Baseline phenotypes with preserved ß-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies.

BACKGROUND: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. METHODS: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). RESULTS: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and ß-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. CONCLUSIONS: Individuals with preserved ß-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.

Decreased expression of mitochondrial aminoacyl-tRNA synthetases causes downregulation of OXPHOS subunits in type 2 diabetic muscle.

Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is one of the most important tissues involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2). GSEA analysis from microarray studies revealed the repression of mitochondrial mt-aaRSs independently of age, which was validated by real-time PCR assays. In agreement with this, a reduced expression of several encoding mt-aaRSs was also detected in skeletal muscle from diabetic (db/db) mice but not in obese ob/ob mice. In addition, the expression of the mt-aaRSs proteins most relevant in the synthesis of mitochondrial proteins, threonyl-tRNA, and leucyl-tRNA synthetases (TARS2 and LARS2) were also repressed in muscle from db/db mice. It is likely that these alterations participate in the reduced expression of proteins synthesized in the mitochondria detected in db/db mice. We also document an increased iNOS abundance in mitochondrial-enriched muscle fractions from diabetic mice that may inhibit aminoacylation of TARS2 and LARS2 by nitrosative stress. Our results indicate a reduced expression of mt-aaRSs in skeletal muscle from T2D patients, which may participate in the reduced expression of proteins synthesized in mitochondria. An enhanced mitochondrial iNOS could play a regulatory role in diabetes.

Perspectives on a Way Forward to Implementation of Precision Medicine in Patients With Diabetic Kidney Disease; Results of a Stakeholder Consensus-Building Meeting.

Aim: This study aimed to identify from different stakeholders the benefits and obstacles of implementing precision medicine in diabetic kidney disease (DKD) and to build consensus about a way forward in order to treat, prevent, or even reverse this disease. Methods: As part of an ongoing effort of moving implementation of precision medicine in DKD forward, a two-day consensus-building meeting was organized with different stakeholders involved in drug development and patient care in DKD, including patients, patient representatives, pharmaceutical industry, regulatory agencies representatives, health technology assessors, healthcare professionals, basic scientists, and clinical academic researchers. The meeting consisted of plenary presentations and discussions, and small group break-out sessions. Discussion topics were based on a symposium, focus groups and literature search. Benefits, obstacles and potential solutions toward implementing precision medicine were discussed. Results from the break-out sessions were presented in plenary and formed the basis of a broad consensus discussion to reach final conclusions. Throughout the meeting, participants answered several statement and open-ended questions on their mobile device, using a real-time online survey tool. Answers to the statement questions were analyzed descriptively. Results of the open-ended survey questions, the break-out sessions and the consensus discussion were analyzed qualitatively. Results and conclusion: Seventy-one participants from 26 countries attended the consensus-building meeting in Amsterdam, April 2019. During the opening plenary on the first day, the participants agreed with the statement that precision medicine is the way forward in DKD (n = 57, median 90, IQR [75-100]). Lack of efficient tools for implementation in practice and generating robust data were identified as significant obstacles. The identified benefits, e.g., improvement of the benefit-risk ratio of treatment, offer substantive incentives to find solutions for the identified obstacles. Earlier and increased multi-stakeholder collaboration and specific training may provide solutions to alter clinical and regulatory guidelines that lie at the basis of both obstacles and solutions. At the end of the second day, the opinion of the participants toward precision medicine in DKD was somewhat more nuanced (n = 45, median 83, IQR [70-92]) and they concluded that precision medicine is an important way forward in improving the treatment of patients with DKD.

Metabolite Changes After Metabolic Surgery - Associations to Parameters Reflecting Glucose Homeostasis and Lipid Levels.

