Abstract
Slowly progressive type 1 diabetes mellitus (SPIDDM), solely positive for zinc transporter 8 autoantibody (ZnT8A) is rare, and the factors involved in the single positivity remain largely unknown. Thus, this case report aimed to infer the factors based on a literature review. A 40-year-old female was hospitalized for hyperglycemia. She was diagnosed with sensorineural hearing loss and steroid-induced diabetes at 29 and 30 years of age, respectively. She started insulin therapy at 36 years of age, following oral hypoglycemic medication. Blood test results at admission showed fasting serum C-peptide level of 0.29 ng/mL; single positivity for ZnT8A; mitochondrial DNA 3243 mutation; and human leukocyte antigen-DRB1*09:01-DQB1*03:03 associated with Japanese type 1 diabetes. She was diagnosed with ZnT8A-single-positive SPIDDM accompanying mitochondrial diabetes. Most islet cell antibody (ICA)-positive SPIDDM cases with mitochondrial DNA 3243 mutations are negative for glutamic acid decarboxylase autoantibodies, suggesting ZnT8A-single-positive SPIDDM cases among such cases. Therefore, mitochondrial DNA 3243 mutation may be associated with ZnT8A single positivity in SPIDDM.
Keywords: Islet cell antibody (ICA), Latent autoimmune diabetes in adults, Mitochondrial DNA 3243 mutation, Slowly progressive type 1 diabetes mellitus (SPIDDM), Zinc transporter 8 autoantibody (ZnT8A)
Introduction
Slowly progressive type 1 diabetes mellitus (SPIDDM), sometimes referred to as “latent autoimmune diabetes in adults,” is characterized by positivity for islet-associated autoantibodies and a gradual decline in insulin secretion, progressing to insulin dependency [1]. Glutamic acid decarboxylase autoantibody (GADA) is one of the most sensitive markers for SPIDDM, whereas SPIDDM cases solely positive for zinc transporter 8 autoantibody (ZnT8A) are relatively rare [2, 3], and the factors involved in the positivity remain largely unknown. We recently encountered a case of ZnT8A-single-positive SPIDDM with a mitochondrial DNA 3243 mutation, often detected in patients with mitochondrial diabetes [4]. Thus, we aimed to investigate an association between the mitochondrial DNA 3243 mutation and ZnT8A positivity in SPIDDM.
Case report
A 40-year-old female was admitted to our hospital because of hyperglycemia. At 27-years-old, she was diagnosed with Behcet’s disease and started taking oral prednisolone (initially 20 mg/day; thereafter, the dose was gradually reduced). Two years later, she was diagnosed with bilateral sensorineural hearing loss. At 30-years-old, she first presented with hyperglycemia and subsequently diagnosed with steroid-induced diabetes; she started taking acarbose (150 mg/day). At 31-years-old, she was diagnosed with mesangial proliferative glomerulonephritis based on renal biopsy results for persistent proteinuria. At 36 years of age, she started receiving insulin therapy (8 units/day of insulin aspart) in combination with oral hypoglycemic agents (100 mg/day vildagliptin and 500 mg/day metformin) to control hyperglycemia (Fig. 1). The patient’s serum C-peptide level was 2.13 ng/mL. Although her glycemic control subsequently improved slightly temporarily, her plasma glucose levels worsened at the age of 39; her serum C-peptide level decreased to 0.4 ng/mL after eating (the corresponding plasma glucose level of 251 mg/dL), whereas a GADA test result was negative. Because insulin secretion was markedly decreased, treatment with oral hypoglycemic drugs was temporarily discontinued, and the total daily insulin dose was temporally increased to 44 units (17 units of insulin degludec and 7, 6, and 14 units of insulin aspart before breakfast, lunch, and dinner, respectively). Thereafter, the patient was treated with a total of 32 units/day of insulin in combination with an additional linagliptin (5 mg/day), prednisolone (7 mg/day), and methotrexate (4 mg/week) for Behçet’s disease. However, her glycemic control did not improve, leading to this hospitalization.
Fig. 1.
