Identification of a SIRT1 mutation in a family with type 1 diabetes

Cell Metab. 2013 Mar 5;17(3):448-455. doi: 10.1016/j.cmet.2013.02.001.


Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Autoimmunity / genetics*
  • Base Sequence
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Immunoprecipitation
  • Male
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation, Missense / genetics
  • Nitric Oxide / metabolism
  • Pedigree
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Sirtuin 1 / genetics*
  • Switzerland


  • Chemokines
  • Cytokines
  • Nitric Oxide
  • SIRT1 protein, human
  • Sirtuin 1