Metabolic syndrome (MetS) is increasingly present in breast cancer survivors, possibly worsened by cancer-related treatments, such as chemotherapy. MetS greatly increases risk of cardiovascular disease and diabetes, co-morbidities that could impair the survivorship experience, and possibly lead to cancer recurrence. Exercise has been shown to positively influence quality of life (QOL), physical function, muscular strength and endurance, reduce fatigue, and improve emotional well-being; however, the impact on MetS components (visceral adiposity, hyperglycemia, low serum high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension) remains largely unknown. In this trial, we aim to assess the effects of combined (aerobic and resistance) exercise on components of MetS, as well as on physical fitness and QOL, in breast cancer survivors soon after completing cancer-related treatments.
This study is a prospective randomized controlled trial (RCT) investigating the effects of a 16-week supervised progressive aerobic and resistance exercise training intervention on MetS in 100 breast cancer survivors. Main inclusion criteria are histologically-confirmed breast cancer stage I-III, completion of chemotherapy and/or radiation within 6 months prior to initiation of the study, sedentary, and free from musculoskeletal disorders. The primary endpoint is MetS; secondary endpoints include: muscle strength, shoulder function, cardiorespiratory fitness, body composition, bone mineral density, and QOL. Participants randomized to the Exercise group participate in 3 supervised weekly exercise sessions for 16 weeks. Participants randomized to the Control group are offered the same intervention after the 16-week period of observation.
This is the one of few RCTs examining the effects of exercise on MetS in breast cancer survivors. Results will contribute a better understanding of metabolic disease-related effects of resistance and aerobic exercise training and inform intervention programs that will optimally improve physiological and psychosocial health during cancer survivorship, and that are ultimately aimed at improving prognosis.
NCT01140282; Registration: June 10, 2010
Exercise; Breast cancer; Metabolic syndrome
Articular loading is an important factor in the joint degenerative process for individuals with anterior cruciate ligament (ACL) rupture. Evaluation of loading for a population that exhibits neuromuscular compensation for injury requires an approach which can incorporate individual muscle activation strategies in its estimation of muscle forces. The purpose of this study was to evaluate knee joint contact forces for patients with ACL deficiency using an EMG-driven modeling approach to estimate muscle forces. Thirty (30) athletes with acute, unilateral ACL rupture underwent gait analysis after resolving range of motion, effusion, pain and obvious gait impairments. Electromyography was recorded bilaterally from 14 lower extremity muscles and input to a musculoskeletal model for estimation of muscle forces and joint contact forces. Gait mechanics were consistent with previous reports for individuals with ACL-deficiency. Our major finding was that joint loading was altered in the injured limb after acute ACL injury; patients walked with decreased contact force on their injured knee compared to their uninjured knee. Both medial and lateral compartment forces were reduced without a significant change in the distribution of tibiofemoral load between compartments. This is the first study to estimate medial and lateral compartment contact forces in patients with acute ACL rupture using an approach which is sensitive to individual muscle activation patterns. Further work is needed to determine whether this early decreased loading of the injured limb is involved in the development of osteoarthritis in these patients.
To examine the association between self-reported physical activity (PA) and diabetes-related quantitative traits.
RESEARCH DESIGN AND METHODS
The observational cohort was 1,152 Mexican American adults with dual-energy X-ray absorptiometry, oral and intravenous glucose tolerance tests, and self-reported dietary and PA questionnaires. PA was categorized into three mutually exclusive groups according to the U.S. Department of Health and Human Services PA guidelines for Americans: low (vigorous <75 min/week and moderate <150 min/week), moderate (vigorous ≥75 min/week or moderate ≥150 min/week), and high (vigorous ≥75 min/week and moderate ≥150 min/week). Trends in PA groups were tested for association with metabolic traits in a cross-sectional analysis.
The participants’ mean age was 35 years (range, 18–66 years), mean BMI was 29.6 kg/m2, and 73% were female. Among them, 501 (43%), 448 (39%), and 203 (18%) were classified as having low, moderate, and high PA, respectively. After adjustment for age, a higher PA was significantly associated with lower 2-h glucose, fasting insulin, and 2-h insulin and greater β-cell function (P = 0.001, 0.0003, 0.0001, and 0.004, respectively). The association did not differ significantly by sex. Results were similar after further adjustment for age, sex, BMI, or percent body fat.
An increasing level of PA is associated with a better glucose and insulin profile and enhanced β-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to β-cell function and glucose regulation independent of obesity.
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
The Achilles tendon (AT) moment arm is an important biomechanical parameter most commonly estimated using one of two methods: (A) center of rotation and (B) tendon excursion. Conflicting findings regarding magnitude and whether it changes with contraction intensity have been reported when using these methods. In this study, we present an alternate method of measuring the AT moment arm by combining ultrasound and video-based motion capture. Moment arms for 10 healthy male subjects were measured at five different joint angles in 10° increments ranging from 20° of dorsiflexion (DF) to 20° of plantar flexion (PF). Moment arms were measured at rest and also during maximum voluntary contraction (MVC). For both conditions, the AT moment arm increased in magnitude as the ankle moved from DF to PF. In 20° of DF, the moment arm at rest averaged 34.6 ± 1.8 mm and increased to a maximum value of 36.9 ± 1.9 mm when plantar flexed to 10°. Moment arms during MVC ranged from 35.7 ± 1.8 mm to 38.1 ± 2.6 mm. The moment arms we obtained were much more consistent with literature values derived using ultrasound and tendon excursion compared to center of rotation or in vitro methods. This is noteworthy as the hybrid method is easy to implement and as it is less costly and timing consuming than other methods, including tendon excursion, it is well suited for large-scale studies involving many subjects.
Ankle joint; center of rotation; displacement; lever arm; tendon excursion
The decreased internal knee extensor moment is a significant gait asymmetry among patients with anterior cruciate ligament (ACL) deficiency, yet the muscular strategy driving this altered moment for the injured limb is unclear.
To determine whether patients with ACL deficiency and characteristic knee instability would demonstrate normal extensor and increased flexor muscle force to generate a decreased internal extensor moment (i.e. employ a hamstring facilitation strategy).
Gait analysis was performed on 31 athletes with acute ACL rupture who exhibited characteristic knee instability after injury. Peak internal knee extensor moment was calculated using inverse dynamics and muscle forces were estimated using an EMG-driven modeling approach. Comparisons were made between the injured and contralateral limbs.
As expected, patients demonstrated decreased peak knee flexion (p=0.028) and internal knee extensor moment (p=0.0004) for their injured limb, but exhibited neither an isolated decrease in extensor force (quadriceps avoidance), nor an isolated increase in flexor force (hamstring facilitation) at peak knee moment. Instead, they exhibited decreased muscle force from both flexor (p=0.0001) and extensor (p=0.0103) groups. This strategy of decreased muscle force may be explained in part by muscle weakness which frequently accompanies ACL injury, or by apprehension, low confidence and fear of further injury.
This is the first study to estimate muscle forces in the ACL-deficient knee using an EMG-driven approach. These results affirm the existence of neuromuscular asymmetries in the individuals with ACL deficiency and characteristic knee instability.
Knee Moment; Muscle Force; Quadriceps Avoidance; Hamstring Facilitation; Instability
Hypertension represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).
Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type and LSD-1 heterozygote knockout (LSD-1+/−) mice. Clinical relevance was tested by multivariate associations between single nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American).
LSD1 expression was modified by dietary salt in wild-type mice with lower levels associated with liberal salt intake. LSD-1+/− mice expressed lower LSD-1 protein levels than wild-type mice in kidney tissue. Similar to LSD-1+/− mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP in response to change from low to liberal salt diet (rs671357, p=0.01; rs587168, p=0.005). This association was replicated in the Hispanic (rs587168, p=0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1+/− mice, decreased alpha-EnaC expression in LSD-1+/− mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.
The results of this translational research study support a role for LSD1 in the pathogenesis of salt-sensitive hypertension.
Hypertension; Salt-sensitivity; LSD1; Genetics; Epigenetic
The semitendinosus‐gracilis tendon autograft is often used to reconstruct the anterior cruciate ligament. Tendon regeneration appears to occur for most individuals in the short term, but little is known about the long‐term effects of graft harvest. The purpose of this study was to describe the effect of semitendinosis‐gracilis tendon graft harvest on muscle and tendon morphology at least five years following reconstruction in a case series.
