Introduction
Latent autoimmune diabetes in adults (LADA) is type 1 diabetes with an onset in adulthood and a slow progression. In LADA, beta cell failure occurs slowly and insulin treatment is not required within at least 6 months of diagnosis [
1‐
3]. Islet autoantibodies are key markers of islet autoimmunity in LADA and type 1 diabetes [
4]. Five major autoantibody types have been identified in autoimmune diabetes—islet cell autoantibodies (ICA), GAD autoantibodies (GADA), insulin autoantibodies (IAA), protein tyrosine phosphatase autoantibodies (IA-2A) and zinc transporter 8 autoantibodies (ZnT8A). A sixth type, tetraspanin 7 autoantibodies (TSPAN7A), has been identified only recently [
5,
6].
Tetraspanin 7 (TSPAN7) is a member of the transmembrane 4 superfamily, also called the tetraspanin family [
7]. Tetraspanin family proteins are characterised by four transmembrane domains, with one short and one large extracellular loop. TSPAN7 is a glycoprotein located at the cell surface and is expressed in the brain, lung and pancreas [
5]. In the pancreas, TSPAN7 is specifically expressed in the islets [
8]. Previous studies have found that TSPAN7A are present in 19–43% of white individuals with type 1 diabetes [
5,
6,
9,
10]. Unfortunately, its diagnostic value for type 1 diabetes is limited. However, the prevalence and clinical value of TSPAN7A in individuals with LADA have not been reported; in particular, information regarding their association with beta cell function is lacking. Therefore, the major aim of our study was to evaluate the prevalence of TSPAN7A and their potential clinical value in individuals with LADA. Furthermore, we investigated the frequency of TSPAN7A in Chinese individuals with type 1 diabetes because all previous studies have been restricted to white people.
Discussion
TSPAN7A are newly discovered islet autoantibodies in autoimmune diabetes. In this study, we confirmed that TSPAN7A are valid islet autoantibodies for East Asian populations. Using cross-sectional and longitudinal cohort studies, for the first time we demonstrate that TSPAN7A can be a valuable predictor for the progressive loss of beta cell function in individuals with LADA.
TSPAN7, a four-transmembrane glycoprotein, is difficult to properly express with in vitro transcription/translation systems, making it is unsuitable for the radioligand binding assay. In contrast, the LIPS assay offers several advantages for detecting TSPAN7A. First, it is cheaper and more convenient. More importantly, because TSPAN7 is expressed by 293T cells, a mammalian cell line, it may undergo post-translational modifications, such as glycosylation [
18]. Therefore, the LIPS assay was used to test TSPAN7A in our study. Correlation assays showed that TSPAN7A were positively correlated with IA-2A and ZnT8A. One possible explanation is that TSPAN7, IA-2 and ZnT8 are beta cell secretory granule membrane proteins. When beta cells are damaged, those proteins could easily be released and cause seroreaction [
19‐
21].
LADA, an important type of autoimmune diabetes, is defined as a subgroup of individuals who are independent of insulin for the first 6 months after diagnosis but have detectable islet autoantibodies [
22]. We found that the prevalence of TSPAN7A in individuals with LADA was 21.4% (similar to IA-2A and ZnT8A), whereas in individuals with type 2 diabetes the prevalence was 0.5%. Considering the very low frequency of TSPAN7A in individuals with type 2 diabetes, TSPAN7A do not appear to increase the diagnostic rate of LADA.
GADA are the most widely used of the islet autoantibodies for the diagnosis of LADA because positivity for GADA is not affected by the age at diagnosis and GADA are more sensitive than IA-2A or ZnT8A [
22]. However, previous studies have suggested that the majority of GADA, as well as IAA, measured by the radioligand binding assay in single-antibody-positive individuals, are low-affinity [
23,
24], which does not completely reflect the degree of islet autoimmunity [
25]. Several laboratories have also reported that GAD autoantibody affinity is higher in multiple-antibody-positive individuals than in single-antibody-positive individuals [
25,
26], suggesting that the number of islet autoantibody types present could be an indicator of islet autoimmunity. Due to the complicated procedure involved in testing antibody affinity, it is more convenient and feasible to test for more islet autoantibodies than for antibody affinity in clinical practice on a large scale. Interestingly, our study found that the combination of TSPAN7 autoantibody measurement can improve the diagnosis of multiple-antibody-positive individuals with LADA. Therefore, it is meaningful to test for TSPAN7A in individuals with LADA to improve the identification of those with multiple islet autoantibodies.
Multiple islet autoantibodies have been reported to be associated with the rapid loss of beta cell function [
27]. The detection of TSPAN7A in individuals with LADA increased the number of multiple-antibody-positive individuals detected, raising the question of whether TSPAN7A are associated with the poor beta cell function in individuals with LADA. We addressed this question using cross-sectional and follow-up studies. Because individuals with LADA who had FCP <250 pmol/l are unable to achieve glycaemic control without insulin [
28], we divided participants with LADA into two groups, FCP <250 pmol/l and FCP ≥250 pmol/l, in a cross-sectional study. Logistic regression analysis indicated that TSPAN7A were risk factors for lower C-peptide levels. This was confirmed by comparing FCP and PCP levels in single-antibody-positive individuals with LADA who were positive and negative for TSPAN7A. Interestingly, ZnT8A were not associated with beta cell function in another cross-sectional study [
29]. The subsequent cohort study with a 3 year follow-up proved the predictive value of TSPAN7A for beta cell function. Taken together, positivity for TSPAN7A can predict a rapid loss of beta cell function in individuals with LADA.
We also explored the diagnostic value of TSPAN7A for type 1 diabetes in a Chinese population. Although TSPAN7A exist in 26% of Chinese individuals with type 1 diabetes, they largely overlap with other islet autoantibodies and only provide a minor value in type 1 diabetes diagnosis. This is consistent with data reported by Walther et al [
6]. Consistent with our previous studies [
30,
31], the frequencies of GADA, IA-2A and ZnT8A were much lower in Chinese individuals with type 1 diabetes when compared with white individuals with type 1 diabetes. This may be due to differences in genetic background between races. HLA plays an essential role in type 1 diabetes susceptibility and is associated with islet autoantibodies.
HLA-DR3 is associated with GADA, while
HLA-DR4 is strongly associated with IA-2A [
32,
33]. However, the distribution of
HLA-DR3 and
HLA-DR4 is lower in Chinese than in white individuals with type 1 diabetes [
4], which may in part explain the low frequencies of islet autoantibodies in Chinese individuals with type 1 diabetes.
In conclusion, TSPAN7A are valuable in discriminating individuals with poor beta cell function after disease progression in LADA. There are several potential limitations of our study. The number of individuals with LADA in the prospective study was relatively small and the time of follow-up was relatively short. It will be helpful to perform a longer course of study and a larger-scale randomised control trial to confirm our findings.
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