Allison L. Kuipers

Effects of weight loss and insulin reduction on arterial stiffness in the SAVE trial.

BackgroundChronic arterial stiffness contributes to the negative health effects of obesity and insulin resistance, which include hypertension, stroke, and increased cardiovascular and all-cause mortality. Weight loss and improved insulin sensitivity are individually associated with improved central arterial stiffness; however, their combined effects on arterial stiffness are poorly understood. The purpose of this study was to determine how insulin levels modify the improvements in arterial stiffness seen with weight loss in overweight and obese young adults.MethodsTo assess the effects of weight loss and decreased fasting insulin on vascular stiffness, we studied 339 participants in the Slow the Adverse Effects of Vascular Aging (SAVE) trial. At study entry, the participants were aged 20–45, normotensive, non-diabetic, and had a body-mass index of 25–39.9 kg/m2. Measures of pulse wave velocity (PWV) in the central (carotid-femoral (cf PWV)), peripheral (femoral-ankle (fa PWV)), and mixed (brachial-ankle (ba PWV)) vascular beds were collected at baseline and 6 months. The effects of 6-month change in weight and insulin on measures of PWV were estimated using multivariate regression.ResultsAfter adjustment for baseline risk factors and change in systolic blood pressure, 6-month weight loss and 6-month change in fasting insulin independently predicted improvement in ba PWV but not fa PWV or cf PWV. There was a significant interaction between 6-month weight change and change in fasting insulin when predicting changes in ba PWV (p < 0.001). Individuals experiencing both weight loss and insulin reductions showed the greatest improvement in ba PWV.ConclusionsYoung adults with excess weight who both lower their insulin levels and lose weight see the greatest improvement in vascular stiffness. This improvement in vascular stiffness with weight loss and insulin declines may occur throughout the vasculature and may not be limited to individual vascular beds.Trial registrationNCT00366990

Greater Skeletal Muscle Fat Infiltration Is Associated With Higher All-Cause and Cardiovascular Mortality in Older Men

BACKGROUND Skeletal muscle fat infiltration (myosteatosis) increases with aging, and has been associated with poor metabolic and musculoskeletal health, independent of overall adiposity. Studies examining the relationship of myosteatosis and mortality among older individuals recruited without regard to their health status are sparse. METHODS We evaluated the association of peripheral computed tomography measured calf myosteatosis (intermuscular fat and muscle density as a measure of intramuscular fat) with mortality in 1,063 community-dwelling older men. Cox proportional hazards models were used to estimate the risk of mortality independent of potential confounders. RESULTS During a mean follow-up of 7.2 years, 317 participants died. After adjustment for potential covariates and additional adjustment for whole body fat, lower skeletal muscle density was associated with increased all-cause mortality and cardiovascular disease mortality (hazard ratio [95% confidence interval] per standard deviation lower skeletal muscle density: 1.24 [1.09-1.41] and 1.46 [1.15-1.86], respectively), and to some extent with noncardiovascular disease mortality (1.18 [1.0-1.38], p = .053). After adjusting for trunk fat in a separate multivariable model, the association between skeletal muscle density and all-cause and cardiovascular disease mortality remained significant (both p < .01), while its association with noncardiovascular disease mortality became of borderline significance (p = .085). No other measures of adiposity, including calf intermuscular fat, were associated with mortality. CONCLUSION Our study reveals an independent association between skeletal muscle density and mortality in a community-based sample of older, predominantly Caucasian men. Further studies are needed to establish if this association is independent of other ectopic fat depots, and to identify the biological mechanisms underlying this relationship.

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

African ancestry individuals have a more favorable lipoprotein profile than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 Afro-Caribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21–113, 3,426 relative pairs). All lipoproteins were significantly heritable (P < 0.05). Gender-specific analysis showed that heritability for triglycerides was much higher (P < 0.01) in women than in men (women, 0.62 ± 0.18, P < 0.01; men, 0.13 ± 0.17, P > 0.10), but the heritability for LDL cholesterol (LDL-C) was higher (P < 0.05) in men than in women (men, 0.79 ± 0.21, P < 0.01; women, 0.39 ± 0.12, P < 0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed significant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9) and LDL-C in both the family study and in the replication study. Our findings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals. Future sequencing and functional studies of these loci may advance our understanding of genetic factors contributing to LDL-C in African ancestry populations.

