wakasugi, T., Takeda, Y., & Yamagishi, M. (2013) · Internal medicine · doi:10.2169/internalmedicine.52.0570 · Cited by 12 · see citing works
“(7) reported the case of an IAS patient diagnosed based on the clinical course of a marked increase in the plasma insulin level without a history of insulin injection, a high titer of anti-insulin autoantibodies and the presence of the HLA DRB10406 phenotype, which is strikingly associated with IAS (4).”
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Looi, E., & Lawler, H. M. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14134393 · Cited by 10 · see citing works
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Yao, D., Jiang, J.-F., Zhou, Q., Feng, C., Chu, J.-P., Chen, Z., Yang, J., Xia, J., & Chen, Y. (2024) · Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy · doi:10.2147/dmso.s456466 · Cited by 10 · see citing works
Autoimmune hypoglycemia presenting as seizure one week after surgery.
Vogeser, M., Parhofer, K., Fürst, H., Jacob, K., Brödl, U. C., & Seidel, D. (2001) · Clinical Chemistry · doi:10.1093/clinchem/47.4.795 · Cited by 10 · see citing works
Clopidogrel as a Distinctive Cause of Insulin Autoimmune Syndrome: A Systematic Case Review
Chen, S., Qiang, J.-Q., Zhao, B.-L., Tian, R., Yuan, T., Li, M., Li, M., Gu, Z.-Q., Yang, L., Zhu, H., et al. (2023) · Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy · doi:10.2147/dmso.s418845 · Cited by 9 · see citing works
“This result was inconsistent with the geographic distribution of IAS that more Asian patients were found than Caucasians.”
Long-term follow-up of methimazole-associated insulin autoimmune syndrome: a rare case report
Sun, Y., Tian, L., Du, X., Wang, H., Li, Y.-S., & Li, Y. (2023) · Journal of International Medical Research · doi:10.1177/03000605221122749 · Cited by 9 · see citing works
HLA DRB1*0415: a new possible genetic susceptibility factor for Hirata’s disease
Cambria, V., Beccuti, G., Gatti, F., Bona, C., Maccario, M., & Gasco, V. (2019) · Endocrine · doi:10.1007/s12020-019-02132-3 · Cited by 9 · see citing works
“Indeed, HLA-DRB1*0406 is prevalent in Eastern Asian population while HLA DRB1*0403 is mainly expressed in Caucasians [4].”
BackgroundMurakami, M., Mizuide, M., Kashima, K., Kojima, A., Tomioka, S., Kohama, T., Araki, O., Ogiwara, T., Mizuma, H., & Mori, M. (2001) · Hormone Research in Paediatrics · doi:10.1159/000063437 · Cited by 9 · see citing works
Chen, S., Qiang, J., Zhang, Y., Zhao, B., Tian, R., Yuan, T., Li, M., Li, M., Li, Y., Zhu, H., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1091933 · Cited by 9 · see citing works
“This was validated by higher Asian carrier proportions of DRB1*0406 and DRB1*0403 alleles from our calculation (32).”
BackgroundHan, R.-F., & Jiang, X. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9221 · Cited by 7 · see citing works
“In addition, studies have demonstrated that 84% of patients from Japan carry the HLA‐DRB1*0406 allele (20), while European and American populations primarily carry the HLA‐DRB1*0403 allele (21,22).”
BackgroundSudano, M., Turchi, F., & Sossai, P. (2012) · Clinical Medicine and Diagnostics · doi:10.5923/j.cmd.20120205.02 · Cited by 7 · see citing works
“Since the association of IAS with specific genetic loci is well known[7], we took blood samples for HLA Class II typing.”
MethodInsulin Autoimmune Syndrome: A Case Report Highlighting Diagnostic Pitfalls
Okumura, H., Inaba, S., Kawashima, A., & Shimizu, T. (2024) · Cureus · doi:10.7759/cureus.64130 · Cited by 6 · see citing works
“The higher prevalence of HLA-DRB1*0406 in Asian populations has been suggested as a determinant of the higher incidence of IAS in Japan compared to Western countries [8].”
BackgroundAnalysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha‐lipoic acid
Li, Z.-J., Su, Y.-H., Yi, D., Wu, C.-F., Fang, W.-J., & Wang, C.-J. (2021) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.13427 · Cited by 6 · see citing works
Human serum albumin: Possible cause of insulin autoimmune syndrome
Kamei, S., Kaneto, H., Shigemoto, R., Ejiri, S., Tanabe, A., Tatsumi, F., Kimura, T., Obata, A., Shimoda, M., Tawaramoto, K., et al. (2016) · Journal of Diabetes Investigation · doi:10.1111/jdi.12515 · Cited by 6 · see citing works
A Case of Hirata Syndrome in Pregnancy Induced by α-Lipoic Acid: Diagnosis and Management
Viti, L., Tartaglione, L., Rizzi, A., Perri, A., Mazzotta, F., Carolis, S. D., Vento, G., Lanzone, A., & Pitocco, D. (2025) · AACE endocrinology and diabetes · doi:10.1016/j.aed.2025.03.012 · Cited by 5 · see citing works
Fux-Otta, C., Reynoso, R., Chedraui, P., Estario, P., Estario, M. E., Iraci, G., Ramos, N., Carlo, M. D., Gamba, V., & Sembaj, A. (2024) · Case Reports in Women's Health · doi:10.1016/j.crwh.2024.e00644 · Cited by 5
Exogenous insulin autoimmune syndrome: A case report and review of literature
Xu, L.-L., Chen, J.-X., Cheng, J.-P., & Luo, N. (2024) · World Journal of Clinical Cases · doi:10.12998/wjcc.v12.i9.1691 · Cited by 5 · see citing works
“However, in recent years, some scholars have also reported that HLA-DRB1 * 0415, HLA-DRB1 * 0404, and other genes may also be susceptibility genes for IAS[21,22].”
Zhao, L.-L., He, J.-Y., Ye, S.-D., Chen, C., Zhu, J., Xiao, C.-C., Wu, T., & Liu, Z.-C. (2023) · BMC Endocrine Disorders · doi:10.1186/s12902-023-01410-6 · Cited by 5 · see citing works
“Regarding the genotypic characteristics of IAS patients, the presence of HLA-DR4 alleles, including HLA-DRB1*0403, HLADRB1*0406, and HLA-DRB1*0407, have been previously documented [5].”
BackgroundYu, S., Yang, G.-Q., Dou, J.-T., Wang, B.-A., Gu, W.-J., Lv, Z.-H., Ba, J.-M., Mu, Y., & Lu, J.-M. (2019) · Hormone and Metabolic Research · doi:10.1055/a-1005-0071 · Cited by 5 · see citing works
“IAS is significantly influenced by the ethnic background of the subject, and the low prevalence of IAS among Caucasians could be explained, at least in part, by the low prevalence of DRB1 * 0406 [14].”
BackgroundLichtman, M. A., & Balderman, S. R. (2015) · Rambam Maimonides Medical Journal · doi:10.5041/rmmj.10212 · Cited by 5 · see citing works
Ai, S.-N., Zhang, Z.-Y., & Wu, X.-A. (2024) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2024.111906 · Cited by 4 · see citing works
Complete laboratory diagnosis of Insulin Autoimmune Syndrome
Galván, R., Fernández-Riejos, P., Sánchez-Martinez, P. M., Rodríguez-Chacón, C., Mora, C. S., & León-Justel, A. (2023) · Practical Laboratory Medicine · doi:10.1016/j.plabm.2023.e00320 · Cited by 4 · see citing works
“To some authors, this uneven geographical distribution is partially explained by the more prevalent immunogenic determinants of IAS (HLA-DR4, specifically DRB1*0406) in Asian population [5].”
