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Large-scale genomic studies are beginning to identify genetic predictors of physical activity (PA). For those genetically predisposed to engage in low PA, a behavioral intervention may target a malleable factor that mediates genetic predisposition to low PA (i.e., intermediate phenotype) to mitigate the genetic influences. In a non-randomized exercise promotion pilot study, we test the feasibility of examining affective response to PA (how one feels during PA) as an intermediate phenotype between genetic variation and PA adherence. We hypothesized that three single nucleotide polymorphisms (SNPs; rs8044769 and rs3751812 in FTO; rs6265 in BDNF), identified from a prior systematic review, would be predictive of affective response to PA, and that affective response to PA would mediate the SNP-PA link. Forty five healthy, low-active adults received a 12-week print-based PA promotion program. Baseline affective response to PA was assessed using the Feeling Scale, a single-item measure of affective valence. Moderate to vigorous PA (MVPA) was assessed using accelerometers pre- and post-intervention. We examined the three SNPs in a weighted genetic score. Age, sex, body mass index, race, and neighborhood walkability were potential covariates. Affective response to PA and MVPA at follow-up (minutes/day over 4–7 days) were regressed on variation in SNPs, controlling for covariates. One unit increase in genetic score was associated with a 0.14 higher mean Feeling Scale, though was not statistically significant (p = 0.13). Among individual SNPs, having an additional FTO rs8044769 C allele was associated with a mean Feeling Scale score of 0.53 units higher (p = 0.015), which was statistically significant after applying the corrected p-value of 0.016. The genetic score or individual SNPs were not predictive of MVPA 12 weeks later, thereby mediation analyses were not performed. The preliminary findings demonstrate the promise of the intermediate phenotype approach.

OBJECTIVE Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P < 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.

Type 2 diabetes mellitus (T2DM) has been linked to accelerated biological aging and the accumulation of health deficits. It is unknown whether glycemic control can slow the progression of aging, as expressed by deficit accumulation frailty indices (FIs). We examined the cross-sectional and longitudinal associations that glycemic control, diabetes medication use, and weight change (predictors) had with a FI calculated as the percent of 36 deficits in behavioral, functional, and clinical characteristics (outcome). We drew data from 4177 participants across 8 years of follow-up in the Look AHEAD clinical trial of a multidomain intensive lifestyle intervention in individuals aged 45-76 years with T2DM and overweight or obesity. At baseline, the means(SD) FI(as a percent) for participants grouped as HbA1c< 7%, 7-7.9%, and >8% were: 19.93(6.45), 20.82(6.89), and 21.53(7.27), p< 0.001. Compared with HbA1c>8%, HbA1c< 7% at baseline was associated with 23% less mean 8-year FI progression: 2.42(7.35) vs 3.14(8.02), p< 0.001). Maintaining average HbA1c< 7% vs >8% during follow-up was associated with 47% less 8-year FI progression: 2.05(7.35) vs 3.14(8.02), p< 0.001. With adjustment for HbA1c, sustained weight loss >5% compared with weight gain >5% was associated with an 81% reduction in 8-year FI progression: 1.18(7.25) vs 3.89(8.09), p< 0.001. Use of metformin across >50% of annual visits was associated with a 30% reduction in 8-year progression of FI as compared with less use or no use: 2.25(7.27) vs 3.22(7.90), p=0.002. We conclude that better control of HbA1c, and sustained weight loss (>5%) and metformin use, may slow the accelerated aging associated with T2DM.

Lifestyle intervention, combining calorie restriction and physical activity to induce weight loss, is the frontline treatment for overweight or obesity and well-known to reduce waist circumference (WC). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with WC adjusted for body mass index (WCadjBMI), but it remains unclear whether these SNPs relate to the change in WCadjBMI with lifestyle intervention. Here, we examined whether 59 SNPs previously associated with WCadjBMI in GWAS predicted change in WCadjBMI at one year in 5 lifestyle intervention trials and at 8-10 weeks in two lifestyle intervention trials. Look AHEAD, Diabetes Prevention Program, Diabetes Prevention Study, DIETFITS, and PrediMed Plus contributed one-year data, and NUGENOB and DiOGenes contributed 8-10 week data. Genetic risk scores (GRS) combined associated alleles for each SNP weighted by association with WCadjBMI from Shungin et al, 2015 and meta-analyses with random effects for each trial were used to pool results. Among White participants, higher GRS related to smaller year one change in WCadjBMI in the lifestyle intervention arms, and thus predicted poorer response (p=0.009). With a point estimate of 0.002 (SE=0.001) across trials, for a person with an initial BMI of 34 and a year 1 reduction in BMI of 2.5, each weighted risk allele in the GRS contributed to a 0.06 cm (SE=0.03) higher WC at year 1. With a 25th%ile, median, and 75th%ile GRS of 42.77, 46.75, and 50.48, this translates to 0.46 cm less change in WC between the 25th%ile and 75th%ile. No significant findings emerged in men and women separately, in the African-American subset, for the 8-10 week outcomes, or for the individuals SNPs after correcting for multiple comparisons. These results may help to define the molecular pathways through which lifestyle intervention impacts central adiposity. Disclosure J. Mccaffery: None. T. Hansen: None. T. O. Kilpelainen: None. D. Corella: None. W. H. M. Saris: Advisory Panel; Self; Friesland Campina International, Consultant; Self; Nutrition et sante. T. I. A. Sørensen: None. J. Tuomilehto: None. R. R. Wing: None. T. Agurs-collins: None. K. A. Jablonski: None. Q. Pan: None. A. Astrup: Consultant; Self; Groupe Éthique et Santé, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). M. R. Christiansen: None. L. M. Corso: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. C. D. Gardner: None. Funding WESTAT/National Cancer Institute

