Recently we identified a family carrying a mutation in the SIRT1 gene, in which affected members display not only the classical features of type 1 diabetes, but also insulin resistance. At the time of diagnosis, a 26-year-old lean man presented signs of type 1 diabetes, including auto-antibodies to ƒÒ-cell antigens and a rapid dependence on insulin. Intriguingly, several of the patients¡¦ family members were also affected. Given the hereditary nature of the phenotype, genomic sequencing was performed in order to identify possible DNA mutations associated with the disease. Analysis of the SIRT1 gene revealed the presence of a T to C exchange in exon 1 of a single allele, corresponding to a Leucine-Proline mutation at residue 107 in the protein. Expression of SIRT1-L107P in the £]-cell line Min6 resulted in NF-ƒÛB hyperacetylation (p65 acetyl K3109) and overproduction of inducible nitric oxide, cytokines, and chemokines, relative to an equal expression of the wild-type protein. These observations underscore the importance of SIRT1 in glucose metabolism in humans and identify a novel role for SIRT1 in auto-immunity. Furthermore these results unveil the first monogenic form of type 1 diabetes with intersecting symptoms of type 2 diabetes. Our data provide evidence that SIRT1 activators may prevent or treat this condition in humans.