BackgroundTsuji, T., Iwasaki, S., Makita, K., Furukawa, S., Watanabe-Kusunoki, K., Takeda-Otera, S., Itoh, T., Shimamoto, M., Yamaji, H., Yoshimura, T., et al. (2022) · medRxiv · doi:10.1101/2022.12.02.22282616 · Cited by 4 · see citing works
de Castro, T., Beier, C., Terkamp, C., Oehler, L., Schmidt, B. M. W., Heck, J., Stichtenoth, D., Wedemeyer, H., & Leitolf, H. (2021) · Der Internist · doi:10.1007/s00108-021-01180-0 · Cited by 4 · see citing works
Eine seltene Ursache für eine hyperinsulinämische Hypoglykämie
Gördes, L., Achenbach, P., Roden, M., & Müssig, K. (2017) · Diabetologie und Stoffwechsel · doi:10.1055/s-0043-104820 · Cited by 4
“Diabetes Res Clin Pract 1990; 10: 211–214 [3] Uchigata Y et al.”
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Wu, X.-L., Bao, L., Fan, G.-R., & Wang, S. (2025) · Medicine · doi:10.1097/md.0000000000045456 · Cited by 3 · see citing works
Insulin autoimmune syndrome: not just one but two different diseases with therapeutic implications
Wammer, A. C. P., Nermoen, I., Thorsby, P. M., Bolstad, N., Lima, K., Tran, H. T. T., & Følling, I. (2023) · Endocrinology Diabetes and Metabolism Case Reports · doi:10.1530/edm-23-0032 · Cited by 3 · see citing works
“It is much rarer than polyclonal IAS (11).”
BackgroundInsulin autoimmune syndrome possibly caused by coenzyme Q10
Kusano, Y. (2019) · Journal of Rural Medicine · doi:10.2185/jrm.2975 · Cited by 3
Insulin autoimmune syndrome induced by methimazole in a patient with Graves’ disease
Zhao, W.-C., Jin, J., & Zhang, J.-Z. (2013) · Journal of Endocrinological Investigation · doi:10.1007/bf03347108 · Cited by 3
Recurrent Drug-Induced Insulin Autoimmune Syndrome in a Patient with Premature Ovarian Failure
Krysiak, R., & Okopień, B. (2012) · doi:10.1177/1721727x1201000115 · Cited by 3
Exogenous insulin autoimmune syndrome: a case report and literature review
Gao, Y., Wang, N., Huang, Z.-S., & Bai, N. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1700742 · Cited by 2
“For instance, the presented case showed glycemic variability with alternating hypoglycemia and hyperglycemia, positive IAA, insulin-C-peptide dissociation, and HLA-DR4 susceptibility, ful fi lling the full EIAS diagnostic criteria (1, 9).”
Unmasking Hirata: a mysterious case of Hypoglycemia triggered by immunologic storm
AbuBaha, M., Salameh, H., Abubaha, B., Dahabreh, Y., Marouf, O., Atary, M., Qubaja, H., Mansor, A., & Taha, H. (2026) · Oxford Medical Case Reports · doi:10.1093/omcr/omaf289 · Cited by 2 · see citing works
“…04:06 in Japanese patients , and HLA-DRB104:03 and 104:07 in Caucasians, which allows efficient presentation of insulin peptides to T cells [6], combined with environmental triggers, most notably sulfhydryl-containing compounds such as alpha-lipoic acid, methimazole, carbimazole,…”
Insulin autoimmune syndrome: A case associated with HLA-DRB1 polymorphism
Zhang, Q., Chen, S.-G., Sheng, C., Cheng, X.-Y., Li, H., Sheng, H., Yang, P., Qian, C.-H., Li, W.-J., & Qu, S. (2011) · Journal of Endocrinological Investigation · doi:10.1007/bf03345394 · Cited by 2
Hirata's Disease: Rare Cause of Hypoglycaemia in Caucasian Male.