Aims: To test the hypothesis that adipose tissue gene expression patterns would be affected by metabolic surgery and we aimed to identify genes and metabolic pathways as well as metabolites correlating with metabolic changes following metabolic surgery. Materials and Methods: This observational study was conducted at the Obesity Unit at the Catholic University Hospital of the Sacred Heart in Rome, Italy. Fifteen patients, of which six patients underwent Roux-en-Y gastric bypass and nine patients underwent biliopancreatic diversion, were included. The participants underwent an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Small polar metabolites were analyzed with a two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Gene expression analysis of genes related to metabolism of amino acids and fatty acids were analyzed in subcutaneous adipose tissue. All procedures were performed at study start and at follow-up (after 185.3 ± 72.9 days). Results: Twelve metabolites were significantly changed after metabolic surgery. Six metabolites were identified as 3-indoleacetic acid, 2-hydroxybutyric acid, valine, glutamic acid, 4-hydroxybenzeneacetic acid and alpha-tocopherol. The branched chain amino acids displayed a significant decrease together with a decrease in BCAT1 adipose tissue mRNA levels. Changes in the identified metabolites were associated to changes in lipid, insulin and glucose levels. Conclusions: Our study has identified metabolites and metabolic pathways that are altered by metabolic surgery and may be used as biomarkers for metabolic improvement.

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.

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 realise 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.

Insulin sensitivity depends on the route of glucose administration.

AIMS/HYPOTHESIS: The small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels. METHODS: In this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment. RESULTS: Glucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min-1 kg-1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min-1 kg-1 (nmol/l)-1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration. CONCLUSIONS/INTERPRETATION: Our study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT03223129. Graphical abstract.

Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From a Diabetes Care Editors' Expert Forum.

Individualization of therapy based on a person's specific type of diabetes is one key element of a "precision medicine" approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic diabetes, for which single gene mutations are causal, is the category most suited to a precision approach. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of Diabetes Care convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.

Phenotypic Responses to a Lifestyle Intervention Do Not Account for Inter-Individual Variability in Glucose Tolerance for Individuals at High Risk of Type 2 Diabetes.

Background: Lifestyle interventions have been shown to delay or prevent the onset of type 2 diabetes among high risk adults. A better understanding of the variability in physiological responses would support the matching of individuals with the best type of intervention in future prevention programmes, in order to optimize risk reduction. The purpose of this study was to determine if phenotypic characteristics at baseline or following a 12 weeks lifestyle intervention could explain the inter-individual variability in change in glucose tolerance in individuals with high risk for type 2 diabetes. Methods: In total, 285 subjects with normal glucose tolerance (NGT, FINDRISC score > 12), impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were recruited for a 12 weeks lifestyle intervention. Glucose tolerance, insulin sensitivity, anthropometric characteristics and aerobic fitness were measured. Variability of responses was examined by grouping participants by baseline glycemic status, by cluster analysis based on the change in glucose tolerance and by Principal Component Analysis (PCA). Results: In agreement with other studies, the mean response to the 12 weeks intervention was positive for the majority of parameters. Overall, 89% improved BMI, 80% waist circumference, and 81% body fat while only 64% improved fasting plasma glucose and 60% 2 h glucose. The impact of the intervention by glycaemic group did not show any phenotypic differences in response between NGT, IFG, and IGT. A hierarchical cluster analysis of change in glucose tolerance identified four sub-groups of "responders" (high and moderate) and "non-responders" (no response or deteriorated) but there were few differences in baseline clincal and physiological parameters or in response to the intervention to explain the overall variance. A further PCA analysis of 19 clinical and physiological univariables could explain less than half (48%) of total variability. Conclusion: We found that phenotypic characteristics from standard clinical and physiological parameters were not sufficient to account for the inter-individual variability in glucose tolerance following a 12 weeks lifestyle intervention in inidivuals at high risk for type 2 diabetes. Further work is required to identify biomarkers that complement phenotypic traits and better predict the response to glucose tolerance.

Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation.

AIMS: Epigenetic mechanisms regulate gene expression and may influence the pathogenesis of type 2 diabetes through the loss of insulin sensitivity. The aims of this study were to measure variation in DNA methylation at the type 2 diabetes locus KCNQ1 and assess its relationship with metabolic measures and with genotype. METHODS: DNA methylation from whole blood DNA was quantified using pyrosequencing at 5 CpG sites at the KCNQ1 locus in 510 individuals without diabetes from the 'Relationship between Insulin Sensitivity and Cardiovascular disease' (RISC) cohort. Genotype data was analysed at the same locus in 1119 individuals in the same cohort. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp. RESULTS: DNA methylation at the KCNQ1 locus was inversely associated with insulin sensitivity and serum adiponectin. This association was driven by a methylation-altering Single Nucleotide Polymorphism (SNP) (rs231840) which ablated a methylation site and reduced methylation levels. A second SNP (rs231357), in weak Linkage Disequilibrium (LD) with rs231840, was also associated with insulin sensitivity and DNA methylation. These SNPs have not been previously reported to be associated with type 2 diabetes risk or insulin sensitivity. CONCLUSION: Evidence indicates that genetic and epigenetic determinants at the KCNQ1 locus influence insulin sensitivity.

Lipidome as a predictive tool in progression to type 2 diabetes in Finnish men.

BACKGROUND: There is a need for early markers to track and predict the development of type 2 diabetes mellitus (T2DM) from the state of normal glucose tolerance through prediabetes. In this study we tested whether the plasma molecular lipidome has biomarker potential to predicting the onset of T2DM. METHODS: We applied global lipidomic profiling on plasma samples from well-phenotyped men (107 cases, 216 controls) participating in the longitudinal METSIM study at baseline and at five-year follow-up. To validate the lipid markers, an additional study with a representative sample of adult male population (n=631) was also conducted. A total of 277 plasma lipids were analyzed using the lipidomics platform based on ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. Lipids with the highest predictive power for the development of T2DM were computationally selected, validated and compared to standard risk models without lipids. RESULTS: A persistent lipid signature with higher levels of triacylglycerols and diacyl-phospholipids as well as lower levels of alkylacyl phosphatidylcholines was observed in progressors to T2DM. Lysophosphatidylcholine acyl C18:2 (LysoPC(18:2)), phosphatidylcholines PC(32:1), PC(34:2e) and PC(36:1), and triacylglycerol TG(17:1/18:1/18:2) were selected to the full model that included metabolic risk factors and FINDRISC variables. When further adjusting for BMI and age, these lipids had respective odds ratios of 0.32, 2.4, 0.50, 2.2 and 0.31 (all p<0.05) for progression to T2DM. The independently-validated predictive power improved in all pairwise comparisons between the lipid model and the respective standard risk model without the lipids (integrated discrimination improvement IDI>0; p<0.05). Notably, the lipid models remained predictive of the development of T2DM in the fasting plasma glucose-matched subset of the validation study. CONCLUSION: This study indicates that a lipid signature characteristic of T2DM is present years before the diagnosis and improves prediction of progression to T2DM. Molecular lipid biomarkers were shown to have predictive power also in a high-risk group, where standard risk factors are not helpful at distinguishing progressors from non-progressors.

Study protocol for the Cities Changing Diabetes programme: a global mixed-methods approach.

INTRODUCTION: Urban living has been shown to affect health in various ways. As the world is becoming more urbanised and almost two-thirds of people with diabetes now live in cities, research into the relationship between urban living, health and diabetes is key to improving the lives of many. The majority of people with diabetes have type 2 diabetes, a subset linked to overweight and obesity, decreased physical activity and unhealthy diets. Diabetes has significant consequences for those living with the condition as well as their families, relationships and wider society. Although care and management are improving, complications remain common, and diabetes is among the leading causes of vision loss, amputation, neuropathy and renal and cardiovascular disease worldwide. We present a research protocol for exploring the drivers of type 2 diabetes and its complications in urban settings through the Cities Changing Diabetes (CCD) partnership programme. METHODS AND ANALYSIS: A global study protocol is implemented in eight collaborating CCD partner cities. In each city, academic institutions, municipal representatives and local stakeholders collaborate to set research priorities and plan implementation of findings. Local academic teams execute the study following the global study protocol presented here. A quantitative Rule of Halves analysis obtains measures of the magnitude of the diabetes burden, the diagnosis rates in each city and the outcomes of care. A qualitative Diabetes Vulnerability Assessment explores the urban context in vulnerability to type 2 diabetes and identifies social factors and cultural determinants relevant to health, well-being and diabetes. ETHICS AND DISSEMINATION: The protocol steers the collection of primary and secondary data across the study sites. Research ethics board approval has been sought and obtained in each site. Findings from each of the local studies as well as the result from combined multisite (global) analyses will be reported in a series of core scientific journal papers.

Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism.

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes.

Is there evidence of potential overtreatment of glycaemia in elderly people with type 2 diabetes? Data from the GUIDANCE study.

