CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients
| Autor: | 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 |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine) |
| Rok vydání: | 2014 |
| Předmět: |
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 |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:10305-10310 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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