SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians

Mol Genet Metab. 2011 Dec;104(4):661-5. doi: 10.1016/j.ymgme.2011.08.001. Epub 2011 Aug 7.

Abstract

Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5' region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P=0.01, OR=1.25 95%CI 1.05-1.48, and P=0.02, OR=1.17 95%CI 1.02-1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N=243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P=0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P=0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Arizona
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Association Studies
  • Genotype
  • Humans
  • Indians, North American
  • Insulin / metabolism*
  • Insulin Secretion
  • Linkage Disequilibrium
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Sequence Analysis, DNA
  • Sex Characteristics
  • Sex Factors
  • Sirtuin 1 / genetics*
  • Young Adult

Substances

  • Insulin
  • SIRT1 protein, human
  • Sirtuin 1