Wenzlau Janet M, Gu Yong, Michels Aaron, Rewers Marian, Haskins Kathryn, Yu Liping
Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Mail Stop 8333, Aurora, CO 80045, USA.
Barbara Davis Center for Childhood Diabetes, 1775 Aurora Court, Mail Stop B140, Aurora, CO 80045, USA.
Diagnostics (Basel). 2023 Sep 4;13(17):2859. doi: 10.3390/diagnostics13172859.
Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing b cells of the pancreatic islets. Autoantibodies to b cell proteins typically appear in the circulation years before disease onset, and serve as the most accurate biomarkers of T1D risk. Our laboratory has recently discovered novel b cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides (IAPP). T cells from a diabetic mouse model and T1D patients are activated by these hybrid peptides. In this study, we asked whether these hybrid molecules could serve as antigens for autoantibodies in T1D and prediabetic patients. We analyzed sera from T1D patients, prediabetics and healthy age-matched donors. Using a highly sensitive electrochemiluminescence assay, sera were screened for binding to recombinant proinsulin:IAPP probes or truncated derivatives. Our results show that sera from T1D patients contain antibodies that bind larger hybrid proinsulin:IAPP probes, but not proinsulin or insulin, at significantly increased frequencies compared to normal donors. Examination of sera from prediabetic patients confirms titers of antibodies to these hybrid probes in more than 80% of individuals, often before seroconversion. These results suggest that hybrid insulin peptides are common autoantigens in T1D and prediabetic patients, and that antibodies to these peptides may serve as valuable early biomarkers of the disease.
1型糖尿病（T1D）是一种慢性自身免疫性疾病，它会攻击胰腺胰岛中产生胰岛素的β细胞。针对β细胞蛋白质的自身抗体通常在疾病发作前数年就出现在循环系统中，并且是T1D风险最准确的生物标志物。我们实验室最近发现了由杂合胰岛素原：胰岛淀粉样多肽肽（IAPP）组成的新型β细胞蛋白质。来自糖尿病小鼠模型和T1D患者的T细胞会被这些杂合肽激活。在这项研究中，我们询问这些杂合分子是否可以作为T1D和糖尿病前期患者自身抗体的抗原。我们分析了T1D患者、糖尿病前期患者和年龄匹配的健康供体的血清。使用高灵敏度的电化学发光测定法，筛选血清与重组胰岛素原：IAPP探针或截短衍生物的结合情况。我们的结果表明，与正常供体相比，T1D患者的血清中含有能与更大的杂合胰岛素原：IAPP探针结合的抗体，但不能与胰岛素原或胰岛素结合，且频率显著增加。对糖尿病前期患者血清的检测证实，超过80%的个体中存在针对这些杂合探针的抗体滴度，通常在血清转化之前。这些结果表明，杂合胰岛素肽是T1D和糖尿病前期患者常见的自身抗原，并且针对这些肽的抗体可能是该疾病有价值的早期生物标志物。