Clinical time course of the patient. Time courses of glycated hemoglobin (HbA1c) levels, total daily insulin doses, islet-related autoantibodies titer, serum C-peptide levels, and the doses of administered diabetes-related drugs (prednisolone and methotrexate). Due to the patient’s long clinical history, the clinical course illustrated is limited to a period in which the serum C-peptide levels could be followed. *GADA: negative. **GADA, IA-2A, and IAA: all negative, and ZnT8A: 35.6 U/mL. GADA glutamic acid decarboxylase autoantibody, HbA1c glycated hemoglobin, IA-2A insulinoma-associated antigen-2 autoantibody, IAA insulin autoantibody, ZnT8A zinc transporter 8 autoantibody
The patient’s height, weight, and body mass index were 162.9 cm, 46.3 kg, and 17.6 kg/m2, respectively. Laboratory data on admission showed the following results: urine ketones, negative; urine protein, 3+ ; serum creatinine level, 0.37 mg/dL; casual plasma glucose level, 503 mg/dL; and glycated hemoglobin (HbA1c), 14.8%. GADA, insulinoma-associated antigen-2 autoantibody (IA-2A), and insulin autoantibody (IAA) were negative, whereas ZnT8A was positive (35.6 U/mL). Her fasting serum C-peptide and corresponding plasma glucose levels were 0.29 ng/mL and 127 mg/dL, respectively, while the serum C-peptide levels and corresponding plasma glucose levels 120 min after eating were 0.8 ng/mL and 308 mg/dL, respectively. A mitochondrial DNA 3243 mutation was identified in DNA extracted from peripheral blood leukocytes. She carried the human leukocyte antigen (HLA)-class I alleles HLA-A*26:03, -A*31:01, -B*15:01, and -B*55:02, and HLA class II haplotypes HLA-DRB1*09:01-DQA1*03:02-DQB1*03:03, which is associated with the risk of type 1 diabetes in Japan [5], and HLA-DRB1*04:04-DQA1*03:01-DQB1*03:02. Her mother also had hearing loss and died at the age of 50, although no detailed clinical information was available. Therefore, based on the diagnostic criteria for SPIDDM described in the Discussion section [6], she was diagnosed with ZnT8A-single-positive SPIDDM (definite) accompanying mitochondrial diabetes. Her plasma glucose levels improved with 33 units of insulin detemir and 8, 8, and 7 units of insulin aspart before breakfast, lunch, and dinner, respectively. Thereafter, the insulin dose was increased as the patient’s plasma glucose level worsened. Despite this, the patient remained in a markedly hyperglycemic state. Written informed consent was obtained from the present patient.
GADA, IA-2A, and ZnT8A were measured using enzyme-linked immunosorbent assay kits (RSR Ltd., Cardiff, United Kingdom) with cutoff values of 5.0, 0.6, and 15 U/mL, respectively, according to the manufacturer’s instructions. IAA was measured using a radioimmunoassay kit (RSR Ltd.) with a cutoff value of 0.4 U/mL. According to the manufacturer’s product information, all these kits have shown excellent sensitivity and specificity in the performance evaluation program of the Immunology Diabetes Society.
Discussion
Generally, patients with SPIDDM at the time of diabetes diagnosis are in a non-insulin-dependent state, and hyperglycemia can be controlled with diet or oral hypoglycemic agents in the early stage of the disease. Thereafter, they progress to insulin dependency over 6 months to years in typical cases [6]. Thus, the clinical picture of SPIDDM in the early stage is indistinguishable from that of type 2 diabetes, making measurement of islet-associated autoantibodies, i.e., GADA, IA-2A, ZnT8A, IAA, and islet cell antibody (ICA), as the only way to accurately identify SPIDDM. Meanwhile, to the best of our knowledge, the clinical picture and future risk for progression to an insulin-dependent state in each islet-associated antibody-single-positive SPIDDM (probable) patient are largely unknown owing to the low frequency of such patients. For example, Kawasaki et al. reported that 8.6% (30/349), 1.4% (5/349), 1.4% (5/349), and 1.7% (6/349) of patients initially diagnosed with type 2 diabetes were GADA-, IA-2A-, IAA-, and ZnT8A-single-positive SPIDDM patients, respectively [3]. They also demonstrated that 16.7% (5/30) of GADA-single-positive SPIDDM patients required insulin therapy within 9 years of follow-up. Meanwhile, Tanaka et al. reported that 33.3% (2/6) of both GADA- and ICA-negative SPIDDM (probable) patients with IA-2A positivity progressed to an insulin-dependent state at a mean of 107 months [7]. However, owing to their rarity, reports on the clinical course of IAA-single-positive or ZnT8A-single-positive SPIDDM patients are lacking.