Magnetic resonance images were taken of the knees of three subjects at least five years following anterior cruciate ligament reconstruction. These subjects represented the different regeneration patterns at the time of return‐to‐sport. Muscle and tendon morphology were analyzed by calculating the volume, peak cross‐sectional area, and length of the knee flexors. Muscle and tendon morphological changes were analyzed individually, and then in combination as defined as a knee flexor group.
Muscle and tendon regeneration continued in those tendons that had begun regeneration at the time of return‐to‐sports in two subjects. There was significant additional muscle degeneration in those muscles whose tendons had not regenerated at the time of return‐to‐sports, in the remaining subject. Compensatory hypertrophy of the remaining knee flexors restored the knee flexor group to near preoperative peak cross‐sectional area and volume across the each of the three case subjects.
Knee flexor morphology at the time of return‐to‐sports foreshadowed the long‐term outcome in the three studied subjects. Preservation of the tendon sheath in situ may play a role in tendon regeneration. When tendon regeneration did not occur, fatty infiltration of the muscle may be a worst‐case outcome. Semitendinosus‐gracilis muscle synergists demonstrated hypertrophy, perhaps in an effort to compensate for knee flexor group morphology deficits that existed after Semitendinosus gracilis tendon graft harvest.
Semitendinosus and gracilis tendon harvest technique may play a role in regeneration. Additionally, knee flexor morphology at the time of return‐to‐sports may foreshadow the long‐term outcome.
Level of Evidence:
prospective (longitudinal) cohort ‐ level II
Anterior cruciate ligament; magnetic resonance imaging; tendon regrowth
To identify determinants of quadriceps weakness among persons with end-stage knee osteoarthritis (OA).
One-hundred twenty-three individuals (mean age 64.9 ± 8.5 yr) with Kellgren/Lawrence grade IV knee OA participated. Quadriceps strength (MVIC) and volitional muscle activation (CAR) were measured using a burst superimposition test. Muscle composition (lean muscle cross-sectional area (LMCSA) and fat CSA (FCSA)) were quantified using magnetic resonance imaging. Specific strength (MVIC/LMCSA) was computed. Interlimb differences were analyzed using paired-sample t-tests. Regression analysis was applied to identify determinants of MVIC. An alpha level of 0.05 was adopted.
The OA limb was significantly weaker, had lower CAR, and had smaller LMCSA than the contralateral limb. CAR explained 17% of the variance in the contralateral limb's MVIC compared with 40% in the OA limb. LMCSA explained 41% of the variance in the contralateral limb's MVIC compared with 27% in the OA limb.
Both reduced CAR and LMCSA contribute to muscle weakness in persons with knee OA. Similar to healthy elders, the best predictor of strength in the contralateral, nondiseased limb was largely determined by LMCSA, whereas CAR was found to be the primary determinant of strength in the OA limb. Deficits in CAR may undermine the effectiveness of volitional strengthening programs in targeting quadriceps weakness in the OA population.
STRENGTH; ARTHRITIS; MUSCLE ACTIVATION; ATROPHY
Muscle-actuated simulations of pathological gait have the capacity to identify muscle impairments and compensatory strategies, but the lack of subject-specific solutions prevents the prescription of personalized therapies. Conversely, electromyographic-driven models are limited to muscles for which data are available but can capture the true neural drive initiated by an individual subject. In order to improve subject-specificity and enforce physiological constraints on muscle activity, we propose a hybrid strategy for the optimization of subject-specific muscle patterns that involves forward dynamic simulation of whole body movement coupled with electromyographic-driven models of muscle subsets. In this paper we apply the hybrid approach to an example of post-stroke gait and demonstrate its unique ability to account for the unusual muscle activation patterns and muscle properties in patients with neuromuscular impairments.
Neuromuscular; musculoskeletal; model; gait; optimization
The real-time estimation of muscle forces could be a very valuable tool for rehabilitation. By seeing how much muscle force is being produced during rehabilitation, therapists know whether they are working within safe limits in their therapies and patients know if they are producing enough force to expect improvement. This is especially true for rehabilitation of Achilles tendon ruptures where, out of fear of overloading and causing a re-rupture, minimal therapy is typically done for eight weeks post-surgery despite animal studies that show that low-level loading is beneficial. To address this need, we have developed a biomechanical model that allows for the real-time estimation of forces in the triceps surae muscle and Achilles tendon. Forces are estimated using a Hill-type muscle model. To account for differences in neuromuscular control of each subject, the model used EMGs as input. To make this clinically useful, joint angles were measured using electrogoniometers. A dynamometer was used to measure joint moments during the model calibration stage, but was not required during real-time studies. The model accounts for the force-length and force-velocity properties of muscles, and other parameters such as tendon slack length and optimal fiber length. Additional parameters, such as pennation angle and moment arm of each muscle in the model, vary as functions of joint angle. In this paper, the model is presented and it application is demonstrated in two subjects: one with a healthy Achilles tendon and a second six months post Achilles tendon rupture and repair.
Muscle Force; Joint Moment; Multibody Dynamics; Rehabilitation; Feedback
To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 = × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci.
Muscle atrophy is one of many factors contributing to post-stroke hemiparetic weakness. Since muscle force is a function of muscle size, the amount of muscle atrophy an individual muscle undergoes has implications for its overall force-generating capability post-stroke. In this study, post-stroke atrophy was determined bilaterally in fifteen leg muscles with volumes quantified using magnetic resonance imaging (MRI). All muscle volumes were adjusted to exclude non-contractile tissue content, and muscle atrophy was quantified by comparing the volumes between paretic and non-paretic sides. Non-contractile tissue or intramuscular fat was calculated by determining the amount of tissue excluded from the muscle volume measurement. With the exception of the gracilis, all individual paretic muscles examined had smaller volumes in the non-paretic side. The average decrease in volume for these paretic muscles was 23%. The gracilis volume, on the other hand, was approximately 11% larger on the paretic side. The amount of non-contractile tissue was higher in all paretic muscles except the gracilis, where no difference was observed between sides. To compensate for paretic plantar flexor weakness, one idea might be that use of the paretic gracilis actually causes the muscle to increase in size and not develop intramuscular fat. By eliminating non-contractile tissue from our volume calculations, we have presented volume data that more appropriately represents force-generating muscle tissue. Non-uniform muscle atrophy was observed across muscles and may provide important clues when assessing the effect of muscle atrophy on post-stroke gait.
stroke; hemiparesis; magnetic resonance imaging (MRI); muscle volume; non-contractile tissue
Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5) − 18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African-Americans (TARA)” study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.
Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.
To identify physiological and clinical variables associated with development of type 2 diabetes up to 12 years after pregnancies complicated by gestational diabetes.
RESEARCH DESIGN AND METHODS
Seventy-two islet cell antibody–negative nondiabetic Hispanic women had oral (oGTT) and intravenous (ivGTT) glucose tolerance tests, glucose clamps, and body composition assessed between 15 and 30 months after pregnancies complicated by gestational diabetes mellitus (GDM). They returned for oGTTs at 15-month intervals until they dropped out, developed diabetes, or reached 12 years postpartum. Cox regression analysis was used to identify baseline predictors and changes during follow-up that were associated with development of type 2 diabetes.
At baseline, relatively low insulin sensitivity, insulin response, and β-cell compensation for insulin resistance were independently associated with development of diabetes. During follow-up, weight and fat gain and rates of decline in β-cell compensation were significantly associated with diabetes, while additional pregnancy and use of progestin-only contraception were marginally associated with diabetes risk.
In Hispanic women, GDM represents detection of a chronic disease process characterized by falling β-cell compensation for chronic insulin resistance. Women who are farthest along at diagnosis and/or deteriorating most rapidly are most likely to develop type 2 diabetes within 12 years after the index pregnancy. Weight gain, additional pregnancy, and progestin-only contraception are potential modifiable factors that increase diabetes risk.
In this article, we outline a method for computing Achilles tendon moment arm. The moment arm is computed from data collected using two reliable measurement instruments: ultrasound and video-based motion capture. Ultrasound is used to measure the perpendicular distance from the surface of the skin to the midline of the tendon. Motion capture is used to determine the perpendicular distance from the bottom of the probe to the ankle joint center. The difference between these two measures is the Achilles tendon moment arm. Unlike other methods, which require an angular change in joint position to approximate the moment arm, the hybrid method can be used to compute the moment arm directly at a specific joint angle. As a result, the hybrid method involves fewer error-prone measurements and the moment arm can be computed at the limits of the joint range of motion. The method is easy to implement and uses modalities that are less costly and more accessible than MRI. Preliminary testing using a lamb shank as a surrogate for a human ankle revealed good accuracy (3.3% error). We believe the hybrid method outlined here can be used to measure subject-specific moment arms in vivo and thus will potentially benefit research projects investigating ankle mechanics.
tendon excursion; center of rotation; lever arm; ankle joint; line of action
Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.
RESEARCH DESIGN AND METHODS
We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).
The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.
Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body-mass-index (up to 77,167 participants), following up 16 loci in an additional 29 studies (up to 113,636 subjects). We identified 13 novel loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1, and CPEB4 (P 1.9 × 10−9 to 1.8 × 10−40), and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex-difference 1.9 × 10−3 to 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution, independent of overall adiposity, and reveal powerful gene-by-sex interactions.
genome-wide association; waist-hip-ratio; body fat distribution; central obesity; meta-analysis; genetics; visceral adipose tissue; metabolism; body composition; Expression Quantitative Trait Loci; sex difference
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Obesity is globally prevalent and highly heritable, but the underlying
genetic factors remain largely elusive. To identify genetic loci for
obesity-susceptibility, we examined associations between body mass index (BMI)
and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of
42 SNPs in up to 125,931 additional individuals. We confirmed 14 known
obesity-susceptibility loci and identified 18 new loci associated with BMI
(P<5×10−8), one of which
includes a copy number variant near GPRC5B. Some loci
(MC4R, POMC, SH2B1, BDNF) map near key hypothalamic
regulators of energy balance, and one is near GIPR, an incretin
receptor. Furthermore, genes in other newly-associated loci may provide novel
insights into human body weight regulation.
To identify factors associated with declining β-cell compensation for insulin resistance.
RESEARCH DESIGN AND METHODS
In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining β-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on β-cell compensation decline.
A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance.
These results identify weight gain as the strongest factor associated with declining β-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
Glucokinase (GCK) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) regulate the glucose-cycling step in pancreatic β-cells and may regulate insulin secretion. GCK rs1799884 and G6PC2 rs560887 have been independently associated with fasting glucose, but their interaction on glucose-insulin relationships is not well characterized.
RESEARCH DESIGN AND METHODS
We tested whether these variants are associated with diabetes-related quantitative traits in Mexican Americans from the BetaGene Study and attempted to replicate our findings in Finnish men from the METabolic Syndrome in Men (METSIM) Study.
rs1799884 was not associated with any quantitative trait (corrected P > 0.1), whereas rs560887 was significantly associated with the oral glucose tolerance test 30-min incremental insulin response (30′ Δinsulin, corrected P = 0.021). We found no association between quantitative traits and the multiplicative interaction between rs1799884 and rs560887 (P > 0.26). However, the additive effect of these single nucleotide polymorphisms was associated with fasting glucose (corrected P = 0.03) and 30′ Δinsulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 × 10−10 30′ Δinsulin, P = 0.028). When we examined the relationship between fasting glucose and 30′ Δinsulin stratified by GCK and G6PC2, we noted divergent changes in these quantitative traits for GCK but parallel changes for G6PC2. We observed a similar pattern in METSIM.
Our data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.
Individuals following stroke exhibit altered muscle activation and movement patterns. Improving the efficiency of gait can be facilitated by knowing which muscles are affected and how they contribute to the pathological pattern. In this paper we present an electromyographically (EMG) driven musculoskeletal model to estimate muscle forces and joint moments. Subject specific EMG for the primary ankle plantar and dorsiflexor muscles, and joint kinematics during walking for four subjects following stroke were used as inputs to the model to predict ankle joint moments during stance. The model’s ability to predict the joint moment was evaluated by comparing the model output with the moment computed using inverse dynamics. The model did predict the ankle moment with acceptable accuracy, exhibiting an average R2 value ranging between 0.87 and 0.92, with RMS errors between 9.7% and 14.7%. The values are in line with previous results for healthy subjects, suggesting that EMG-driven modeling in this population of patients is feasible. It is our hope that such models can provide clinical insight into developing more effective rehabilitation therapies and to assess the effects of an intervention.
EMG; Musculoskeletal model; Stroke; Hill-type muscle model; joint moment