AIMS: We used data from the GUIDANCE Study to determine the care of people with type 2 diabetes according to age and accompanying cardiovascular diseases and to assess indicators of overtreatment of glycaemia. METHODS: The GUIDANCE study was a retrospective, cross-sectional study from 2009-2010 based on the records of 7597 people in France, Belgium, Italy, the Netherlands, Sweden, UK, Ireland and Germany. We analysed the level of metabolic control achieved and blood glucose-lowering medication used in different age groups and in relation to accompanying diseases. RESULTS: 4.459 patients (59.1%) were 65 years or older. Their HbA1c levels were similar to those with <65 years. 44.7% of patients ≥65 years had an HbA1c ≤7% (53 mmol/mol) and were treated with insulin or sulfonylureas, and 27.1% of them had ischaemic heart disease or congestive heart failure. Significantly more patients with heart disease had HbA1c values ≤7% (53 mmol/mol) and were treated more often with insulin or sulfonylureas compared to patients of the same age without heart disease. CONCLUSIONS: Most patients were treated according to guidelines valid at the time this large international patient sample was surveyed. Older and younger patients were at a similar level of metabolic control, and almost half of the patients with an age of ≥65 years and treated with insulin or sulfonylurea had HbA1c levels below the target range (≤7%) for younger patients. However, these patients have an increased risk of severe hypoglycaemic events with potentially dangerous complications, particularly in those with cardiovascular diseases.

Testosterone causes both prosocial and antisocial status-enhancing behaviors in human males.

Although popular discussion of testosterone's influence on males often centers on aggression and antisocial behavior, contemporary theorists have proposed that it instead enhances behaviors involved in obtaining and maintaining a high social status. Two central distinguishing but untested predictions of this theory are that testosterone selectively increases status-relevant aggressive behaviors, such as responses to provocation, but that it also promotes nonaggressive behaviors, such as generosity toward others, when they are appropriate for increasing status. Here, we tested these hypotheses in healthy young males by injecting testosterone enanthate or a placebo in a double-blind, between-subjects, randomized design (n = 40). Participants played a version of the Ultimatum Game that was modified so that, having accepted or rejected an offer from the proposer, participants then had the opportunity to punish or reward the proposer at a proportionate cost to themselves. We found that participants treated with testosterone were more likely to punish the proposer and that higher testosterone levels were specifically associated with increased punishment of proposers who made unfair offers, indicating that testosterone indeed potentiates aggressive responses to provocation. Furthermore, when participants administered testosterone received large offers, they were more likely to reward the proposer and also chose rewards of greater magnitude. This increased generosity in the absence of provocation indicates that testosterone can also cause prosocial behaviors that are appropriate for increasing status. These findings are inconsistent with a simple relationship between testosterone and aggression and provide causal evidence for a more complex role for testosterone in driving status-enhancing behaviors in males.

Beta-cell function is associated with carotid intima-media thickness independently of insulin resistance in healthy individuals.

OBJECTIVE: It is a common belief that early atherosclerosis in prediabetes is causally linked to endothelial insulin resistance. Another condition, a low insulin secretion, may be associated with insufficient insulin action on the vascular wall and consequently favor atherosclerosis. Our aim was to test this hypothesis in people without diabetes, taking into account the gold-standard measurement of insulin sensitivity, a major confounder in the relationship between insulin secretion and atherosclerosis. METHODS: We studied the European Relationship between Insulin Sensitivity and Cardiovascular Risk cohort of 451 men and 593 women (44 ±â€Š8 years, mean ±â€ŠSD) who were free of diabetes, hypertension, dyslipidemia, and other known chronic or acute conditions. All underwent an oral glucose tolerance test, a euglycemic-hyperinsulinemic clamp (M/I measured insulin sensitivity), and B-mode carotid ultrasound. RESULTS: Intima-media thickness (IMT) in the common carotid artery was negatively associated with insulin secretion indexes, with Spearman partial correlation coefficients: -0.09, -0.08, -0.06 for respectively, the disposition index, the early insulin response and the beta cell glucose sensitivity, after adjusting for established factors, including clamp-measured insulin sensitivity (all P < 0.05). For quartiles 1 (lowest) to 4 of the disposition index, the covariate-adjusted geometric means of IMT (mm) were 0.605 (95% confidence interval: 0.596-0.614), 0.596 (0.587-0.605), 0.597 (0.587-0.606), and 0.586 (0.577-0.596) (Ptrend = 0.004). Similar results were found for the two other surrogate measures of insulin secretion. No interaction with sex was observed. CONCLUSION: Insulin secretion was associated with early carotid atherosclerosis in nondiabetic individuals, independently of other risk factors, including insulin sensitivity measured by the gold-standard method.