Žibřidová, K., Havlínová, B., Svobodová, E., Žák, P., Cap, J., & Gabalec, F. (2021) · Acta medica · doi:10.14712/18059694.2021.9 · Cited by 2 · see citing works
“This condition was associated more frequently with particular alleles of HLA antigens – specifically with HLA DRB1*0406 and less frequently with DRB1*0403(8).”
BackgroundInsulin Autoimmune Syndrome Presenting With Recurrent Hypoglycemia and Extreme Hyperinsulinemia
Stanton, A. M., & Stamatiades, G. (2026) · Annals of Internal Medicine: Clinical Cases · doi:10.7326/aimcc.2025.1181 · Cited by 1
Hypoglycemia and Multivitamins.
Revankar, V., Lakhpatia, P., Kelkar, S., Chincholkar, S., Dalal, K., & Kewalramani, K. (2024) · Journal of Association of Physicians of India · doi:10.59556/japi.72.0595 · Cited by 1 · see citing works
Persistent Insulin Autoimmune Syndrome in a Caucasian Male in the Absence of Triggers
Edem, D., Maradana, J., Majety, P., Antony, M., & Menon, L. P. (2024) · Cureus · doi:10.7759/cureus.58270 · Cited by 1 · see citing works
“It is postulated that IAS in East Asians is more drug-induced, has higher rates of self-remission, and is more associated with HLA subtype DRB1*0406, whereas the IAAs are polyclonal [15].”
BackgroundGuney, S. C., Miskioğlu, M., Engurulu, S. F., Çavdar, G., Akcura, C., Alkan, S., Ozdemir, N., & Hekimsoy, Z. (2023) · International Journal of Diabetes in Developing Countries · doi:10.1007/s13410-023-01263-8 · Cited by 1 · see citing works
“IAS is autoimmune in nature, and its connection with human leukocyte antigen DRB1*0406 may be the reason why it is seen more frequently in Japanese populations [3].”
Pop, A., Ruscanu, C., Roman, G., & Pașcanu, I. (2022) · Acta Marisiensis - Seria Medica · doi:10.2478/amma-2022-0011 · Cited by 1 · see citing works
Sheng, X., Ye, X., Shi, X., Lu, L., Lu, A., Xue, Y., Du, Y.-F., & Cheng, J.-L. (2020) · Endokrynologia Polska · doi:10.5603/ep.a2020.0085 · Cited by 1
“The HLA test result was positive for DRB1*0406, which may be the main susceptibility gene in Asian populations, while HLA-DRB1*0403 may be involved in genetic susceptibility to IAS in people of non-Asian background [3].”
BackgroundInsulin autoimmune syndrome associated with the use of thiocolchicoside: A Case report
Acıbucu, F., Timuçin, M., & Acıbucu, D. O. (2016) · Cumhuriyet Tıp Dergisi/Cumhuriyet Üniversitesi Tıp Fakültesi dergisi · doi:10.7197/cmj.v38i1.5000136016 · Cited by 1 · see citing works
Insulin Autoimmune Syndrome in a Patient with Hashimoto's Thyroiditis
Song, I., Han, E., Nan, H.-C., & Ho, C.-C. (2014) · Journal of Korean Thyroid Association · doi:10.11106/cet.2014.7.2.180 · Cited by 1 · see citing works
Hypoglycaemia due to autoimmune insulin syndrome in a 78-year-old Chinese man
Yeung, C.-W., Mak, C., Lam, K., & Tam, S. (2012) · British Journal of Biomedical Science · doi:10.1080/09674845.2012.12002442 · Cited by 1
Baykan, E. K. (2021) · Turkish journal of endocrinology and metobolism · doi:10.25179/tjem.2021-83643 · Cited by 1 · see citing works
Exogenous insulin antibody syndrome presenting with concurrent hypoglycemia and hyperglycemia
Wang, X.-P., Wu, Y., Wu, J., Liu, Y., & Jiang, H. (2026) · Medicine · doi:10.1097/md.0000000000050281
“[3,4] EIAS remains exceptionally uncommon, [5] with only one documented case following insulin therapy after total pancreatectomy.”