Mitochondrial diabetes, a subtype of diabetes accounting for 0.5–2.8% of individuals with diabetes, is typically characterized by a high prevalence of maternal inheritance of diabetes and deafness and short and thin stature, mainly attributed to a mitochondrial DNA 3243 mutation [8]. Approximately 90% of patients with mitochondrial diabetes require insulin therapy owing to the progressive decline of insulin secretion capacity in an average of 3 years after diagnosis [8], resembling the clinical course of SPIDDM.
A previous study reported that 11.1% (3/27) of patients with ICA-positive SPIDDM have a mitochondrial DNA 3243 mutation, suggesting that immune responses to beta cells may be triggered by beta cell damage arising from mitochondrial dysfunction [9]. Thus, several studies investigated islet-associated autoantibodies in cases of mitochondrial diabetes. Kobayashi et al. detected ICA in 41.9% (13/31) of patients diagnosed with mitochondrial diabetes with a mitochondrial DNA 3243 mutation. However, only 6.5% (2/31) of the patients with the mitochondrial DNA 3243 mutation were positive for both ICA and GADA, whereas the remaining 29 patients were negative for GADA. Hence, 84.6% (11/13) of the ICA-positive patients with a mitochondrial DNA 3243 mutation were negative for GADA [10]. Meanwhile, another study did not detect IA-2A in individuals with diabetes with a mitochondrial DNA 3243 mutation, indicating no association between IA-2A and mitochondrial diabetes [11]. Considering that the target antigens for ICA are reportedly GAD [12], IA-2 [13], and ZnT8 [14], some of the ICA-positive and GADA-negative patients with a mitochondrial DNA 3243 mutation reported by Kobayashi et al. [10] might have been positive for ZnT8A. This suggests the possibility of some ZnT8A-single-positive SPIDDM patients among ICA-positive patients with mitochondrial diabetes, necessitating further investigation.
Kobayashi et al. [10] demonstrated that 92.5% (12/13) of ICA-positive patients with mitochondrial diabetes carried HLA-DQA1*03:01. This frequency was significantly higher than that in ICA-negative patients with mitochondrial diabetes [33.3% (6/18)] or control participants [61.1% (55/90)] [10]. This finding suggests that the presence of DQA1*03:01 may be associated with the development of anti-islet autoimmunity triggered by beta cell damage associated with the mitochondrial dysfunction due to the mitochondrial DNA 3243 mutation. Our patient carried both DRB1*09:01-DQA1*03:02-DQB1*03:03, a susceptible HLA class II allele for Japanese type 1 diabetes [5], and DQA1*03:01, which might be associated with the development of ZnT8A in SPIDDM.
In this case, it was difficult to conclude whether the development of SPIDDM, which was positive for ZnT8A alone, was incidental, whether it was due to Bechet’s disease, or whether the use of immunosuppressive drugs influenced the clinical course. To the best of our knowledge, there have been no reports showing a direct relationship between a mitochondrial DNA 3243 mutation and the single positivity of ZnT8A. Zinc plays an important role in mitochondrial function and likely regulates mitochondrial processes in all tissues, including glycolysis, the tricarboxylic acid cycle, and the electron transport system [15–18]. In addition, ZnT8 is reportedly expressed in rodent and human mitochondria and involved in the transport of zinc from the cytoplasm into mitochondria [19, 20]. Meanwhile, in a recent study, an excess of intracellular reactive oxygen species (ROS) was found to enhance the expression of ZnT8 in mitochondria [19]. Considering that a mitochondrial DNA 3243 mutation results in mitochondrial dysfunction and elevated ROS generation [21], the mutation may increase the expression level of ZnT8 in mitochondria via excess ROS. Consequently, when β cells are destroyed, the amount of ZnT8 exposed to the immune system may increase in local islets, inducing the production of ZnT8A in individuals with both mitochondrial DNA 3243 mutation and HLA associated with type 1 diabetes. Further research will be needed to address this hypothesis via an iterative analysis of similar cases in the future.
