CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients
| العنوان: | CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients |
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| المؤلفون: | Grant Morahan, Bernhard O. Boehm, Decio L. Eizirik, Regine Bergholdt, Thomas Reinheckel, Michela Miani, Lars Hansen, Lotte B Nielsen, Anne Julie Overgaard, Flemming Pociot, Quang Nguyen, Claus Heiner Bang-Berthelsen, Caroline Brorsson, Ramesh Ram, Allan Vaag, Patrick Concannon, Anna Wiberg, Henrik B. Mortensen, Martin Friedrichsen, Jens Høiriis Nielsen, Tina Fløyel, Munish Mehta, Joachim Størling, Matthias von Herrath, Pernille Poulsen, Lukas Adrian Berchtold, Silke Rosinger |
| المساهمون: | Lee Kong Chian School of Medicine (LKCMedicine) |
| المصدر: | Proceedings of the National Academy of Sciences. 111:10305-10310 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Cathepsin H, Candidate gene, medicine.medical_specialty, endocrine system diseases, Adolescent, Genotype, medicine.medical_treatment, Apoptosis, Inflammation, Biology, Cell Line, Diabetes Mellitus, Experimental, Proinflammatory cytokine, Mice, Insulin-Secreting Cells, Internal medicine, medicine, Animals, Humans, Child, Alleles, Mice, Knockout, Regulation of gene expression, Type 1 diabetes, Multidisciplinary, Insulin, Biological Sciences, medicine.disease, Rats, Science::Biological sciences [DRNTU], Diabetes Mellitus, Type 1, Endocrinology, Gene Expression Regulation, Child, Preschool, medicine.symptom |
| الوصف: | Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat β-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh−/− mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower β-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of β-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic β-cells, the target cells of the autoimmune assault. Published version |
| وصف الملف: | application/pdf |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::47b1256550b037d800bf3892ecf8f3d9Test https://doi.org/10.1073/pnas.1402571111Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....47b1256550b037d800bf3892ecf8f3d9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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