Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study.

ObjectiveWe aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.Research design and methodsWe investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S(I)), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.ResultsWe observed that S(I) and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30-3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI).ConclusionsOur data showed that lower MCRI predicts the incidence of type 2 diabetes

Innovative Test Operations to Support Orion and Future Human Rated Missions

This paper describes how the Orion program is implementing new and innovative test approaches and strategies in an evolving development environment. The early flight test spacecraft are evolving in design maturity and complexity requiring significant changes in the ground test operations for each mission. The testing approach for EM-2 is planned to validate innovative Orion production acceptance testing methods to support human exploration missions in the future. Manufacturing and testing at Kennedy Space Center in the Neil Armstrong Operations and Checkout facility will provide a seamless transition directly to the launch site avoiding transportation and checkout of the spacecraft from other locations

Components of Metabolic Syndrome and 5-Year Chance in Insulin Clearance - The Resistance Atherosclerosis Study (IRAS)

Aims Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidaemia and glycaemia are associated with reduced metabolic clearance rate of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI. Methods At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Results We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR [β = −0.057 (95% confidence interval, CI: −0.11, −0.0084) for TG, β = −0.0019 (95% CI: −0.0035, −0.00023) for systolic BP and β  = −0.0084 (95% CI: −0.013, −0.0039) for WC; all p \u3c 0.05]. Higher HDL cholesterol at baseline was associated with an increase in MCRI [multivariable-adjusted β = 0.0029 (95% CI: 0.0010, 0.0048), p = 0.002]. FBG at baseline was not associated with MCRI at follow-up [multivariable-adjusted β = 0.0014 (95% CI: −0.0026, 0.0029)]. Conclusions MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI

Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium.

ObjectivePopulations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.MethodsLevels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis.ResultsIn the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2  = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT.ConclusionsPNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry

Lessons from clinical implementation of a preemptive pharmacogenetic panel as part of a testing pilot program with an employer-sponsored medical plan

Introduction: This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing.Methods: The pilot program adopted a partially preemptive approach, targeting patients on current prescriptions for medications with relevant gene-drug associations. Patients were contacted via phone or through the MyChart system and offered pharmacogenetic testing with no additional direct costs.Results: Of 244 eligible patients, 110 agreed to participate. However, only 61 returned the mailed DNA collection kits. Among these, 89% had at least one potentially actionable genotype-based phenotype. Post-test follow-up revealed that while the majority viewed the process positively, 71% preferred a consultation with a pharmacogenetic specialist for better understanding of their results. Barriers to implementation ranged from fatigue with the healthcare system to a lack of understanding of the pharmacogenetic testing and concerns about privacy and potential misuse of genetic data.Conclusion: The findings underscore the need for clearer patient education on pharmacogenetic results and suggest the importance of the role of pharmacogenetic-trained pharmacists in delivering this education. They also highlight issues with relying on incomplete or inaccurate medication lists in patients’ electronic health record. The implementation revealed less obvious challenges, the understanding of which could be beneficial for the success of future preemptive pharmacogenetic implementation programs. The insights from the pilot program served to bridge the information gap between patients, providers, and pharmacogenetic -specialists, with the ultimate goal of improving patient care

25(OH)D Levels in Infancy Is Associated With Celiac Disease Autoimmunity in At-Risk Children: A Case–Control Study

Objectives: An observed variation in the risk of celiac disease, according to the season of birth, suggests that vitamin D may affect the development of the disease. The aim of this study was to investigate if vitamin D concentration is associated with the risk of celiac disease autoimmunity (CDA) in genetically at-risk children.Study Design: Children prospectively followed in the multinational The Environmental Determinants of Diabetes in the Young study, conducted at six centers in Europe and the US, were selected for a 1-to-3 nested case-control study. In total, 281 case-control sets were identified. CDA was defined as positivity for tissue transglutaminase autoantibodies (tTGA) on two or more consecutive visits. Vitamin D was measured as 25-hydroxyvitamin D [25(OH)D] concentrations in all plasma samples prior to, and including, the first tTGA positive visit. Conditional logistic regression was used to examine the association between 25(OH)D and risk of CDA.Results: No significant association was seen between 25(OH)D concentrations (per 5 nmol/L increase) and risk for CDA development during early infancy (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.95-1.04) or childhood (OR 1.02, 95% CI 0.97-1.07). When categorizing 25(OH)D concentrations, there was an increased risk of CDA with 25(OH)D concentrations 75 nmol/L (OR 2.10, 95% CI 1.28-3.44) in early infancy, as compared with 50-75 nmol/L.Conclusion: This study indicates that 25(OH)D concentrations 75 nmol/L during early infancy were associated with an increased risk of developing CDA in genetically at-risk children. The non-linear relationship raises the need for more studies on the possible role of 25(OH)D in the relation to celiac disease onset.</p

Precision Medicine in Diabetes: A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as "diabetes." Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.R01 HD094150/HD/NICHD NIH HHS/United States DP3 DK111906/DK/NIDDK NIH HHS/United States U01 DK105535/DK/NIDDK NIH HHS/United States R01 DK104942/DK/NIDDK NIH HHS/United States U54 DK118612/DK/NIDDK NIH HHS/United States R21 AI142483/AI/NIAID NIH HHS/United States R01 DK122586/DK/NIDDK NIH HHS/United States P30 DK026687/DK/NIDDK NIH HHS/United States WT_/Wellcome Trust/United Kingdom R01 DK052431/DK/NIDDK NIH HHS/United States UL1 TR001873/TR/NCATS NIH HHS/United States R01 DK104351/DK/NIDDK NIH HHS/United Statesaccepted version, submitted versio