Behçet’s disease is an autoimmune disease characterized by systemic vasculitis characterized by recurrent oral and genital ulcerations, repeated attacks of uveitis, and erythema nodosum-like skin lesions [22]. T helper (Th) 1 and Th17 cells are involved in its pathogenesis [23, 24], and heat shock proteins have been reported as autoantigens associated with this disease [25]. In addition, environmental factors, such as infections, are thought to trigger disease onset [22]. These findings suggest that the immunological pathogenesis of Behçet’s disease appears to largely overlap with that of type 1 diabetes. However, Behçet’s disease is known to lack the classical clinical features of autoimmunity, such as anti-nuclear antibody positivity, female dominance, and an association with other autoimmune diseases [26]. In fact, as far as we could gather from the PubMed (MEDLINE) and Ichushi-Web (Japan Medical Abstracts Society) databases, using a search period up to June 30, 2024, only three cases of concurrent Behçet’s disease and type 1 diabetes have been reported, all of which originate in Japan, at academic conferences. Thus, detailed clinical information regarding these cases was not available. Moreover, HLAs involved in Behçet’s disease in Japan are reportedly HLA-B*51, particularly -B*51:01 [27], and HLA-A*26:01 [28], both of which are different from the HLAs associated with type 1 diabetes [5]. Therefore, the presence of Behçet’s disease seems to be an unlikely factor in the induction of ZnT8A and the development of type 1 diabetes. By contrast, the HLA class I alleles of the case reported herein were HLA-A*26:03, -A*31:01, -B*15:01, and -B*55:02, all of which were associated with neither Behçet’s disease nor type 1 diabetes [5, 27, 28]. Therefore, it was difficult to speculate to what degree HLA class I alleles were involved in the induction of ZnT8A and the development of SPIDDM in our patient.
In a previous study, the use of cyclosporine-A for one year did not affect the positivity rate of GADA in patients with recent-onset type 1 diabetes [29]. Moreover, another study revealed that the use of triple-immunosuppressive combined therapy (cyclosporine-A, azathioprine, and steroids) also did not affect the positivity rate of neither GADA nor IA-2A in established type 1 diabetes with a median diabetes duration of 29 years in patients who had received kidney transplantation after a median post-transplant duration of four years [30]. These findings suggest that the use of immunosuppressive drugs does not affect the positivity rate of GADA and IA-2A. Thus, although IA-2A was not measured in the patient reported herein prior to their hospitalization, it seems reasonable to assume that the GADA and IA-2A test results would have not changed from positive to negative after the administration of prednisolone and/or methotrexate, but rather that the two autoantibodies may have remained negative. On the other hand, it could not be concluded from our findings whether immunosuppressive drugs, including steroids, affect the positivity rate of ZnT8A, and this would require further investigation.
A limitation of this report is that the concomitant use of prednisolone and methotrexate might have affected the detection of islet-associated autoantibodies. Additionally, although the diagnostic criteria for SPIDDM (definite) were met in our patient, determining whether the decline in insulin secretion was primarily due to islet-associated autoimmunity or beta cell dysfunction or apoptosis associated with the mitochondrial DNA 3243 mutation was difficult. Furthermore, the factors that link autoimmunity against ZnT8 and mitochondrial gene mutations remain to be elucidated. Finally, the points we raised in the discussion earlier cannot be concluded based on a single case; accumulating similar cases may help in understanding the mechanisms for ZnT8A positivity in SPIDDM cases with a mitochondrial DNA 3243 mutation.
In the present case, a diagnosis of slowly progressive type 1 diabetes was achieved based on new diagnostic criteria detailed hereafter. In Japan, SPIDDM is classified as an insulin-dependent state, diagnosed as “definite” cases (SPIDDM (definite)) or an insulin-independent state, diagnosed as “probable” cases (SPIDDM (probable)) [6]. The diagnostic criteria for SPIDDM have been described elsewhere [6]; briefly, the criteria are as follows: (i) positivity for any islet-associated autoantibodies; (ii) the absence of ketosis/ketoacidosis at the diagnosis of diabetes; (iii) no requirement of insulin treatment for at least three months following diabetes diagnosis, after which insulin secretion gradually declines, eventually showing severe endogenous insulin deficiency (fasting serum C-peptide level < 0.6 ng/mL) [6]. If all these criteria are met, the patient can be diagnosed as SPIDDM (definite). However, if criteria (i) and (ii) but not (iii) are met, the patient can be diagnosed as SPIDDM (probable).
In summary, the mitochondrial DNA 3243 mutation may be associated with a single positivity for ZnT8A in SPIDDM cases. If islet-related autoantibodies are measured in patients with mitochondrial diabetes, patients with ZnT8A-single-positive SPIDDM may be efficiently identified, leading to further clarification of their clinical picture.
Acknowledgements
Personal Thanks: We would like to thank Honyaku Center, Inc. for English language editing.
No specific funding or grant was received for this work.
