FT1DM is a rare and often misdiagnosed T1DM. There are few follow-up studies about FT1DM, especially those with a history of more than 5 years.
In this study, 13 patients with FT1DM were followed up for an average of 7.38 years. Patient WBC, AST, K, Cr, GGT, CK and AKP follow-up were significantly lower than those at onset of FT1DM, while TC and HDL were significantly higher than those in FT1DM follow-up, and tended to normalize, indicating that acute metabolic disorders recovered over time.
The results showed that the blood glucose of FT1DM patients was poorer, the function of islets was worse, and HbA1c was significantly higher compared than those at the onset stage of the disease. FT1DM had the characteristics of higher blood glucose and lower HbA1c at the onset stage of the disease. With the prolongation of the course of disease, the increased HbA1c indicated that the control of blood glucose was still unsatisfactory even after insulin treatment in the later stage of the disease. C-P and C-P 120 were significantly lower than those at the onset of FT1DM, indicating that islet beta cells did not completely damaged and they progressively reduced function after acute phase. It is different from our previous knowledge that the islet function of FT1DM patients was almost lost at onset of the disease [1, 4, 6]. This may be related to the short follow-up time and limited case reported.
A short-term follow-up of FT1DM patients by Imagawa [11] et al., showed that there was no difference in HbA1c between FT1DM patients and T1DM patients in 3, 6, and 12 months of follow-up. However, a 5-year follow-up study of FT1DM patients by Murase et al. [12] indicated that C-P120 maintained a low level for 5 years and C-P120 was lower in FT1DM patients than in T1DM patients. Furthermore, Tang et al., reported five FT1DM patients with follow-ups of 52 months [13]. The study showed that the HbA1c level of the F1DM patients increased and the islet function of all patients was worse than at the onset of the disease even after intensive treatment. This is similar to the current study.
Lan Liu et al. showed that HbA1c was elevated after 6 months of follow-up of FT1DM patients and C-P0 and C-P120 were not significantly different from onset of the disease [5]. 5 FT1DM patients were followed up by Lu Zeyuan et al. for 3–26 months indicated that C-P0 and C-P 120 were extremely poor, and there was no difference with the onset of FT1DM[14]. 6 patients were followed up with FT1DM for 9–72 months by Fan Yujuan et al. [15].They found that C-P0 and C-P120 were close to the level at admission, suggesting that pancreatic beta cells were completely and irreversibly destroyed. Huang Huibin et al., reported 2 patients and followed up the function of their pancreatic beta cell at 1 and 7 months respectively [16]. The results showed no improvement in the function of their pancreatic beta cell and the second case showed the function of islet B cells decreased significantly in the later stage. But our study showed followed-up C-P0 and C-P120 were significantly decreased compared with baseline.
At present, the pathogenesis of FT1DM is not completely clear. The pathogenesis of FT1DM may be mediated by many factors, including viral infection, pregnancy, drugs, autoimmune and genetic factors [17]. A study in Japan reported that the onset of the disease was related to genetic background and viral infection in 2012 [18].
In our study, we found that the HSV and Coxsackievirus antibodies were detected in 5 (out of 13 patients) during follow-up of FT1DM. Imagawa et al. reported that the positive rate of enterovirus antibodies was 6/19 (31.58%) at onset of FT1DM [19].Zheng et al. reported that the positive rate of coxsackievirus and mumps virus antibodies in acute stage was 6/20 (30%) [2] and HanafusaT et al. reported that the viral antibodies (Coxsackievirus, Cytomegalovirus, Human Herpes Virus 6) were found in 16.36% patients with acute FT1DM [6]. Thus, it is speculated that the pathogenesis of FT1DM is not caused by the virus itself, but the secondary immune response caused by virus infection.
Studies suggested that enteroviruses and chemokines not only destroyed the islet beta, but also further accelerated the autoimmune response mediated by remaining islet beta cells until all function of islet beta cells was destroyed [20, 21]. Our study shows that there is a high positive rate of viral antibody titer detected in the non-acute stage of FT1DM, which may support the above pathogenesis mechnism.
To explore the role of genetic background in FT1DM, we performed PCT and found the higher frequencies of HLA-DQB1 alleles at DQB1*0201 (50.0%), DQB1*0502 (33.3%) and DQB1*0301 (25.0%), higher frequencies of HLA-DQA1 alleles at DQA1*0104 (55.6%) and DQA1*0103 (44.4%), and higher frequencies of HLA-DRB1 alleles at DRB1*0301 (88.9%) and DRB1*07 (44.4%). These were not identified by the studies reported by Tsutsum or Tanaka et al. [22, 23]. They found higher frequencies of HLA-DQB1 alleles were DQB1*0401 (32.1%), DQB1*0303 (26.3%), DRB1*0405 (32.6%), DRB1*0901 (25.6%), DQA1*0303 (68%) and DQA1*0302 (36%). Xu et al., also reported the higher frequencies of DQB1*0303 (28%) and DRB1*0901 (28%) [24]. The study of 19 FT1DM patients showed the higher frequencices of DQA1-DQB1 genotype were DQA1*03-DQB1*0303 (18.4%) and DQA1*0102-DQB1*0601 (15.8%) by Zheng Chao et al. [2]. Our study has some same genotypes with the Japanese study, which showed that DRBl*0405-DQBl*0401 (32%) and DRB1*0901-DQB1*0303 (25%) were higher genotype frequencies in 255 cases and 414 cases of Japanese FT1DM patients, respectively [6, 22]. DQA1*0303-DQB1*0401 (68%), DQA1*0302-DQB1*0303 (36%), DQA1*0102-DQB1*0604 (14%) and DQA1*0103-DQB1*0601 (9%) were found with higher genotype frequencies in 22 FT1DM patients by Tanaka et al. [23]. However, the frequency of distribution is mostly inconsistent. This may be due to the different races and sample size. The results showed that the mechanism of HLA-II gene in FT1DM was different among different populations.
Imagawa et al. showed that GAD-Ab and INS-Ab were detected in FT1DM patients with low titer and short duration [11], while the ICA-Ab did not appear in FT1DM [4]. In the current study, it was found that GAD-Ab in the FT1DM patients was initially 20% and decreased to 7.7% during follow-up, while INA-Ab increased from 30.8% initially in the early stage of FT1DM to 38.5% during follow-up, and ICA-Ab was detected in 11.1% FT1DM patients during follow-up. These findings are quite surprising contrast with Imagawa’s study, which showed only 4.8% (7/138) patients had GAD-Ab detected in a national survey in 2003 [12]. However, they are consistent with Zheng or Liu’s studies that detected GAD-Ab in 35% and 30%, respectively, of FT1DM patients [2, 5].
The increased INA-Ab was probably due to the use of insulin. These results showed that the persistence of multiple antibodies in FT1DM from the initial stage of onset to several years later might be one of the reasons for the progressive decline and irreversible function of beta cells. In this study, multiple antibodies detected may support the autoimmune involvement in the occurrence of FT1DM [2].
In summary, with the progress of the disease, the function of FT1DM islet beta cells showed a trend of progressively irreversible destruction; various metabolic disorders and stress reactions of FT1DM were alleviated at the later stage of onset. Viral infection (herpes simplex virus, coxsackievirus), virus antibody production, HLA-DQ, DR gene, GAD-Ab and other related antibodies may be involved in the occurrence of FT1DM.