TY - JOUR

T1 - CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

AU - Fløyel, Tina

AU - Brorsson, Caroline

AU - Nielsen, Lotte B

AU - Miani, Michela

AU - Bang-Berthelsen, Claus Heiner

AU - Friedrichsen, Martin

AU - Overgaard, Anne Julie

AU - Berchtold, Lukas Adrian

AU - Wiberg, Anna

AU - Poulsen, Pernille

AU - Hansen, Lars

AU - Rosinger, Silke

AU - Boehm, Bernhard O

AU - Ram, Ramesh

AU - Nguyen, Quang

AU - Mehta, Munish

AU - Morahan, Grant

AU - Concannon, Patrick

AU - Bergholdt, Regine

AU - Nielsen, Jens Høiriis

AU - Reinheckel, Thomas

AU - von Herrath, Matthias

AU - Vaag, Allan

AU - Eizirik, Decio Laks

AU - Mortensen, Henrik B

AU - Størling, Joachim

AU - Pociot, Flemming

N1 - CURIS 2014 NEXS 225 PNAS

PY - 2014/7/15

Y1 - 2014/7/15

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1402571111

DO - 10.1073/pnas.1402571111

M3 - Journal article

C2 - 24982147

VL - 111

SP - 10305

EP - 10310

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 28

ER -