Author contributions
E.M. and A.Sa. drafted the manuscript. A.Sa. and A.H. managed the patient health. Y.O. and A.Sh. reviewed the manuscript and contributed to the discussions. Y.O. is the guarantor of this work and, as such, has full access to all data used in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
Data availability
The data used in the present study are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
A.Sh. has received lecture fees from Novo Nordisk Pharma Inc., Sanofi K.K., and Eli Lilly Japan K.K. The other authors declare no conflicts of interest.
Human or animal rights
This study was conducted according to the principles of the Declaration of Helsinki. This article does not contain any studies with human or animal subjects performed by any of the authors. The patient’s identity is protected. Written informed consent was obtained from all the patients.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Erika Mitsui and Atsushi Satomura contributed equally to this work.
References
- 1.Kobayashi T, Tamemoto K, Nakanishi K, Kato N, Okubo M, Kajio H, et al. Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care. 1993;16(5):780–8. 10.2337/diacare.16.5.780. [DOI] [PubMed] [Google Scholar]
- 2.Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: action LADA 7. Diabetes Care. 2013;36(4):908–13. 10.2337/dc12-0931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kawasaki E, Nakamura K, Kuriya G, Satoh T, Kuwahara H, Kobayashi M, et al. Autoantibodies to insulin, insulinoma-associated antigen-2, and zinc transporter 8 improve the prediction of early insulin requirement in adult-onset autoimmune diabetes. J Clin Endocrinol Metab. 2010;95(2):707–13. 10.1210/jc.2009-1733. [DOI] [PubMed] [Google Scholar]
- 4.van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992;1(5):368–71. 10.1038/ng0892-368. [DOI] [PubMed] [Google Scholar]
- 5.Kawabata Y, Ikegami H, Awata T, Imagawa A, Maruyama T, Kawasaki E, et al. Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset. Diabetologia. 2009;52(12):2513–21. 10.1007/s00125-009-1539-9. [DOI] [PubMed] [Google Scholar]
- 6.Shimada A, Kawasaki E, Abiru N, Awata T, Oikawa Y, Osawa H, et al. New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): report from Committee on Type 1 Diabetes in Japan Diabetes Society (English version). Diabetol Int. 2024;15(1):1–4. 10.1007/s13340-023-00679-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Tanaka S, Okubo M, Nagasawa K, Takizawa S, Ichijo M, Ichijo S, et al. Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM). Diabetol Int. 2016;7(1):42–52. 10.1007/s13340-015-0211-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Suzuki S, Oka Y, Kadowaki T, Kanatsuka A, Kuzuya T, Kobayashi M, et al. Clinical features of diabetes mellitus with the mitochondrial DNA 3243 (A–G) mutation in Japanese: maternal inheritance and mitochondria-related complications. Diabetes Res Clin Pract. 2003;59(3):207–17. 10.1016/s0168-8227(02)00246-2. [DOI] [PubMed] [Google Scholar]
- 9.Oka Y, Katagiri H, Yazaki Y, Murase T, Kobayashi T. Mitochondrial gene mutation in islet-cell-antibody-positive patients who were initially non-insulin-dependent diabetics. Lancet. 1993;342(8870):527–8. 10.1016/0140-6736(93)91649-7. [DOI] [PubMed] [Google Scholar]
- 10.Kobayashi T, Oka Y, Katagiri H, Falorni A, Kasuga A, Takei I, et al. Association between HLA and islet cell antibodies in diabetic patients with a mitochondrial DNA mutation at base pair 3243. Diabetologia. 1996;39(10):1196–200. 10.1007/BF02658506. [DOI] [PubMed] [Google Scholar]
- 11.Taniyama M, Kasuga A, Suzuki Y, Ozawa Y, Handa M, Kobayashi A, et al. Absence of antibodies to ICA512/IA-2 in NIDDM patients with the mitochondrial DNA bp 3243 mutation. Diabetes Care. 1997;20(5):905–6. 10.2337/diacare.20.5.905. [DOI] [PubMed] [Google Scholar]
- 12.Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990;347(6289):151–6. 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
- 13.Lan MS, Lu J, Goto Y, Notkins AL. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol. 1994;13(5):505–14. 10.1089/dna.1994.13.505. [DOI] [PubMed] [Google Scholar]
