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

Tina Flyøel, Caroline Brorsson, Lotte B. Nielsen, Michela Miani, Claus Heiner Bang-Berthelsen, Martin Friedrichsen, Anne Julie Overgaard, Lukas A. 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 H. NielsenThomas Reinheckel, Matthias Von Herrath, Allan Vaag, Decio Laks Eizirik, Henrik B. Mortensen, Joachim Strøling, Flemming Pociot

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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 languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number28
Pages (from-to)10305-10310
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Multidisciplinary
  • EQTL
  • GWAS
  • Polymorphism
  • Remission
  • Susceptibility gene
  • BIM protein
  • cathepsin H
  • dp5 protein
  • gamma interferon
  • ins2 protein
  • insulin
  • interleukin 1beta
  • jnk protein
  • p38 protein
  • protein
  • tumor necrosis factor alpha
  • unclassified drug
  • allele
  • animal cell
  • animal experiment
  • apoptosis
  • article
  • cell function
  • clinical study
  • controlled study
  • disease course
  • female
  • gene control
  • gene linkage disequilibrium
  • gene overexpression
  • genetic transfection
  • genetic variability
  • genotype
  • glucose tolerance
  • glycemic control
  • human
  • human cell
  • human tissue
  • immunohistochemistry
  • in vitro study
  • in vivo study
  • insulin dependent diabetes mellitus
  • insulin release
  • insulin sensitivity
  • lymphoblastoid cell line
  • male
  • mouse
  • nonhuman
  • oncogene c myc
  • pancreas
  • pancreas islet beta cell
  • priority journal
  • protein expression
  • quantitative trait locus
  • real time polymerase chain reaction
  • signal transduction
  • upregulation
  • eQTL
  • polymorphism
  • remission
  • susceptibility gene
  • Adolescent
  • Alleles
  • Animals
  • Apoptosis
  • Cathepsin H
  • Cell Line
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 1
  • Gene Expression Regulation
  • Genotype
  • Humans
  • Insulin-Secreting Cells
  • Mice
  • Mice, Knockout
  • Rats
  • CTSH protein, human
  • Ctsh protein, mouse
  • Ctsh protein, rat
  • Biological Sciences
  • Medical Sciences
  • Diabetes Mellitus, Insulin-Dependent
  • Cytology - Animal
  • Cytology - Human
  • Genetics - General
  • Genetics - Animal
  • Genetics - Human
  • Biochemistry studies - Proteins, peptides and amino acids
  • Enzymes - General and comparative studies: coenzymes
  • Pathology - General
  • Pathology - Diagnostic
  • Pathology - Therapy
  • Metabolism - General metabolism and metabolic pathways
  • Metabolism - Metabolic disorders
  • Endocrine - General
  • Endocrine - Pancreas
  • Pharmacology - Clinical pharmacology
  • Pharmacology - Endocrine system
  • Pediatrics
  • Immunology - Immunopathology, tissue immunology
  • JNK kinase
  • Animals, Chordates, Humans, Mammals, Primates, Vertebrates
  • Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates
  • genetic variation

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