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

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Tina Fløyel, Caroline Brorsson, Lotte B Nielsen, Michela Miani, Claus Heiner Bang-Berthelsen, Martin Friedrichsen, Anne Julie Overgaard, Lukas Adrian Berchtold, Anna Wiberg, Pernille Poulsen, Lars Hansen, Silke Rosinger, Bernhard O Boehm, Ramesh Ram, Quang Nguyen, Munish Mehta, Grant Morahan, Patrick Concannon, Regine Bergholdt, Jens Høiriis Nielsen & 7 andre Thomas Reinheckel, Matthias von Herrath, Allan Vaag, Decio Laks Eizirik, Henrik B Mortensen, Joachim Størling, Flemming Pociot

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.

OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind111
Udgave nummer28
Sider (fra-til)10305-10310
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 15 jul. 2014

Bibliografisk note

CURIS 2014 NEXS 225
PNAS

ID: 120078432