Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetes

Yang, Meiling; Kibbey, Richard G.; Mamula, Mark J.

doi:10.3389/fimmu.2022.1028130

Cited by 7 publications

(3 citation statements)

References 162 publications

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“…Downregulated genes in β-cells are associated with metabolic pathways (GO:0031966, GO:0005747, GO:0005761, GO:0045333). Metabolism is essential for the proper function of pancreatic β-cells, and metabolic changes could result in differences in post-translational modifications that are related to T1D 43 .…”

Section: Resultsmentioning

confidence: 99%

Identification of unique cell type responses in pancreatic islets to stress

Maestas,

Ishahak,

Augsornworawat

et al. 2024

Nat Commun

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Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that β-, α-, and ductal cells have the greatest transcriptional response. We utilize stem cell-derived islets to study islet health through the candidate gene CIB1, which was upregulated under stress in primary human islets. Our findings provide insights into cell type-specific responses to diabetes-associated stress and establish a resource to identify targets for diabetes therapeutics.

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Section: Resultsmentioning

confidence: 99%

Identification of unique cell type responses in pancreatic islets to stress

Maestas,

Ishahak,

Augsornworawat

et al. 2024

Nat Commun

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“…Additionally, a higher prevalence of anti-HERV-K envelope antibodies has been reported in the sera of T1D patients compared to healthy controls [10]. A number of PTMs have been reported to induce T cell immunoreactivity in T1D, including oxidation, deamidation, transglutamination, citrullination, and aberrant secondary structure [8,12,13], all of which may increase binding affinity to disease-associated HLA binding grooves. The predominant T1D antigens for B cells are also established T cell antigens and, in some cases, the antigenic epitopes overlap [14,15].…”

Section: Introductionmentioning

confidence: 99%

Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

Wenzlau,

Gu,

Michels

et al. 2023

Diagnostics

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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.

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“…The ER lumen contains the necessary factors to support this function, including molecular chaperones, ATP, an oxidizing environment and millimolar concentrations of calcium (Ca 2+ ) (19). PTM defects may contribute to autoimmune disorders, if proteins are modified differently in peripheral tissues than in the thymus (20,21). In recent years, ER stress and the adaptive UPR have aroused great interest due to their crucial role in the pathogenesis of multiple diseases including neurodegenerative diseases, cancer, and metabolic disorders.…”

Section: Introductionmentioning

confidence: 99%

NOD mouse dorsal root ganglia display morphological and gene expression defects before and during autoimmune diabetes development

et al. 2023

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IntroductionDuring the development of Autoimmune Diabetes (AD) an autoimmune attack against the Peripheral Nervous System occurs. To gain insight into this topic, analyses of Dorsal Root Ganglia (DRG) from Non-Obese Diabetic (NOD) mice were carried out.MethodsHistopathological analysis by electron and optical microscopy in DRG samples, and mRNA expression analyzes by the microarray technique in DRG and blood leukocyte samples from NOD and C57BL/6 mice were performed.ResultsThe results showed the formation of cytoplasmic vacuoles in DRG cells early in life that could be related to a neurodegenerative process. In view of these results, mRNA expression analyses were conducted to determine the cause and/or the molecules involved in this suspected disorder. The results showed that DRG cells from NOD mice have alterations in the transcription of a wide range of genes, which explain the previously observed alterations. In addition, differences in the transcription genes in white blood cells were also detected.DiscussionTaken together, these results indicate that functional defects are not only seen in beta cells but also in DRG in NOD mice. These results also indicate that these defects are not a consequence of the autoimmune process that takes place in NOD mice and suggest that they may be involved as triggers for its development.

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Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetes

Cited by 7 publications

References 162 publications

Identification of unique cell type responses in pancreatic islets to stress

Identification of unique cell type responses in pancreatic islets to stress

Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

NOD mouse dorsal root ganglia display morphological and gene expression defects before and during autoimmune diabetes development

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