Objective To determine the effects of an intensive lifestyle intervention vs. a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years.

The present study examines cognitive function among transcription factor 7-like 2 (TCF7L2) genotype groups in a sample of older adults with cardiovascular disease.We recruited 111 older adults with diagnosed cardiovascular disease from outpatient cardiology clinics. Neuropsychological tests assessed the following domains of cognitive functioning: global function, attention/executive/psychomotor speed, learning and memory, visuospatial/construction, motor, and language. Genotyping of TCF7L2 single nucleotide polymorphism rs7903146 was conducted to determine membership in the TT, CT, or CC genotype groups.Controlling for diabetes status, participants with the TT genotype of TCF7L2 (n= 12) performed worse on tests of attention/executive function/processing speed than those with the CC (n= 46) and CT (n= 53) genotypes, despite no between-group differences in demographic or medical variables.Older cardiovascular disease patients with the TCF7L2 TT genotype performed worse on tests of attention/executive/ psychomotor speed than CC and CT genotype carriers. Further work using neuroimaging and glucose tolerance indices is needed to clarify underlying mechanisms.

Cardiovascular disease has long been associated with poor neurocognitive outcome, with multiple pathophysiological mechanisms that are linked to cognitive impairment in older adults. Although less frequently examined, insulin dysregulation is known to affect vascular function and the associated brain dysfunction in cardiovascular disease. Accordingly, genetic factors tied to insulin regulation may make certain people with cardiovascular disease more susceptible to cognitive dysfunction. Specifically, the calmodulin-binding transcription activator 1 (CAMTA1) genotype, which has been examined as a risk factor for Type 2 diabetes and has been linked to reduced episodic memory performance in healthy young adults, is a potential candidate gene.Blood samples were obtained from 113 older adults with cardiovascular disease who also underwent neuropsychological testing. Carriers of either one or two copies of the T allele of CAMTA1 were categorized into one group (n = 63), whereas non-carriers were categorized into a second group (n = 50).Analyses showed that carriers of the T allele performed more poorly on tests of attention, executive function, and psychomotor speed, but not on tests of memory. Carriers of the T allele also performed more poorly on a measure of global cognitive function.Results indicate that CAMTA1 genotype is associated with cognitive function in older adults with cardiovascular disease, because carriers of the T allele performed more poorly on tests of attention, executive function, and psychomotor speed. Contrary to expectations, there were no differences in memory performance among carriers and non-carriers of the T allele. Given these mixed findings, further studies are necessary to elucidate the association between CAMTA1 and cognition, particularly gene expression and neuroimaging studies.

The effects of duodenal infusions of fats on sham feeding was measured in two strains of rats that differ in their susceptibility to fat-induced obesity. Osborne-Mendel rats are prone to developing obesity on a high-fat diet and preferentially choose fats over carbohydrates in macronutrient selection paradigms. In contrast, S 5B/PL rats are resistant to developing obesity when eating a high-fat diet, and preferentially choose carbohydrates in macronutrient selection paradigms. To test the hypothesis that differences in the satiating potency of fats in the small intestine contributed to these differences between the two strains, we measured the effects of duodenal infusions of Intralipid and sodium linoleate on sham-feeding intakes. The results were consistent with the hypothesis. Duodenal infusions of either of these fats decreased intake significantly more in S5B/PL rats than in Osborne-Mendel rats. Both rat strains sham fed similar amounts when intestinally infused with 0.15 M NaCl. These results suggest that differences in responses to intestinal satiating mechanisms may contribute to the differences in susceptibility to fat-induced obesity in these rat strains.