Asymptomatic Hirata syndrome with thionamide use – An underdiagnosed entity
Mishra, B., Bhuyan, S. S., Behera, K., & Ray, S. (2026) · Thyroid Research and Practice · doi:10.4103/trp.trp_8_26
A case report and literature review of proton pump inhibitors inducing insulin autoimmune syndrome
Zhang, W., Wen, J., Qi, S., Zhang, G., Yang, X.-B., Zeng, L.-Y., Xu, W., & Deng, H.-R. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1784299
Uchida, T., Awata, T., Nanahara, Y., Suzuki, Y., Matsumura, K., Nagasawa, K., Kobayashi, T., & Mori, Y. (2025) · Diabetology International · doi:10.1007/s13340-025-00850-w
“The significance of the DRB1*04:06-DQB1*03:02 haplotype in the present case, which is strongly associated with insulin autoimmune syndrome (Hirata disease) [42], in relation to ZnT8 positivity may be explained in future studies.”
Optimisation of the Investigation of Antibody-Mediated Dysglycaemia
Church, D. S. (2019) · doi:10.17863/cam.42391
Lee, S. B., Lee, M., You, J.-H., Kim, S. H., & Nam, J. (2017) · doi:10.12701/yujm.2017.34.1.115
“더 많이 보고되고 있다는 점에서 인슐린자가면역증후군과 유전적 소인의 상관성을 확인할 수 있다[5].”
La sindrome di Hirata (stato dell’arte)
Betterle, C., & Presotto, F. (2016) · L Endocrinologo · doi:10.1007/s40619-016-0189-7
“Mentre i pazienti caucasici con SIA correlano prevalentemente con HLA-DRB1∗0403 [17].”
Background[Case report; a case of insulin autoimmune syndrome with frequent hypoglycemic attack].
Ogata, T., Honkura, K., Niitsuma, S., Yamashita, R., Takahashi, M., Kaise, K., & Seino, J. (2011) · Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine · doi:10.2169/naika.100.2263
Glucose Counterregulatory Hormone Response During Hypoglycemia due to Endogenous Hyperinsulinemia
Kim, J. G. (2009) · doi:10.3803/jkes.2009.24.3.162
“1972년 Hirata 등[1]이 처음 보고한 이래로 일본뿐만 아니라 우리나라에서도 내인성 고인슐린혈증에 의한 저혈당 의 흔한 원인으로 알려져 있으며, 일본에서 특히 서양인에 비해 IAS 환자가 많은 이유는 특정 HLA type 인구가 많은 것으로 DRB1*0406과 관련 있다고 하였다[2].”
- Authors
- Uchigata, Y., Hirata, Y., Omori, Y., Iwamoto, Y., & Tokunaga, K.
- Affiliations
- Tokyo Women's Medical University (JP)
- The University of Tokyo (JP)
- Corresponding author
- Uchigata, Yasuko
- Venue
- Human Immunology
- Publisher
- Elsevier BV
- Published
- 2000-02
- Volume
- 61
- Issue
- 2
- Pages
- 154-157
- ISSN
- 0198-8859 (ISSN-L)
- OpenAlex
- W2092127279
- Cited by
- 99
- References
- 0
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 2 · 2014: 2 · 2013: 6 · 2012: 4
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- insulin autoimmune syndrome, HLA-DR4, susceptibility genes, ancestral alleles, disease incidence
- MeSH terms
- Alleles, Diabetes Mellitus, Type 1, Biological Evolution, Humans, Retrospective Studies, Risk Factors, Global Health, HLA-DR4 Antigen, Incidence
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