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SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention--the TULIP Study.

Weyrich P, Machicao F, Reinhardt J, Machann J, Schick F, Tschritter O, Stefan N, Fritsche A, Häring HU - BMC Med. Genet. (2008)

Bottom Line: 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).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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany. peter.weyrich@med.uni-tuebingen.de

ABSTRACT

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

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Interaction of rs12413112 SIRT1 genotype with the metabolic responses during a controlled 9-month lifestyle intervention. Rs12413112 SIRT1 genotype (GG): filled circles (●); X/A: opened circles (○). a) Response of plasma glucose determined during the fasting state. b) Response of insulin sensitivity estimated by the formula from Matsuda et al. [12]. c) Response of liver fat content, determined by magnetic resonance spectroscopy. For statistical analyses, all data were log-transformed and adjusted for age, sex, follow-up-time, BMI at both baseline and follow-up and the corresponding variable (plasma glucose, insulin sensitivity or liver fat) measured at baseline. Data are presented as means+SEM (G/G: n = 152, X/A: n = 45 TULIP participants).
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Figure 1: Interaction of rs12413112 SIRT1 genotype with the metabolic responses during a controlled 9-month lifestyle intervention. Rs12413112 SIRT1 genotype (GG): filled circles (●); X/A: opened circles (○). a) Response of plasma glucose determined during the fasting state. b) Response of insulin sensitivity estimated by the formula from Matsuda et al. [12]. c) Response of liver fat content, determined by magnetic resonance spectroscopy. For statistical analyses, all data were log-transformed and adjusted for age, sex, follow-up-time, BMI at both baseline and follow-up and the corresponding variable (plasma glucose, insulin sensitivity or liver fat) measured at baseline. Data are presented as means+SEM (G/G: n = 152, X/A: n = 45 TULIP participants).

Mentions: We did not detect significant associations between rs12413112 genotype and weight (p = 0.37) or BMI (p = 0.38) change. By contrast, minor allele carriers of rs12413112 were resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04, adjusted for age, sex, follow-up time, BMI at baseline and follow-up and fasting plasma glucose at baseline; Fig. 1A), had a weaker increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05, adjusted for age, sex, follow-up time, BMI at baseline and follow-up and insulin sensitivity at baseline; Fig. 1B) and a remarkably attenuated decline in liver fat content (GG: -38.4%, X/A: -7.5%; p = 0.01, adjusted for age, sex, follow-up time, BMI at baseline and follow-up and liver fat content at baseline; Fig. 1C). The effect on liver fat content remained significant even after Bonferroni's correction for multiple testing (2 tests: energy expenditure and obesity), and we had a power of 0.76 to detect this effect. The rs12413112 genotype effects on fasting glucose (0.50) and insulin sensitivity (0.56) change did not show a sufficient statistical power and also did not remain significant after correction for multiple comparisons. The rs7069102 genotype did not significantly associate with longitudinal changes in weight (p = 0.40; dominant model), BMI (p = 0.41), fasting glucose (p = 0.08), insulin sensitivity (p = 0.45) and liver fat (p = 0.09) in the longitudinal TULIP analysis.


SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention--the TULIP Study.

Weyrich P, Machicao F, Reinhardt J, Machann J, Schick F, Tschritter O, Stefan N, Fritsche A, Häring HU - BMC Med. Genet. (2008)

Interaction of rs12413112 SIRT1 genotype with the metabolic responses during a controlled 9-month lifestyle intervention. Rs12413112 SIRT1 genotype (GG): filled circles (●); X/A: opened circles (○). a) Response of plasma glucose determined during the fasting state. b) Response of insulin sensitivity estimated by the formula from Matsuda et al. [12]. c) Response of liver fat content, determined by magnetic resonance spectroscopy. For statistical analyses, all data were log-transformed and adjusted for age, sex, follow-up-time, BMI at both baseline and follow-up and the corresponding variable (plasma glucose, insulin sensitivity or liver fat) measured at baseline. Data are presented as means+SEM (G/G: n = 152, X/A: n = 45 TULIP participants).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2626584&req=5

Figure 1: Interaction of rs12413112 SIRT1 genotype with the metabolic responses during a controlled 9-month lifestyle intervention. Rs12413112 SIRT1 genotype (GG): filled circles (●); X/A: opened circles (○). a) Response of plasma glucose determined during the fasting state. b) Response of insulin sensitivity estimated by the formula from Matsuda et al. [12]. c) Response of liver fat content, determined by magnetic resonance spectroscopy. For statistical analyses, all data were log-transformed and adjusted for age, sex, follow-up-time, BMI at both baseline and follow-up and the corresponding variable (plasma glucose, insulin sensitivity or liver fat) measured at baseline. Data are presented as means+SEM (G/G: n = 152, X/A: n = 45 TULIP participants).
Mentions: We did not detect significant associations between rs12413112 genotype and weight (p = 0.37) or BMI (p = 0.38) change. By contrast, minor allele carriers of rs12413112 were resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04, adjusted for age, sex, follow-up time, BMI at baseline and follow-up and fasting plasma glucose at baseline; Fig. 1A), had a weaker increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05, adjusted for age, sex, follow-up time, BMI at baseline and follow-up and insulin sensitivity at baseline; Fig. 1B) and a remarkably attenuated decline in liver fat content (GG: -38.4%, X/A: -7.5%; p = 0.01, adjusted for age, sex, follow-up time, BMI at baseline and follow-up and liver fat content at baseline; Fig. 1C). The effect on liver fat content remained significant even after Bonferroni's correction for multiple testing (2 tests: energy expenditure and obesity), and we had a power of 0.76 to detect this effect. The rs12413112 genotype effects on fasting glucose (0.50) and insulin sensitivity (0.56) change did not show a sufficient statistical power and also did not remain significant after correction for multiple comparisons. The rs7069102 genotype did not significantly associate with longitudinal changes in weight (p = 0.40; dominant model), BMI (p = 0.41), fasting glucose (p = 0.08), insulin sensitivity (p = 0.45) and liver fat (p = 0.09) in the longitudinal TULIP analysis.

Bottom Line: 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).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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany. peter.weyrich@med.uni-tuebingen.de

ABSTRACT

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Show MeSH
Related in: MedlinePlus