Unbalanced Medial-to-Lateral Knee Muscle Co-Contractions are Associated with Medial Tibiofemoral Underloading during Gait Three Months after Anterior Cruciate Ligament Reconstruction.

Altered medial/lateral knee muscle co-contraction (measure by co-contraction indices, CCI) occurs during gait early after anterior cruciate ligament reconstruction (ACLR). Changes in peak medial compartment forces (pMCF) are also observed early after ACLR and are linked to the development of knee osteoarthritis. We do not know if imbalanced co-contraction is associated with these alterations in knee load. The purpose of this study was to evaluate the association between pMCF and the CCIs of medial/lateral knee muscle pairs during walking three months after ACLR. Bilateral knee gait mechanics and electromyography (EMG) data were collected from 44 participants 3 months following surgery. CCIs of six muscle pairs and medial-to-lateral (M:L) CCIs ratios were calculated during the weight acceptance interval. Bilateral pMCFs were calculated using a subject-based neuromusculoskeletal model. Based on interlimb pMCF symmetry, participants were divided into three groups: symmetric loaders, underloaders, and overloaders. A 2 × 3 (limb × group) ANOVA was used to compare CCIs between limbs in all groups. A partial Spearman's test was performed to examine the association between CCIs ratios and pMCF. The CCIs of the vastus lateralis-lateral gastrocnemius muscle pair was higher in the involved limb of underloaders (vs. the uninvolved limb and vs. the involved limb of symmetric loaders). The ratio of M:L CCIs was significantly lower (more lateral CCIs) in the involved limb, which was associated with lower pMCF. These results suggest that individuals early after ACLR who walk with higher CCIs of lateral knee musculature (vs. medial), have medial tibiofemoral underloading.

Associations among prenatal exposure to gestational diabetes mellitus, brain structure, and child adiposity markers.

OBJECTIVE: The aim of this study was to investigate the mediating role of child brain structure in the relationship between prenatal gestational diabetes mellitus (GDM) exposure and child adiposity. METHODS: This was a cross-sectional study of 9- to 10-year-old participants and siblings across the US. Data were obtained from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study®. Brain structure was evaluated by magnetic resonance imaging. GDM exposure was self-reported, and discordance for GDM exposure within biological siblings was identified. Mixed effects and mediation models were used to examine associations among prenatal GDM exposure, brain structure, and adiposity markers with sociodemographic covariates. RESULTS: The sample included 8521 children (7% GDM-exposed), among whom there were 28 sibling pairs discordant for GDM exposure. Across the entire study sample, prenatal exposure to GDM was associated with lower global and regional cortical gray matter volume (GMV) in the bilateral rostral middle frontal gyrus and superior temporal gyrus. GDM-exposed siblings also demonstrated lower global cortical GMV than unexposed siblings. Global cortical GMV partially mediated the associations between prenatal GDM exposure and child adiposity markers. CONCLUSIONS: The results identify brain markers of prenatal GDM exposure and suggest that low cortical GMV may explain increased obesity risk for offspring prenatally exposed to GDM.

Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

The Interplay Between Walking Speed, Economy, and Stability After Stroke.

BACKGROUND AND PURPOSE: Energy minimization is thought to underlie the naturally selected, preferred walking speed; however, people post-stroke walk slower than their most economical speed, presumably to optimize other objectives, such as stability. The purpose of this study was to examine the interplay between walking speed, economy, and stability. METHODS: Seven individuals with chronic hemiparesis walked on a treadmill at 1 of 3 randomized speeds: slow, preferred, and fast. Concurrent measurements of speed-induced changes in walking economy (ie, the energy needed to move 1 kg of bodyweight 1 ml O 2 /kg/m) and stability were made. Stability was quantified as the regularity and divergence of the mediolateral motion of the pelvic center of mass (pCoM) during walking, as well as pCoM motion relative to the base of support. RESULTS: Slower walking speeds were more stable (ie, pCoM motion was 10% ± 5% more regular and 26% ± 16% less divergent) but 12% ± 5% less economical. Conversely, faster walking speeds were 9% ± 8% more economical, but also less stable (ie, pCoM motion was 17% ± 5% more irregular). Individuals with slower walking speeds had an enhanced energetic benefit when walking faster ( rs = 0.96, P < 0.001). Individuals with greater neuromotor impairment had an enhanced stability benefit when walking slower ( rs = 0.86, P = 0.01). DISCUSSION AND CONCLUSIONS: People post-stroke appear to prefer walking speeds that are faster than their most stable speed but slower than their most economical speed. The preferred walking speed after stroke appears to balance stability and economy. To encourage faster and more economical walking, deficits in the stable control of the mediolateral motion of the pCoM may need to be addressed.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A416 ).

Markerless motion capture: What clinician-scientists need to know right now.

Markerless motion capture (mocap) could be the future of motion analysis. The purpose of this report was to describe our team of clinicians and scientists' exploration of markerless mocap (Theia 3D) and share data for others to explore (link: https://osf.io/6vh7z/?view_only=c0e00984e94a48f28c8d987a2127339d). Simultaneous mocap was performed using markerless and marker-based systems for walking, squatting, and forward hopping. Segment lengths were more variable between trials using markerless mocap compared to marker-based mocap. Sagittal plane angles were most comparable between systems at the knee joint followed by the ankle and hip. Frontal and transverse plane angles were not comparable between systems. The data collection experience using markerless mocap was simpler, faster, and user friendly. The ease of collection was in part offset by the added data transfer and processing times, and the lack of troubleshooting flexibility. If used selectively with proper understanding of limitations, markerless mocap can be exciting technology to advance the field of motion analysis.

Self-reported walking difficulty influences gait characteristics in patients with medial compartment knee osteoarthritis.

BACKGROUND: To differentiate gait strategies per knee osteoarthritis and self-reported walking difficulty during self-selected regular and fast gait speeds. We hypothesize that knee osteoarthritis gait characteristics during self-selected regular and fast gait speeds will be most accentuated by the osteoarthritis and walking difficulty group, followed by osteoarthritis and no walking difficulty, and least in the control group. METHODS: Prospective study of community-dwelling older adults (n = 39) who walk at functional speeds (≥1.0 m per second) were age and sex matched across the three groups. Gait strategies including knee excursion and moments, muscle activation and co-contraction, and limb dynamics (linear acceleration and jerk) were compared between groups during self-selected regular and fast gait speed trials. Significant group differences were defined as P < 0.05 and an effect size greater than small. FINDINGS: Based on walking difficulty, adduction moments (P-range = 0.00-0.03; effect size range,r = 0.42-0.52) and lateral quadriceps-gastrocnemius co-activations (P = 0.01;r = 0.36) were significant during regular gait speeds; and extension (P = 0.03;d = 0.59) and adduction (P-range = 0.00-0.02;d = 0.86;r = 0.40) moments were significant during fast trials. Per knee osteoarthritis presence, adduction moment(P = 0.01;r = 0.49), medial-quadriceps (P = 0.00;d = 1.04;r = 0.61), lateral-hamstrings (P = 0.04;d = 0.55), medial-gastrocnemius (P = 0.02;r = 0.40), medial quadriceps-hamstrings (P = 0.02;r = 0.38), medial quadriceps-gastrocnemius (P = 0.00;r = 0.56), and all limb dynamics (P = 0.00-0.01;d = 1.13-1.18;r = 0.35-0.47) were significant during regular gait speeds. Extension excursion (P = 0.02;d = 0.63), adduction moment (P = 0.01;d = 0.85) and medial-quadriceps (P = 0.01;r = 0.38) were significant during fast trials. INTERPRETATION: Many gait strategies during regular speeds that differ per walking difficulty and knee osteoarthritis attenuated at fast speeds. Perhaps gait training at fast speeds for those with knee osteoarthritis related walking difficulty is biomechanically and functionally beneficial.

Limb and sex-related differences in knee muscle co-contraction exist 3 months after anterior cruciate ligament reconstruction.

Interlimb and sex-based differences in gait mechanics and neuromuscular control are common after anterior cruciate ligament reconstruction (ACLR). Following ACLR, individuals typically exhibit elevated co-contraction of knee muscles, which may accelerate knee osteoarthritis (OA) onset. While directed (medial/lateral) co-contractions influence tibiofemoral loading in healthy people, it is unknown if directed co-contractions are present early after ACLR and if they differ across limbs and sexes. The purpose of this study was to compare directed co-contraction indices (CCIs) of knee muscles in both limbs between men and women after ACLR. Forty-five participants (27 men) completed overground walking at a self-selected speed 3 months after ACLR during which quadriceps, hamstrings, and gastrocnemii muscle activities were collected bilaterally using surface electromyography. CCIs of six muscle pairs were calculated during the weight acceptance interval. The CCIs of the vastus lateralis/biceps femoris muscle pair (lateral musculature) was greater in the involved limb (vs uninvolved; p = 0.02). Compared to men, women exhibited greater CCIs in the vastus medialis/lateral gastrocnemius and vastus lateralis/lateral gastrocnemius muscle pairs (p < 0.01 and p = 0.01, respectively). Limb- and sex-based differences in knee muscle co-contractions are detectable 3 months after ACLR and may be responsible for altered gait mechanics.

Bone-Patellar Tendon-Bone Autograft Harvest Prolongs Extensor Latency during Gait 2 yr after ACLR.

PURPOSE: Bone-patellar tendon-bone (BPTB) graft harvest for anterior cruciate ligament reconstruction alters patellar tendon properties, which inflict poor quadriceps neuromuscular function. BPTB autografts are associated with higher rates of posttraumatic osteoarthritis, which in turn is associated with pathological gait. The purpose of this study was to investigate the latency between the time of peak quadriceps activity and the peak knee flexion moment during gait, between those with BPTB grafts ( n = 23) and other graft types (hamstring autograft or allografts, n = 54), 5 ± 2 months and 2 yr (25 ± 3 months) after anterior cruciate ligament reconstruction. We hypothesized that longer latencies would be observed in the BPTB graft group in the involved limb. We expected latencies to shorten over time. METHODS: Knee moments and quadriceps EMG were collected during gait, and vastus medialis, vastus lateralis, rectus femoris (RF), and quadriceps latencies were calculated. Linear mixed-effects models were used to compare latencies between graft types and over the two time points. RESULTS: The main effects of graft type were observed for vastus medialis ( P = 0.005) and quadriceps ( P = 0.033) latencies with the BPTB graft group demonstrating longer latencies. No main effects of graft type were observed for vastus lateralis ( P = 0.051) and RF ( P = 0.080) latencies. Main effects of time were observed for RF latency ( P = 0.022). CONCLUSIONS: Our hypothesis that the BPTB graft group would demonstrate longer extensor latency was supported. Contrary to our second hypothesis, however, latency only improved in RF and regardless of graft type, indicating that neuromuscular deficits associated with BPTB grafts may persist 2 yr after surgery. Persistent deficits may be mediated by changes in the patellar tendon's mechanical properties. Graft-specific rehabilitation may be warranted to address the long-term neuromechanical deficits that are present after BPTB graft harvest.

Weight loss and ß-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial.

OBJECTIVE: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and ß-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes. METHODS: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and ß-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time. RESULTS: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of ß-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on ß-cell function. CONCLUSIONS: Reducing demand on the ß-cell by improving IS through weight loss does not reverse ß-cell dysfunction. L + M was the only treatment that enhanced ß-cell function.

The Unmet Challenge of Diagnosing and Treating Photophobia.

BACKGROUND: Although patients with abnormal light sensitivity may present to an ophthalmologist or optometrist for the evaluation of photophobia, there are no previous reviews of the most common causes of this symptom. METHODS: We conducted a retrospective chart review of patients who presented to our eye center between 2001 and 2009 primarily for the evaluation of photophobia. We recorded demographics, ocular examination findings, and diagnoses of these patients. RESULTS: Our population included 58 women and 53 men. The mean age at presentation to the clinic was 37 years (range 6 months-94 years). The most frequent cause of photophobia was migraine headache (53.7%), followed by dry eye syndrome (36.1), ocular trauma (8.2%), progressive supranuclear palsy (6.8%), and traumatic brain injury (4.1%). A significant proportion of patients (25.9%) left the clinic without a cause for their photophobia documented by the examining physician (11.7% of adults and 69.4% of children). CONCLUSIONS: Photophobia affects patients of all ages, and many patients are left without a specific diagnosis, indicating a significant knowledge gap among ophthalmologists and optometrists evaluating these patients.

Identifying Gait Pathology after ACL Reconstruction Using Temporal Characteristics of Kinetics and Electromyography.

PURPOSE: Asymmetrical gait mechanics after anterior cruciate ligament reconstruction (ACLR) are associated with the development of posttraumatic knee osteoarthritis. Current measures of gait mechanics have focused heavily on peak magnitudes of knee kinematics, kinetics, and joint contact forces but have seldom considered the rate of knee loading, cumulative knee load, or the timing of motor input surrounding peaks. The purpose of this study was to introduce and describe novel metrics of gait using temporal characteristics of kinetics and EMG to identify neuromuscular deficits of the quadriceps in patients after ACLR. METHODS: Gait mechanics were assessed 6 months (n = 145) and 24 months (n = 116) after ACLR. External knee flexion rate of moment development (RMD) and knee flexion moment impulse (KFMI) leading up to the time of peak knee flexion moment (pKFM), peak RMD between initial contact to pKFM, and cumulative KFMI were calculated. Extensor latencies from the quadriceps, vastus medialis, vastus lateralis, and rectus femoris (time of pKFM - time of peak EMG activity) during the weight acceptance phase of gait were also calculated. Paired-sample t-tests (α = 0.05) were performed between limbs at both time points. RESULTS: Slower RMD, smaller KFMI, and longer extensor latencies in the involved compared with uninvolved limb were observed across all measures at 6 months (P < 0.005). At 24 months, RMDpeak was slower, and KFMI50ms, KFMI100ms, and KFMItotal were lower in the involved limb (P < 0.003), but no other asymmetries were found. CONCLUSIONS: Slower RMD, smaller KFMI, and prolonged extensor latencies may characterize neuromuscular deficits underlying aberrant gait mechanics early after ACLR. RMD, KFMI, and extensor latencies during gait should be considered in the future to quantify asymmetrical movement patterns observed after ACLR and as markers of recovery.

Patellofemoral contact forces after ACL reconstruction: A longitudinal study.

Osteoarthritis (OA) development after ACL reconstruction (ACLR) is common. Patellofemoral OA after ACLR is as prevalent as tibiofemoral OA; however, few have explored the mechanisms leading to disease development in this compartment. Biomechanical alterations may be one mechanism responsible for post-traumatic knee OA. Patellofemoral contact forces during dynamic tasks, such as running and single leg hops, have been assessed at return to sport and later time points. The results of these studies, however, contradict each other, are only cross-sectional in nature, and are limited to specific points in time within the movement pattern. The purpose of this study was to assess patellofemoral contact forces 3, 6, and 24 months after ACLR during level walking over the entirety of the movement pattern. Patellofemoral contact forces were calculated after determination of muscle forces from a validated, subject-specific, EMG-driven neuromusculoskeletal model. Statistical parametric mapping was used to compare patellofemoral contact forces between limbs and across time points. Patellofemoral underloading of the involved limb (vs. uninvolved) was present at 3 months (p < 0.001 from 7 to 30% of stance) and 6 months (p = 0.001 from 11 to 23% of stance and p = 0.025 from 27 to 32%) after ACLR but was resolved by 24 months. Both limbs' load increased from 3 to 6 months. The involved limb displayed relatively consistent loads from 6 months onward, while the uninvolved limb's decreased back down towards their 3-month values. Overall, these results suggest that early patellofemoral underloading exists after ACLR and may be leading to patellofemoral OA development.

Knee joint biomechanics during gait improve from 3 to 6 months after anterior cruciate ligament reconstruction.

Gait alterations after anterior cruciate ligament reconstruction (ACLR) are commonly reported and have been linked to posttraumatic osteoarthritis development. While knee gait alterations have been studied at several time points after ACLR, little is known about how these biomechanical variables change earlier than 6 months after surgery, nor is much known about how they differ over the entire stance phase of gait. The purpose of this study was to examine knee gait biomechanical variables over their entire movement pattern through stance at both 3 and 6 months after ACLR and to study the progression of interlimb asymmetry between the two postoperative time points. Thirty-five individuals underwent motion analysis during overground walking 3 (3.2 ± 0.5) and 6 (6.4 ± 0.7) months after ACLR. Knee biomechanical variables were compared between limbs and across time points through 100% of stance using statistical parametric mapping; this included a 2 × 2 (Limb × Time) repeated measures analysis of variance and two-tailed t-tests. Smaller knee joint angles, moments, extensor forces, and medial compartment forces were present in the involved versus uninvolved limb. Interlimb asymmetries were present at both time points but were less prevalent at 6 months. The uninvolved limb's biomechanical variables stayed relatively consistent over time, while the involved limb's trended toward that of the uninvolved limb. Statement of Clinical Significance: Interventions to correct asymmetrical gait patterns after ACLR may need to occur early after surgery and may need to focus on multiple parts of stance phase.

Knee cartilage T2 relaxation times 3 months after ACL reconstruction are associated with knee gait variables linked to knee osteoarthritis.

Osteoarthritis development after ACL reconstruction (ACLR) is not well understood. Investigators have examined associations between knee biomechanical alterations and quantitative MRI (qMRI) variables, reflective of cartilage health, 12-60 months following ACLR; however, none have done so early after surgery. As part of an exploratory study, 45 individuals (age, 23 ± 7 years) underwent motion analysis during walking and qMRI 3 months after ACLR. For each limb, peak knee adduction moment (pKAM) and peak knee flexion moment (pKFM) were determined using inverse dynamics and peak medial compartment force was calculated using a neuromusculoskeletal model. T2 relaxation times in the medial compartment and linear regressions were used to determine the associations between gait variables and deep and superficial cartilage T2 relaxation times in six regions. pKAM was positively associated with deep layer T2 relaxation times within the femoral central and posterior regions when examined in the involved limb and from an interlimb difference perspective (involved limb - uninvolved limb). After adjusting for age, the association between interlimb difference of pKAM and interlimb difference of deep layer T2 relaxation times in the tibial central region became significant (p = .043). Interlimb difference of pKFM was negatively associated with interlimb difference of deep layer T2 relaxation times within the femoral central and posterior regions. These associations suggest that degenerative pathways leading to osteoarthritis may be detectable as early as 3 months after reconstruction. Preventative therapeutic techniques may need to be employed early in the rehabilitation process to prevent cartilage degradation.

An Efficient One-Step Moment Balancing Algorithm for Computing Medial and Lateral Knee Compartment Contact Forces.

The knee adduction moment is associated with the progression of knee osteoarthritis (OA). The adduction moment reflects the net effect of muscles, passive tissues and bone-on-bone contact forces. Medial compartment OA is more common than lateral and therefore our ability to correctly partition bone-on-bones forces across the medial and lateral compartments is key to understanding mechanical factors associated with the onset and progression of knee OA. In this technical brief we present an efficient one-step moment balancing algorithm linking the sagittal and frontal planes in the determination of musculotendon forces. Novel to the one-step approach is the introduction of a penalty function limiting total compressive force from acting in the lateral compartment when the internal moment is net abduction (i.e., external knee adduction). Medial and lateral knee contact forces were computed using the one-step moment balancing algorithm for 10 subjects walking at a self-selected pace and compared to values determined using a well-established two-step frontal moment balancing approach. Overall, average peak differences in magnitude and timing were small and the ensemble-averaged contact force profiles were similar between methods. The only statistical difference was slightly larger (0.2 BWs) peak medial contact force for the one-step method during the first half of stance, however these differences are small relative to peak values and would not likely alter interpretation of the data. The 1-step moment balancing method is a more efficient methodology for computing medial and lateral knee contact forces that can be used in place of two-step frontal plane moment balancing.

Using Patient-Generated Health Data From Twitter to Identify, Engage, and Recruit Cancer Survivors in Clinical Trials in Los Angeles County: Evaluation of a Feasibility Study.

BACKGROUND: Failure to find and attract clinical trial participants remains a persistent barrier to clinical research. Researchers increasingly complement recruitment methods with social media-based methods. We hypothesized that user-generated data from cancer survivors and their family members and friends on the social network Twitter could be used to identify, engage, and recruit cancer survivors for cancer trials. OBJECTIVE: This pilot study aims to examine the feasibility of using user-reported health data from cancer survivors and family members and friends on Twitter in Los Angeles (LA) County to enhance clinical trial recruitment. We focus on 6 cancer conditions (breast cancer, colon cancer, kidney cancer, lymphoma, lung cancer, and prostate cancer). METHODS: The social media intervention involved monitoring cancer-specific posts about the 6 cancer conditions by Twitter users in LA County to identify cancer survivors and their family members and friends and contacting eligible Twitter users with information about open cancer trials at the University of Southern California (USC) Norris Comprehensive Cancer Center. We reviewed both retrospective and prospective data published by Twitter users in LA County between July 28, 2017, and November 29, 2018. The study enrolled 124 open clinical trials at USC Norris. We used descriptive statistics to report the proportion of Twitter users who were identified, engaged, and enrolled. RESULTS: We analyzed 107,424 Twitter posts in English by 25,032 unique Twitter users in LA County for the 6 cancer conditions. We identified and contacted 1.73% (434/25,032) of eligible Twitter users (127/434, 29.3% cancer survivors; 305/434, 70.3% family members and friends; and 2/434, 0.5% Twitter users were excluded). Of them, 51.4% (223/434) were female and approximately one-third were male. About one-fifth were people of color, whereas most of them were White. Approximately one-fifth (85/434, 19.6%) engaged with the outreach messages (cancer survivors: 33/85, 38% and family members and friends: 52/85, 61%). Of those who engaged with the messages, one-fourth were male, the majority were female, and approximately one-fifth were people of color, whereas the majority were White. Approximately 12% (10/85) of the contacted users requested more information and 40% (4/10) set up a prescreening. Two eligible candidates were transferred to USC Norris for further screening, but neither was enrolled. CONCLUSIONS: Our findings demonstrate the potential of identifying and engaging cancer survivors and their family members and friends on Twitter. Optimization of downstream recruitment efforts such as screening for digital populations on social media may be required. Future research could test the feasibility of the approach for other diseases, locations, languages, social media platforms, and types of research involvement (eg, survey research). Computer science methods could help to scale up the analysis of larger data sets to support more rigorous testing of the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT03408561; https://clinicaltrials.gov/ct2/show/NCT03408561.

Genome-wide association study of body fat distribution traits in Hispanics/Latinos from the HCHS/SOL.

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.

Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study.

OBJECTIVE: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. RESEARCH DESIGN AND METHODS: Glucagon was measured in three randomized, parallel, clinical studies: 1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). RESULTS: No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P < 0.05 for all, except AGR at 12 months [P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. CONCLUSIONS: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions.

Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. RESEARCH DESIGN AND METHODS: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). RESULTS: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived ß-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived ß-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). CONCLUSIONS: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline ß-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Hyperglucagonemia Does Not Explain the ß-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study.

OBJECTIVE: To determine whether ß-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release. RESEARCH DESIGN AND METHODS: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L, and arginine-stimulated glucagon (acute glucagon response [AGR]) and C-peptide (ACPRmax) responses at glucose >25 mmol/L. RESULTS: Mean ± SD fasting glucagon (7.63 ± 3.47 vs. 8.55 ± 4.47 pmol/L; P = 0.063) and steady-state glucagon (2.24 ± 1.46 vs. 2.49 ± 1.96 pmol/L, P = 0.234) were not different in youth and adults, respectively, while AGR was lower in youth (14.1 ± 5.2 vs. 16.8 ± 8.8 pmol/L, P = 0.001). Significant age-group differences in insulin sensitivity, fasting C-peptide, steady-state C-peptide, and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults (r = 0.133, P = 0.012) and negatively correlated in youth (r = -0.143, P = 0.251). In both age-groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r = 0.209, P = 0.091; adults r = 0.335, P < 0.001) and lower insulin sensitivity (youth r = -0.228, P = 0.066; adults r = -0.324, P < 0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth. CONCLUSIONS: Youth with IGT or recently diagnosed type 2 diabetes (drug naive) have hyperresponsive ß-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared with those in adults. Thus, α-cell dysfunction does not appear to explain the difference in ß-cell function and insulin sensitivity in youth versus adults.