CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10305-10. doi: 10.1073/pnas.1402571111.

Tina Fløyel ¹, Caroline Brorsson ¹, Lotte B Nielsen ², Michela Miani ³, Claus Heiner Bang-Berthelsen ¹, Martin Friedrichsen ⁴, Anne Julie Overgaard ¹, Lukas A Berchtold ¹, Anna Wiberg ⁵, Pernille Poulsen ⁶, Lars Hansen ², Silke Rosinger ⁷, Bernhard O Boehm ⁸, Ramesh Ram ⁹, Quang Nguyen ⁹, Munish Mehta ⁹, Grant Morahan ⁹, Patrick Concannon ¹⁰, Regine Bergholdt ¹¹, Jens H Nielsen ¹², Thomas Reinheckel ¹³, Matthias von Herrath ⁵, Allan Vaag ⁴, Decio Laks Eizirik ³, Henrik B Mortensen ², Joachim Størling ¹, Flemming Pociot ¹⁴

Affiliations

1 Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
2 Department of Pediatrics, Herlev University Hospital, 2730 Herlev, Denmark;
3 Laboratory of Experimental Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium;
4 Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, 2100 Copenhagen, Denmark;
5 Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
6 Global Development, Novo Nordisk A/S, 2860 Søborg, Denmark;
7 Department of Internal Medicine, University of Ulm, 89081 Ulm, Germany;
8 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;
9 Centre for Diabetes Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA 6000, Australia;
10 Genetics Institute, University of Florida, Gainesville, FL 32610;
11 Hagedorn Research Institute, Novo Nordisk, 2820 Gentofte, Denmark;
12 Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; and.
13 Institute of Molecular Medicine and Cell Research and Centre for Biological Signalling Studies, Albert Ludwigs University, 79085 Freiburg, Germany.
14 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.

PMID: 24982147 DOI: 10.1073/pnas.1402571111

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.

Keywords

GWAS; eQTL; polymorphism; remission; susceptibility gene.

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