- 14.Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007;104(43):17040–5. 10.1073/pnas.0705894104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Rofe AM, Philcox JC, Coyle P. Activation of glycolysis by zinc is diminished in hepatocytes from metallothionein-null mice. Biol Trace Elem Res. 2000;75(1–3):87–97. 10.1385/BTER:75:1-3:87. [DOI] [PubMed] [Google Scholar]
- 16.Tamaki N, Ikeda T, Funatsuka A. Zinc as activating cation for muscle glycolysis. J Nutr Sci Vitaminol. 1983;29(6):655–62. 10.3177/jnsv.29.655. [DOI] [PubMed] [Google Scholar]
- 17.Sun Q, Zhong W, Zhang W, Zhou Z. Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency. Am J Physiol Gastrointest Liver Physiol. 2016;310(3):G205–14. 10.1152/ajpgi.00270.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Audano M, Pedretti S, Cermenati G, Brioschi E, Diaferia GR, Ghisletti S, et al. Zc3h10 is a novel mitochondrial regulator. EMBO Rep. 2018. 10.15252/embr.201745531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Olgar Y, Tuncay E, Turan B. Mitochondria-targeting antioxidant provides cardioprotection through regulation of cytosolic and mitochondrial Zn(2+) levels with re-distribution of Zn(2+)-transporters in aged rat cardiomyocytes. Int J Mol Sci. 2019. 10.3390/ijms20153783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zhang X, Guan T, Yang B, Chi Z, Wang ZY, Gu HF. A novel role for zinc transporter 8 in the facilitation of zinc accumulation and regulation of testosterone synthesis in Leydig cells of human and mouse testicles. Metabolism. 2018;88:40–50. 10.1016/j.metabol.2018.09.002. [DOI] [PubMed] [Google Scholar]
- 21.Chung CY, Singh K, Kotiadis VN, Valdebenito GE, Ahn JH, Topley E, et al. Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation. Nat Commun. 2021;12(1):6409. 10.1038/s41467-021-26746-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sakane T, Takeno M, Suzuki N, Inaba G. Behcet’s disease. N Engl J Med. 1999;341(17):1284–91. 10.1056/NEJM199910213411707. [DOI] [PubMed] [Google Scholar]
- 23.Nagafuchi H, Takeno M, Yoshikawa H, Kurokawa MS, Nara K, Takada E, et al. Excessive expression of Txk, a member of the Tec family of tyrosine kinases, contributes to excessive Th1 cytokine production by T lymphocytes in patients with Behcet’s disease. Clin Exp Immunol. 2005;139(2):363–70. 10.1111/j.1365-2249.2004.02688.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Shimizu J, Takai K, Takada E, Fujiwara N, Arimitsu N, Ueda Y, et al. Possible association of proinflammatory cytokines including IL1beta and TNFalpha with enhanced Th17 cell differentiation in patients with Behcet’s disease. Clin Rheumatol. 2016;35(7):1857–63. 10.1007/s10067-015-2966-2. [DOI] [PubMed] [Google Scholar]
- 25.Kirectepe Aydin AK, Hatemi G. Heat shock proteins in Behcet syndrome. Balkan Med J. 2023;40(5):314–23. 10.4274/balkanmedj.galenos.2023.2023-6-76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yazici H. The place of Behcet’s syndrome among the autoimmune diseases. Int Rev Immunol. 1997;14(1):1–10. 10.3109/08830189709116840. [DOI] [PubMed] [Google Scholar]
- 27.de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behcet’s disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 2009;61(10):1287–96. 10.1002/art.24642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Meguro A, Inoko H, Ota M, Katsuyama Y, Oka A, Okada E, et al. Genetics of Behcet disease inside and outside the MHC. Ann Rheum Dis. 2010;69(4):747–54. 10.1136/ard.2009.108571. [DOI] [PubMed] [Google Scholar]
- 29.Petersen JS, Dyrberg T, Karlsen AE, Molvig J, Michelsen B, Nerup J, et al. Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of beta-cell function and remission in recent-onset IDDM after cyclosporin treatment. The Canadian-European Randomized Control Trial Group. Diabetes. 1994;43(11):1291–6. 10.2337/diab.43.11.1291. [DOI] [PubMed] [Google Scholar]
- 30.Jaeger C, Brendel MD, Eckhard M, Bretzel RG. Islet autoantibodies as potential markers for disease recurrence in clinical islet transplantation. Exp Clin Endocrinol Diabetes. 2000;108(5):328–33. 10.1055/s-2000-8125. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in the present study are available from the corresponding author upon reasonable request.