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

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.

A Nonsense Polymorphism (R392X) in TLR5 Protects from Obesity but Predisposes to Diabetes

“…Several quantitative traits (including fat deposition) are nevertheless sexually dimorphic in humans and/or show sexspecific heritablity linked to the autosomes (12), thus separating the sexes or modeling for gender-based differences has been suggested in association studies (12). In fact, an interaction between gender and genetic factors has been described for other genes involved in T2D (13)(14)(15)(16). The reasons underlying these sex-specific associations, including the one we describe for TLR5, remain to be elucidated and might include a role for sex hormones, epistatic effects with X-linked variants, or differences in dietary habits and lifestyle between the sexes that interact with the genetic status.…”

Effects of Sirt1 on DNA methylation and expression of genes affected by dietary restriction

“…Sirt1 overexpression and knockout in the brain of mouse models revealed a role for Sirt1 in downregulating production of β-amyloid plaques in brain-the hallmark of Alzheimer disease . Associations between SNPs in SIRT1 and risk for type 2 diabetes and reduced insulin sensitivity were observed in humans (Dong et al 2011), and in other human subjects, higher Sirt1 mRNA expression in adipose tissue was associated with increased energy expenditure and insulin sensitivity (Rutanen et al 2010).…”

<i>SIRT1</i> gene polymorphisms associated with carcass traits in Luxi cattle

“…Previous studies have suggested that SNPs (single nucleotide polymorphisms) within SIRT1 increase the risk of obesity (De Oliveira et al, 2012), type 2 diabetes, and Parkinson's disease (Schug and Li, 2011;Inamori et al, 2013;Shiota et al, 2012;Civelek et al, 2013;Dong et al, 2011;Rai et al, 2012;Figarska et al, 2013). In adipose tissue, Sirtuin 1 inhibits fat storage and increases lipolysis via the repression of peroxisome proliferator-activated receptor-γ (PPAR-γ ).…”