Association of Lipopolysaccharide-Binding Protein With Aging-Related Adiposity Change and Prediabetes Among African Ancestry Men

OBJECTIVE Cross-sectional studies suggest that lipopolysaccharide-binding protein (LBP) may be associated with obesity and metabolic disorders. However, prospective studies examining LBP are lacking. This prospective study investigated the association between LBP and metabolic abnormalities in 580 African ancestry men (mean age, 59.1 ± 10.5 years). RESEARCH DESIGN AND METHODS We measured fasting serum LBP at baseline. Changes in adiposity and glucose homeostasis as well as case subjects with new type 2 diabetes and impaired fasting glucose (IFG) were assessed at a follow-up visit ˜6 years later. Baseline LBP values were tested across quartiles for linear trend with metabolic measures. Multivariable logistic regression was used to determine the odds of new cases of IFG or diabetes per 1-SD greater baseline LBP. RESULTS LBP was significantly associated with baseline BMI, waist circumference, whole-body and trunk fat, skeletal muscle density, fasting serum insulin, and HOMA-insulin resistance (IR) (all P < 0.01). Greater baseline LBP was significantly associated with longitudinal increases in the percentage of trunk fat (P = 0.025) and HOMA-IR (P = 0.034), but only borderline so with a decrease in skeletal muscle density (P = 0.057). In men with normal glucose, baseline LBP was associated with increased odds of having IFG at follow-up after adjustment for age, baseline trunk fat, and lifestyle factors (odds ratio per 1-SD LBP: 1.51; 95% CI 1.02–2.21). This association was attenuated after additional adjustment for change in trunk fat (P = 0.067). CONCLUSIONS LBP may be a marker of prediabetes. Some of this association appears to be mediated through increased central and ectopic skeletal muscle adiposity.

Markers of Inflammation Are Heritable and Associated with Subcutaneous and Ectopic Skeletal Muscle Adiposity in African Ancestry Families

UNLABELLED Abstract Background: Skeletal muscle adipose tissue (AT) infiltration, or myosteatosis, appears to be greater in African compared with European ancestry individuals and may play a role in type 2 diabetes mellitus (T2DM), a disease that disproportionally affects African ancestry populations. Inflammation is one mechanism that may link myosteatosis with increased T2DM risk, but studies examining the relationship between inflammation and myosteatosis are lacking. METHODS To examine these associations, we measured skeletal muscle subcutaneous AT, intermuscular AT, and skeletal muscle density using quantitative computed tomography and serum markers of inflammation in 471 individuals from 8 Afro-Caribbean multigenerational families [mean family size 67; mean age 43 years; mean body mass index (BMI) 28 kg/m(2)]. RESULTS After removing the variation attributable to significant covariates, heritabilities of inflammation markers [C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)] ranged from 33% (TNFα) to 40% (CRP); all P<0.01. Higher CRP, IL-6, and TNF-α were associated with lower subcutaneous AT around skeletal muscle (r=-0.13 to -0.19, P<0.05). Higher CRP was additionally associated with lower skeletal muscle density, indicative of greater intramuscular AT (r=-0.10, P<0.05), hyperinsulinemia (r=0.12, P<0.05), and increased homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.17, P<0.01). CONCLUSIONS Our findings suggest that heredity may play a significant role in the determination of several markers of inflammation in African ancestry individuals. Higher concentrations of CRP appear to be associated with greater skeletal muscle AT infiltration, lower subcutaneous AT, hyperinsulinemia, and insulin resistance. Longitudinal studies are needed to further evaluate the relationship between inflammation with changes in skeletal muscle AT distribution with aging and the incidence of T2DM.

Greater skeletal muscle fat infiltration is associated with higher all-cause mortality among men of African ancestry

BACKGROUND fat infiltration within and around skeletal muscle (i.e. myosteatosis) increases with ageing, is greater in African versus European ancestry men and is associated with poor health. Myosteatosis studies of mortality are lacking, particularly among African ancestry populations. METHODS in the Tobago Health study, a prospective longitudinal study, we evaluated the association of all-cause mortality with quantitative computed tomography (QCT) measured lower leg myosteatosis (intermuscular fat (IM fat) and muscle density) in 1,652 African ancestry men using Cox proportional hazards models. Date of death was abstracted from death certificates and/or proxy. RESULTS one hundred and twelve deaths occurred during follow-up (mean 5.9 years). In all men (age range 40-91 years), higher all-cause mortality was associated with greater IM fat (HR (95% CI) per SD: 1.29 (1.06-1.57)) and lower muscle density (HR (95% CI) per SD lower: 1.37 (1.08-1.75)) in fully adjusted models. Similar mortality hazard rates were seen in the subset of elderly men (aged ≥65 years) with greater IM fat (1.40 (1.11-1.78) or lower muscle density (1.66 (1.24-2.21)) in fully adjusted models. CONCLUSIONS our study identified a novel, independent association between myosteatosis and all-cause mortality in African ancestry men. Further studies are needed to establish whether this association is independent of other ectopic fat depots and to identify possible biological mechanisms underlying this relationship.