An evaluation of the DEXLIFE 'self-selected' lifestyle intervention aimed at improving insulin sensitivity in people at risk of developing type 2 diabetes: study protocol for a randomised controlled trial.

BACKGROUND: With the global escalation of type 2 diabetes and evidence consistently showing that its onset can be prevented or delayed by changing lifestyle behaviours, there is an urgent need to translate practical, affordable and acceptable interventions from the research setting into the real world. One such approach to lifestyle interventions might be the introduction of a programme in which the individual is provided with choice and facilitated to 'self-select' an exercise programme. Previous research has shown that this is likely to be less resource intensive, an essential requirement for success outside the controlled research environment, while at the same time promoting positive responses relating to adherence, competence and self-efficacy, essential attributes for long-term success. Through a two-group parallel-randomised controlled trial, this study aims to assess the clinical and psychological impact of the DEXLIFE 'self-selected' lifestyle modification programme in adults at risk of developing type 2 diabetes. METHODS/DESIGN: A total of 360 subjects at risk of developing type 2 diabetes are randomly assigned in a 1:3 ratio to a control (n = 90) or intervention arm (n = 270). Randomization is stratified by age, sex and body mass index. The control arm receives general information on lifestyle and diabetes risk. The intervention group participate in a 12 week 'self-selected' supervised exercise training programme accompanied with dietary advice to improve food choices. Participants are given access to Dublin City University Sport (an on-campus gym) and asked to perform four exercise classes per week. Dublin City University Sport offers over 50 classes per week, many of which are medically supervised. If weight loss is indicated, reduction in total calorie intake by 600 kcal/day is advised. Common to all food plans is <10% saturated fat intake, as well as a dietary fibre intake of >15 g/1000 kcal. Insulin sensitivity is the primary outcome measure. Secondary outcome measures include glucose function, fitness, body composition, anthropometrics, heart rate variability, lipid profiles, blood pressure, physical activity levels, dietary intake and quality of life. DISCUSSION: "Self-selected" lifestyle intervention has not previously been evaluated in type 2 diabetes prevention and if shown to be successful could be implemented in practice immediately. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN66987085.

Fasting plasma glucose as initial screening for diabetes and prediabetes in irish adults: The Diabetes Mellitus and Vascular health initiative (DMVhi).

OBJECTIVE: Type 2 diabetes has a long pre clinical asymptomatic phase. Early detection may delay or arrest disease progression. The Diabetes Mellitus and Vascular health initiative (DMVhi) was initiated as a prospective longitudinal cohort study on the prevalence of undiagnosed Type 2 diabetes and prediabetes, diabetes risk and cardiovascular risk in a cohort of Irish adults aged 45-75 years. RESEARCH DESIGN AND METHODS: Members of the largest Irish private health insurance provider aged 45 to 75 years were invited to participate in the study. EXCLUSION CRITERIA: already diagnosed with diabetes or taking oral hypoglycaemic agents. Participants completed a detailed medical questionnaire, had weight, height, waist and hip circumference and blood pressure measured. Fasting blood samples were taken for fasting plasma glucose (FPG). Those with FPG in the impaired fasting glucose (IFG) range had a 75gm oral glucose tolerance test performed. RESULTS: 122,531 subjects were invited to participate. 29,144 (24%) completed the study. The prevalence of undiagnosed diabetes was 1.8%, of impaired fasting glucose (IFG) was 7.1% and of impaired glucose tolerance (IGT) was 2.9%. Dysglycaemia increased among those aged 45-54, 55-64 and 65-75 years in both males (10.6%, 18.5%, 21.7% respectively) and females (4.3%, 8.6%, 10.9% respectively). Undiagnosed T2D, IFG and IGT were all associated with gender, age, blood pressure, BMI, abdominal obesity, family history of diabetes and triglyceride levels. Using FPG as initial screening may underestimate the prevalence of T2D in the study population. CONCLUSIONS: This study is the largest screening study for diabetes and prediabetes in the Irish population. Follow up of this cohort will provide data on progression to diabetes and on cardiovascular outcomes.