Search

Objective: To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits.Research Design and Methods: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059).Results: Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10⁻⁶) greater elevation in fasting glucose and a 64% (95% CI: 33-201%) higher risk of developing IFG during 10 years of follow-up.Conclusions: Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant. [ABSTRACT FROM AUTHOR]

Objective: Recent advances in type 2 diabetes genetics have culminated in the discovery and confirmation of multiple risk variants. Two important and largely unanswered questions are whether this information can be used to identify individuals most susceptible to the adverse consequences of sedentary behavior and to predict their response to lifestyle intervention; such evidence would be mechanistically informative and provide a rationale for targeting genetically susceptible subgroups of the population.Research Design and Methods: Gene x physical activity interactions were assessed for 17 polymorphisms in a prospective population-based cohort of initially nondiabetic middle-aged adults. Outcomes were 1) impaired glucose regulation (IGR) versus normal glucose regulation determined with either fasting or 2-h plasma glucose concentrations (n = 16,003), 2) glucose intolerance (in mmol/l, n = 8,860), or 3) incident type 2 diabetes (n = 2,063 events).Results: Tests of gene x physical activity interactions on IGR risk for 3 of the 17 polymorphisms were nominally statistically significant:CDKN2A/B rs10811661 (P(interaction) = 0.015), HNF1B rs4430796 (P(interaction) = 0.026), and PPARG rs1801282 (P(interaction) = 0.04). Consistent interactions were observed for the CDKN2A/B (P(interaction) = 0.013) and HNF1B (P(interaction) = 0.0009) variants on 2-h glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed, and this was for the HNF1B rs4430796 variant (P(interaction) = 0.0004). The interaction effects for HNF1B on IGR risk and incident diabetes remained significant after correction for multiple testing (P(interaction) = 0.015 and 0.0068, respectively).Conclusions: Our observations suggest that the genetic predisposition to hyperglycemia is partially dependent on a person's lifestyle. [ABSTRACT FROM AUTHOR]

Objective: To investigate associations of maternal gestational weight gain and body composition and their impact on offspring body composition and adipocytokine, glucose, and insulin concentrations at age 4 months., Research Design and Methods: This was a prospective study including 31 mother-infant pairs (N = 62). Maternal body composition was assessed using doubly labeled water. Infant body composition was assessed at 4 months using air displacement plethysmography, and venous blood was assayed for glucose, insulin, adiponectin, interleukin-6 (IL-6), and leptin concentrations., Results: Rate of gestational weight gain in midpregnancy was significantly associated with infant fat mass (r = 0.41, P = 0.03); rate of gestational weight in late pregnancy was significantly associated with infant fat-free mass (r = 0.37, P = 0.04). Infant birth weight was also strongly correlated with infant fat-free mass at 4 months (r = 0.63, P = 0.0002). Maternal BMI and maternal fat mass were strongly inversely associated with infant IL-6 concentrations (r = -0.60, P = 0.002 and r = -0.52, P = 0.01, respectively). Infant fat-free mass was inversely related to infant adiponectin concentrations (r = -0.48, P = 0.008) and positively correlated with infant blood glucose adjusted for insulin concentrations (r = 0.42, P = 0.04). No significant associations for leptin were observed., Conclusions: Timing of maternal weight gain differentially impacts body composition of the 4-month-old infant, which in turn appears to affect the infant's glucose and adipokine concentrations.

Objective: We sought to assess the association between maternal gestational physical activity and insulin action and body composition in early infancy., Research Design and Methods: At 28-32 weeks' gestation, pregnant women participating in an observational study in Sweden underwent assessments of height, weight, and body composition, an oral glucose tolerance test, and 10 days of objective physical activity assessment. Thirty mothers and infants returned at 11-19 weeks postpartum. Infants underwent assessments of weight, length, and body composition., Results: Early insulin response was correlated with total physical activity (r = -0.47; P = 0.007). Early insulin response (r = -0.36; P = 0.045) and total physical activity (r = 0.52; P = 0.037) were also correlated with infant fat-free mass. No maternal variable was significantly correlated with infant adiposity., Conclusions: The relationships between maternal physical activity, insulin response, and infant fat-free mass suggest that physical activity during pregnancy may affect metabolic outcomes in the mother and her offspring.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.