RESUMO
Sir2 NAD-dependent deacetylases connect transcription, metabolism, and aging. Increasing the dosage or activity of Sir2 extends life span in yeast, worms, and flies and promotes fat mobilization and glucose production in mammalian cells. Here we show that increased dosage of Sirt1, the mammalian Sir2 ortholog, in pancreatic beta cells improves glucose tolerance and enhances insulin secretion in response to glucose in beta cell-specific Sirt1-overexpressing (BESTO) transgenic mice. This phenotype is maintained as BESTO mice age. Pancreatic perfusion experiments further demonstrate that Sirt1 enhances insulin secretion in response to glucose and KCl. Microarray analyses of beta cell lines reveal that Sirt1 regulates genes involved in insulin secretion, including uncoupling protein 2 (Ucp2). Isolated BESTO islets also have reduced Ucp2, increased ATP production, and enhanced insulin secretion during glucose and KCl stimulation. These findings establish the importance of Sirt1 in beta cell function in vivo and suggest therapeutic interventions for type 2 diabetes.
Assuntos
Dosagem de Genes , Glucose/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Sirtuínas/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glucagon/metabolismo , Teste de Tolerância a Glucose , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Masculino , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Sirtuína 1 , Sirtuínas/genéticaRESUMO
BACKGROUND: Decreased maternal folate levels are associated with having a child with a neural tube defect (NTD), and periconceptual folic acid supplementation reduces this risk by >50%. Vitamin B(12) (as methylcobalamin) is a cofactor for methionine synthase, an enzyme that plays a key role in folate metabolism. Alterations in vitamin B(12) metabolism may influence the development of NTDs. Low levels of maternal plasma vitamin B(12) and reduced binding of vitamin B(12) by transcobalamin II (TCII) are independent risk factors for NTDs. TCII levels are altered in the amniotic fluid of pregnancies affected by NTDs. Given this evidence, inherited variants in genes involved in vitamin B(12) trafficking such as TCII are candidate NTD risk factors. METHODS: We used case/control and family-based association methods to investigate whether six common polymorphisms in the TCII gene influence NTD risk. TCII genotypes were determined for more than 300 Irish NTD families and a comparable number of Irish controls. RESULTS: Allele and genotype frequencies for each polymorphism did not differ between family members and controls. CONCLUSIONS: These six TCII polymorphisms do not strongly influence NTD risk in the Irish population. The Supplementary Material for this article can be found on the Birth Defects Research (Part A) website: http://www.mrw.interscience.wiley.com/suppmat/1542-0752/suppmat/2005/73/v73.4.swanson.html