title: CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients.
abstract: 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.
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors: Tina
authors: T
authors: Fløyel
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors: Caroline
authors: C
authors: Brorsson
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;
authors: Lotte B
authors: LB
authors: Nielsen
authors: Laboratory of Experimental Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium;
authors: Michela
authors: M
authors: Miani
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors: Claus Heiner
authors: CH
authors: Bang-Berthelsen
authors: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark;
authors: Martin
authors: M
authors: Friedrichsen
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors: Anne Julie
authors: AJ
authors: Overgaard
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors: Lukas A
authors: LA
authors: Berchtold
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors: Anna
authors: A
authors: Wiberg
authors: Global Development, Novo Nordisk A/S, 2860 Søborg, Denmark;
authors: Pernille
authors: P
authors: Poulsen
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;
authors: Lars
authors: L
authors: Hansen
authors: Department of Internal Medicine, University of Ulm, 89081 Ulm, Germany;
authors: Silke
authors: S
authors: Rosinger
authors: Department of Internal Medicine, University of Ulm, 89081 Ulm, Germany;Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore 637553;
authors: Bernhard O
authors: BO
authors: Boehm
authors: Centre for Diabetes Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA 6000, Australia;
authors: Ramesh
authors: R
authors: Ram
authors: Centre for Diabetes Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA 6000, Australia;
authors: Quang
authors: Q
authors: Nguyen
authors: Centre for Diabetes Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA 6000, Australia;
authors: Munish
authors: M
authors: Mehta
authors: Centre for Diabetes Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA 6000, Australia;
authors: Grant
authors: G
authors: Morahan
authors: Genetics Institute, University of Florida, Gainesville, FL 32610;
authors: Patrick
authors: P
authors: Concannon
authors: Hagedorn Research Institute, Novo Nordisk, 2820 Gentofte, Denmark;
authors: Regine
authors: R
authors: Bergholdt
authors: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; and.
authors: Jens H
authors: JH
authors: Nielsen
authors: Institute of Molecular Medicine and Cell Research and Centre for Biological Signalling Studies, Albert Ludwigs University, 79085 Freiburg, Germany.
authors: Thomas
authors: T
authors: Reinheckel
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors: Matthias
authors: M
authors: von Herrath
authors: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark;
authors: Allan
authors: A
authors: Vaag
authors: Laboratory of Experimental Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium;
authors: Decio Laks
authors: DL
authors: Eizirik
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;
authors: Henrik B
authors: HB
authors: Mortensen
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors: Joachim
authors: J
authors: Størling
authors: Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark,Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; and flemming.pociot.01@regionh.dk.
authors: Flemming
authors: F
authors: Pociot
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D056655:Cathepsin H / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051381:Rats
chemical_list: C534126:CTSH protein, human; D056655:Cathepsin H; C534127:Ctsh protein, mouse; C534128:Ctsh protein, rat
keywords: GWAS; eQTL; polymorphism; remission; susceptibility gene