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

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; Thomas Reinheckel; Matthias von Herrath; Allan Vaag; Decio Laks Eizirik; Henrik B Mortensen; Joachim Størling; Flemming Pociot

doi:10.1073/pnas.1402571111

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

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 NielsenThomas Reinheckel, Matthias von Herrath, Allan Vaag, Decio Laks Eizirik, Henrik B Mortensen, Joachim Størling, Flemming Pociot

53 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	28
Pages (from-to)	10305-10310
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1402571111
Publication status	Published - 15 Jul 2014

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10.1073/pnas.1402571111

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Fløyel, T., Brorsson, C., Nielsen, L. B., Miani, M., Bang-Berthelsen, C. H., Friedrichsen, M., Overgaard, A. J., Berchtold, L. A., Wiberg, A., Poulsen, P., Hansen, L., Rosinger, S., Boehm, B. O., Ram, R., Nguyen, Q., Mehta, M., Morahan, G., Concannon, P., Bergholdt, R., ... Pociot, F. (2014). CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proceedings of the National Academy of Sciences of the United States of America, 111(28), 10305-10310. https://doi.org/10.1073/pnas.1402571111

CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. / Fløyel, Tina; Brorsson, Caroline; Nielsen, Lotte B et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 28, 15.07.2014, p. 10305-10310.

Research output: Contribution to journal › Journal article › Research › peer-review

Fløyel, T, Brorsson, C, Nielsen, LB, Miani, M, Bang-Berthelsen, CH, Friedrichsen, M, Overgaard, AJ, Berchtold, LA, Wiberg, A, Poulsen, P, Hansen, L, Rosinger, S, Boehm, BO, Ram, R, Nguyen, Q, Mehta, M, Morahan, G, Concannon, P, Bergholdt, R, Nielsen, JH, Reinheckel, T, von Herrath, M, Vaag, A, Eizirik, DL, Mortensen, HB, Størling, J & Pociot, F 2014, 'CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 28, pp. 10305-10310. https://doi.org/10.1073/pnas.1402571111

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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.",

author = "Tina Fl{\o}yel and Caroline Brorsson and Nielsen, {Lotte B} and Michela Miani and Bang-Berthelsen, {Claus Heiner} and Martin Friedrichsen and Overgaard, {Anne Julie} and Berchtold, {Lukas Adrian} and Anna Wiberg and Pernille Poulsen and Lars Hansen and Silke Rosinger and Boehm, {Bernhard O} and Ramesh Ram and Quang Nguyen and Munish Mehta and Grant Morahan and Patrick Concannon and Regine Bergholdt and Nielsen, {Jens H{\o}iriis} and Thomas Reinheckel and {von Herrath}, Matthias and Allan Vaag and Eizirik, {Decio Laks} and Mortensen, {Henrik B} and Joachim St{\o}rling and Flemming Pociot",

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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

SN - 0027-8424

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

IS - 28

ER -

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

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