The FOXO3A rs2802292 G-Allele Associates with Improved Peripheral and Hepatic Insulin Sensitivity and Increased Skeletal Muscle-FOXO3A mRNA Expression in Twins

TY - JOUR

T1 - The FOXO3A rs2802292 G-Allele Associates with Improved Peripheral and Hepatic Insulin Sensitivity and Increased Skeletal Muscle-FOXO3A mRNA Expression in Twins

AU - Banasik, Karina

AU - Ribel-Madsen, Rasmus

AU - Gjesing, Anette P

AU - Wegner, Lise

AU - Andersson, Åsa

AU - Poulsen, Pernille

AU - Borglykke, Anders

AU - Witte, Daniel R

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Vaag, Allan

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Objective: The minor G-allele of FOXO3A rs2802292 has been associated with longevity.Weaimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G-allele. Research Design and Methods: rs2802292 was genotyped in a phenotypically well-characterized population of young and elderly twins (n = 190) and in the population-based Inter99 cohort (n = 5768). All participants underwent oral glucose tolerance tests, and the twin population was additionally examined with an iv glucose tolerance test and a hyperinsulinemic, euglycemic clamp. Basal and insulin-stimulated FOXO3A mRNA expression was assessed in skeletal muscle biopsies from the twin population. Results: In the twin sample, carriers of the minor G-allele of rs2802292 showed reduced fasting plasma insulin [per allele effect (β) = -13% (-24; -1) (95% confidence interval), P = 0.03] and lower incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -14% (-23;-5), P = 0.005]. The G-allele was associated with increased peripheral insulin action [glucose disposal rate clamp, β = 0.85 mg · kg fat-free mass-1 · min-1 (0.049; 1.64), P = 0.04] and lower hepatic insulin resistance index [β = -13% (-25; -1), P = 0.03]. Furthermore, carriers of the G-allele had increased basal FOXO3A mRNA expression in skeletal muscle compared with T-allele carriers [β = 16% (0; 33), P = 0.047]. In the Inter99 sample, we found an association with reduced incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -3% (-5; -0.07), P = 0.04], but this association was not significant after adjustment for body mass index. Conclusion: Our data indicate that the minor G-allele of FOXO3A rs2802292 is associated with enhanced peripheral and hepatic insulin sensitivity in our small twin cohort, which may be mediated through increased FOXO3A mRNA expression, although no major metabolic impact of rs2802292 was found in the large Inter99 cohort.

AB - Objective: The minor G-allele of FOXO3A rs2802292 has been associated with longevity.Weaimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G-allele. Research Design and Methods: rs2802292 was genotyped in a phenotypically well-characterized population of young and elderly twins (n = 190) and in the population-based Inter99 cohort (n = 5768). All participants underwent oral glucose tolerance tests, and the twin population was additionally examined with an iv glucose tolerance test and a hyperinsulinemic, euglycemic clamp. Basal and insulin-stimulated FOXO3A mRNA expression was assessed in skeletal muscle biopsies from the twin population. Results: In the twin sample, carriers of the minor G-allele of rs2802292 showed reduced fasting plasma insulin [per allele effect (β) = -13% (-24; -1) (95% confidence interval), P = 0.03] and lower incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -14% (-23;-5), P = 0.005]. The G-allele was associated with increased peripheral insulin action [glucose disposal rate clamp, β = 0.85 mg · kg fat-free mass-1 · min-1 (0.049; 1.64), P = 0.04] and lower hepatic insulin resistance index [β = -13% (-25; -1), P = 0.03]. Furthermore, carriers of the G-allele had increased basal FOXO3A mRNA expression in skeletal muscle compared with T-allele carriers [β = 16% (0; 33), P = 0.047]. In the Inter99 sample, we found an association with reduced incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -3% (-5; -0.07), P = 0.04], but this association was not significant after adjustment for body mass index. Conclusion: Our data indicate that the minor G-allele of FOXO3A rs2802292 is associated with enhanced peripheral and hepatic insulin sensitivity in our small twin cohort, which may be mediated through increased FOXO3A mRNA expression, although no major metabolic impact of rs2802292 was found in the large Inter99 cohort.

KW - Absorptiometry, Photon

KW - Adult

KW - Aged

KW - Alleles

KW - Area Under Curve

KW - Blood Glucose

KW - Body Composition

KW - Female

KW - Forkhead Transcription Factors

KW - Genotype

KW - Glucose Clamp Technique

KW - Glucose Tolerance Test

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Liver

KW - Male

KW - Middle Aged

KW - Muscle, Skeletal

KW - RNA, Messenger

KW - Twins

U2 - 10.1210/jc.2010-0881

DO - 10.1210/jc.2010-0881

M3 - Journal article

C2 - 20881262

SN - 0021-972X

VL - 96

SP - E119-24

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 1

ER -