Evaluation of the Association of IGF2BP2 Variants With Type 2 Diabetes in French Caucasians

OBJECTIVE—We performed a comprehensive genetic association study of common variation spanning the IGF2BP2 locus in order to replicate the association of the “confirmed” type 2 diabetes susceptibility variants rs4402960 and rs1470579 in the French Caucasian population and to further characterize the susceptibility variants at this novel locus

Life cycle sustainability assessment : a tool for exercising due diligence in life cycle management

Starting from the output ‘The Future We Want’ of the Rio+20 conference 2012, the main focus of this chapter is on social responsibility (SR) in the value chain. The historical context of SR is discussed, related to the international standards as are the Guidance on Social Responsibility and the Global Reporting Initiative, linked with the management of organizations and enterprises. It is emphasized that due diligence along the value chain is seen as a requirement for claiming ‘social responsibility’. Life cycle sustainability assessment (LCSA) contributes to the assessment and life cycle management (LCM) to the follow-up of exercising due diligence, all within the context of sustainable development. The over-arching LCSA is a combination of three different life cycle assessment techniques allowing to assess the impacts along the value chain: environmental LCA, social LCA and life cycle costing

Increases in Waist Circumference and Weight As Predictors of Type 2 Diabetes in Individuals With Impaired Fasting Glucose: Influence of Baseline BMI: Data from the DESIR study

OBJECTIVE To evaluate in impaired fasting glucose (IFG) the relative importance of increases in waist circumference and weight on progression to type 2 diabetes. RESEARCH DESIGN AND METHODS The 9-year incidence of diabetes was studied in 979 men and women with baseline IFG, from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. RESULTS Increases in both waist circumference and weight were significantly associated with diabetes incidence. Standardized odds ratios (95% CI) were 1.79 (1.45–2.21) and 1.86 (1.51–2.30), respectively, after controlling for baseline risk factors. The impact of waist circumference increase was greater for BMI <25 kg/m2 (2.40 [1.63–3.52]) than for BMI ≥25 kg/m2 (1.66 [1.28–2.16]) and persisted after adjusting for concurrent changes in either insulinemia or the homeostasis model assessment of insulin resistance index. Weight change had a similar impact in both BMI groups. CONCLUSIONS In individuals with IFG, it is important to monitor and prevent increases in waist circumference, in particular for those with BMI <25 kg/m2

An Evolutionary Reduction Principle for Mutation Rates at Multiple Loci

A model of mutation rate evolution for multiple loci under arbitrary selection is analyzed. Results are obtained using techniques from Karlin (1982) that overcome the weak selection constraints needed for tractability in prior studies of multilocus event models. A multivariate form of the reduction principle is found: reduction results at individual loci combine topologically to produce a surface of mutation rate alterations that are neutral for a new modifier allele. New mutation rates survive if and only if they fall below this surface - a generalization of the hyperplane found by Zhivotovsky et al. (1994) for a multilocus recombination modifier. Increases in mutation rates at some loci may evolve if compensated for by decreases at other loci. The strength of selection on the modifier scales in proportion to the number of germline cell divisions, and increases with the number of loci affected. Loci that do not make a difference to marginal fitnesses at equilibrium are not subject to the reduction principle, and under fine tuning of mutation rates would be expected to have higher mutation rates than loci in mutation-selection balance. Other results include the nonexistence of 'viability analogous, Hardy-Weinberg' modifier polymorphisms under multiplicative mutation, and the sufficiency of average transmission rates to encapsulate the effect of modifier polymorphisms on the transmission of loci under selection. A conjecture is offered regarding situations, like recombination in the presence of mutation, that exhibit departures from the reduction principle. Constraints for tractability are: tight linkage of all loci, initial fixation at the modifier locus, and mutation distributions comprising transition probabilities of reversible Markov chains.Comment: v3: Final corrections. v2: Revised title, reworked and expanded introductory and discussion sections, added corollaries, new results on modifier polymorphisms, minor corrections. 49 pages, 64 reference

Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown

Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women

International audienceOBJECTIVE: The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. RESEARCH DESIGN AND METHODS: We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. RESULTS: In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). CONCLUSIONS: In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes

Physical Activity and Insulin Sensitivity: The RISC Study

OBJECTIVE— Physical activity is a modifiable risk factor for type 2 diabetes, partly through its action on insulin sensitivity. We report the relation between insulin sensitivity and physical activity measured by accelerometry

Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men

CONTEXT: In men, obesity and the metabolic syndrome are accompanied by decreased testosterone levels, but little is known about the associations between visceral adipose tissue (VAT), VAT-related inflammation and sex steroids.OBJECTIVE: To examine the relative impact of VAT, abdominal subcutaneous adipose tissue (SAT) and interleukin 6 (IL-6), a marker of VAT-induced inflammation, on testosterone (T) and 17β-oestradiol (E2) levels in dysmetabolic men. METHODS: We study the NUMEVOX cohort of 229 men, aged 27-77 years, who all had at least one metabolic syndrome criterion (on average three). IL-6, C-reactive protein, Homeostasis Model Assessment of (HOMA) insulin resistance index (HOMA-IR), liver enzymes, E2, LH, sex hormone-binding globulin (SHBG), T, waist circumference and body mass index (BMI) were measured; bioavailable testosterone (BT) was calculated from T and SHBG; MRI-assessed VAT and SAT were analysed in 109 of these men. RESULTS: Visceral adipose tissue was strongly correlated with E2 (Spearman r = 0.38, P &lt; 0.001) and with BT/E2 ratio (r = -0.42, P &lt; 0.001), while SAT was not correlated with either. IL-6 was correlated with E2 (r = 0.19, P = 0.007), BT (r = -0.19, P = 0.006) and BT/E2 ratio (r = -0.30 P &lt; 0.001). In multivariate linear analysis, the relation between VAT and E2 was independent of age, BMI (P = 0.008), leptin (P &lt; 0.001), T and SHBG. Log(IL-6) was significantly inversely related with log(BT) (P = 0.032) independently of age, VAT, leptin and HOMA-IR. CONCLUSIONS: 17β-oestradiol levels were positively associated with VAT, but not with SAT, while T and BT were negatively and independently associated with IL-6. The significant inverse association between IL-6 and T suggests an important role of low-grade visceral fat inflammation in the central hypogonadism associated with the metabolic syndrome

Predicting Diabetes: Clinical, Biological, and Genetic Approaches: Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR)

OBJECTIVE—To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms