New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. 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 type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Shorter CWR cycling tests as proxies for longer tests in highly trained cyclists [dataset]

Severe-intensity constant work rate (CWR) cycling tests simulate the high-intensity competition environment and are useful for monitoring training progression and adaptation, yet impose significant physiological and psychological strain, require substantial recovery, and may disrupt athlete training or competition preparation. A brief, minimally fatiguing test providing comparable information is desirable. Purpose: To determine whether physiological variables measured during, and functional decline in maximal power output immediately after, a 2-min CWR test can act as a proxy for 4-min test outcomes. Methods: Physiological stress (V̇O2 kinetics, heart rate, blood lactate concentrations ([La-]b)) was monitored and performance fatigability was estimated (as pre-to-post-CWR changes in 10-s sprint power) during 2- and 4-min CWR tests in 16 high-level cyclists (V̇O2peak=64.4±6.0 ml∙kg-1∙min-1). The relationship between the 2- and 4-min CWR tests and the physiological variables that best relate to the performance fatigability were investigated. Results: The 2-min CWR test evoked a smaller decline in sprint mechanical power (32% vs. 47%, p \u3c 0.001). Both the physiological variables (r=0.66-0.96) and sprint mechanical power (r=0.67-0.92) were independently and strongly correlated between 2- and 4-min tests. Differences in V̇O2peak and [La-]b in both CWR tests were strongly associated with the decline in sprint mechanical power. Conclusion: Strong correlations between 2- and 4-min severe-intensity CWR test outcomes indicated that the shorter test can be used as a proxy for the longer test. A shorter test may be more practical within the elite performance environment due to lower physiological stress and performance fatigability and should have less impact on subsequent training and competition preparation

Maturity-related developmental inequalities in age-group swimming: the testing of ‘Mat-CAPs’ for their removal

Objectives: To (1) examine the association between maturity timing and performance-based selection levels in (N=708) Australian male 100-m Freestyle swimmers (12-17 years); (2) identify the relationship between maturation status and 100-m Freestyle performance; and (3) determine whether Maturation-based Corrective Adjustment Procedures (Mat-CAPs) could remove maturation-related differences in swimming performance. Methods: In Part 1, maturity timing category distributions ('Early', 'Early Normative', 'Late Normative' and 'Late') for 'All', 'Top 50%' and '25%' of raw swimming times were examined within and across age-groups. In Part 2, multiple regression analyses quantified the relationship between maturity offset (YPHV) and swimming performance. In Part 3, sample-based maturity timing category distributions were examined based on raw and correctively adjusted swim times for 12-17 year old age-groups. Results: Based on raw swim times, a high prevalence of 'Early-maturing' swimmers, with large effect sizes was identified (e.g., 14 years 'All' - χ2 (3, 151=111.98, p<0.001; 'Early' v 'Late' OR=82.0 95%CI=4.77, 1409.9); while a complete absence of 'Late-maturers' was apparent in the sample (N=708). When maturity categories were re-defined based on sample mean±standard deviation, and when using the expected curvilinear trendline identified in Part 2, Mat-CAPs mitigated maturity timing biases across all age-groups and selection levels, and removed the Freestyle performance advantage afforded by advanced maturity timing and status. Conclusions: Removing the influence of maturation-related developmental differences could help improve youth swimmer participation experiences and improve the accuracy of identifying genuinely skilled age-group swimmers

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance