Weyrich Peter, Machicao Fausto, Reinhardt Julia, Machann Jürgen, Schick Fritz, Tschritter Otto, Stefan Norbert, Fritsche Andreas, Häring Hans-Ulrich
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany.
BMC Med Genet. 2008 Nov 12;9:100. doi: 10.1186/1471-2350-9-100.
Sirtuin1 (SIRT1) regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. In humans, SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes.
A total of 1013 non-diabetic Caucasians from the Tuebingen Family Study (TUEF) were genotyped for four tagging SIRT1 SNPs (rs730821, rs12413112, rs7069102, rs2273773) for cross-sectional association analyses with prediabetic traits. SNPs that associated with basal energy expenditure in the TUEF cohort were additionally analyzed in 196 individuals who underwent a controlled lifestyle intervention (Tuebingen Lifestyle Intervention Program; TULIP). Multivariate regressions analyses with adjustment for relevant covariates were performed to detect associations of SIRT1 variants with the changes in anthropometrics, weight, body fat or metabolic characteristics (blood glucose, insulin sensitivity, insulin secretion and liver fat, measured by magnetic resonance techniques) after the 9-month follow-up test in the TULIP study.
Minor allele (X/A) carriers of rs12413112 (G/A) had a significantly lower basal energy expenditure (p = 0.04) and an increased respiratory quotient (p = 0.02). This group (rs12413112: X/A) was resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04), had less increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05) and an attenuated decline in liver fat (GG: -38.4%, X/A: -7.5%; p = 0.01).
SIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic variants may, therefore, represent a relevant determinant for the response rate of individuals undergoing caloric restriction and increased physical activity.
沉默信息调节因子1（SIRT1）在不同的代谢途径中调节基因表达，并在动物模型中介导热量限制的有益作用。在人类中，SIRT1基因变异与空腹能量消耗相关。为了研究SIRT1与人类代谢及热量限制的相关性，我们分析了SIRT1基因变异与2型糖尿病风险较高的白种人进行的一项对照生活方式干预结果之间的关系。
对来自图宾根家族研究（TUEF）的1013名非糖尿病白种人进行基因分型，检测4个标签SIRT1单核苷酸多态性（SNP，rs730821、rs12413112、rs7069102、rs2273773），用于与糖尿病前期特征进行横断面关联分析。在196名接受对照生活方式干预的个体（图宾根生活方式干预项目；TULIP）中，额外分析了在TUEF队列中与基础能量消耗相关的SNP。进行多变量回归分析，并对相关协变量进行调整，以检测在TULIP研究的9个月随访测试后，SIRT1变异与人体测量学指标、体重、体脂或代谢特征（血糖、胰岛素敏感性、胰岛素分泌和肝脏脂肪，通过磁共振技术测量）变化之间的关联。
rs12413112（G/A）的次要等位基因（X/A）携带者基础能量消耗显著降低（p = 0.04），呼吸商增加（p = 0.02）。该组（rs12413112：X/A）对生活方式诱导的空腹血糖改善具有抗性（GG：-2.01%，X/A：0.53%；p = 0.04），胰岛素敏感性增加较少（GG：17.3%，X/A：9.6%；p = 0.05），肝脏脂肪减少减弱（GG：-38.4%，X/A：-7.5%；p = 0.01）。
SIRT1在个体生活方式干预反应中起作用，可能是由于rs12413112 X/A等位基因携带者基础能量消耗降低和脂质氧化率较低。因此，SIRT1基因变异可能是个体对热量限制和增加体力活动反应率的一个相关决定因素。