Skeletal Muscle Adiposity is associated with Serum Lipid and Lipoprotein Levels in Afro-Caribbean Men

Objective: When compared with other ethnic groups, African ancestry individuals have lower triglycerides and higher High‐density lipoprotein cholesterol (HDL‐C) levels, although the mechanisms for these differences remain unclear. A comprehensive array of factors potentially related to fasting serum lipid and lipoprotein levels in African ancestry men was evaluated.

Functional and association analysis of frizzled 1 (FZD1) promoter haplotypes with femoral neck geometry

Frizzleds are receptors for Wnt signaling and are involved in skeletal morphogenesis. Little is known about the transcriptional regulation of frizzleds in bone cells. In the current study, we determined if two common and potentially functional genetic variants (rs2232157, rs2232158) in the frizzled-1 (FZD1) promoter region and their haplotypes influence FZD1 promoter activity in human osteoblast-like cells. We also determined if these variants are associated with femoral neck bone mineral density (BMD) and geometry in 1319 African ancestry men aged > or =40 years. Real-time quantitative PCR and western blot analysis demonstrated FZD1 mRNA and protein expression in the human osteoblast-like cell lines, MG63 and SaOS-2. Promoter activity was next assessed by transient expression of haplotype specific FZD1 promoter reporter plasmids in these cells. In comparison to the common GG haplotype, promoter activity was 3-fold higher for the TC haplotype in both cell lines (p<0.05). We previously demonstrated that rs2232158 is associated with differential FZD1 promoter activity and Egr1 binding and thus focused further functional analyses on the rs2232157 G-to-T polymorphism. Electrophoretic mobility shift assay demonstrated that distinct nuclear protein complexes were associated with rs2232157 in an allele specific manner. Bioinformatics analysis predicted that the G to T transversion creates an E2F1 binding site, further supporting the functional significance of rs2232157 in FZD1 promoter regulation. Individual SNPs and haplotypes were not associated with femoral neck BMD. The TC haplotype was associated with larger subperiosteal width and greater CSMI (p<0.05). These results suggest that FZD1 expression is regulated in a haplotype-dependent manner in osteoblasts and that these same haplotypes may be associated with biomechanical indices of bone strength.

Myosteatosis increases with aging and is associated with incident diabetes in African ancestry men

Skeletal muscle fat infiltration (known as myosteatosis) is greater in African compared with European ancestry men and may play an important role in the development of type 2 diabetes (T2D). However, prospective studies examining the magnitude of changes in myosteatosis with aging and their metabolic consequences are sparse.

Renal Function and Bone Loss in a Cohort of Afro-Caribbean Men.

Poor renal function is associated with increased rates of bone loss and osteoporotic fractures in Caucasian men. The importance of kidney function for skeletal health in African ancestry men, who are a population segment with a high prevalence of chronic kidney disease as well as high peak bone mass, is not well known. We examined the relationship between estimated glomerular filtration rate (eGFR) and rates of bone loss in a large population cohort of otherwise healthy Afro‐Caribbean men aged 40 years and older. Dual X‐ray absorptiometry of the proximal femur and quantitative computed tomography of the proximal radius and tibia were obtained approximately 6 years apart. We calculated eGFR from serum creatinine that was measured in fasting samples in 1451 men. Impaired kidney function (IKF, eGFR<60 ml/min/1.7 m2) was observed in 8.6% of the cohort. The relationship between IKF and baseline BMD and annualized rate of change in BMD was analyzed controlling for potentially important confounders. IKF was not associated with baseline BMD. In contrast, men with IKF experienced a rate of decline in areal BMD at the total hip, femoral neck and trochanter and cortical volumetric BMD compared to those with normal kidney function (p<0.05 for all). Impaired kidney function was not associated with changes in trabecular volumetric BMD. In conclusion, poorer kidney function is associated with accelerated bone loss among otherwise healthy Afro‐Caribbean men even after controlling for age and other important medical and lifestyle related variables.