Skin microvascular vasodilatory capacity in offspring of two parents with Type 2 diabetes

Aims<br/> Microvascular dysfunction occurs in Type 2 diabetes and in subjects with fasting hyperglycaemia. It is unclear whether this dysfunction relates to dysglycaemia. This study investigated in normogylcaemic individuals whether a genetic predisposition to diabetes, or indices of insulin resistance including endothelial markers, were associated with impaired microvascular function.<br/> Methods<br/> Maximum microvascular hyperaemia to local heating of the skin was measured using laser Doppler flowmetry in 21 normoglycaemic subjects with no family history of diabetes (Group 1) and 21 normoglycaemic age, sex and body mass index-matched offspring of two parents with Type 2 diabetes (Group 2). <br/>Results<br/> Although Group 2 had normal fasting plasma glucose and glucose tolerance tests, the 120-min glucose values were significantly higher at 6.4 (5.3-6.6) mmol/l (median (25th-75th centile)) than the control group at 4.9 (4.6-5.9) mmol/l (P=0.005) and the insulinogenic index was lower at 97.1 (60.9-130.8) vs. 124.0 (97.2-177.7) (P=0.027). Skin maximum microvascular hyperaemia (Group 1: 1.56 (1.39- 1.80) vs. Group 2: 1.53 (1.30-1.98) V, P=0.99) and minimum microvascular resistance which normalizes the hyperaemia data for blood pressure (Group 1: 52.0 (43.2-67.4) vs. Group 2: 56.0 (43.7-69.6) mmHgN, P=0.70) did not differ in the two groups. Significant positive associations occurred between minimum microvascular resistance and indices of the insulin resistance syndrome; plasminogen activator inhibitor type 1 (R-s=0.46, P=0.003), t-PA (R-s=0.36, P=0.03), total cholesterol (R-s=0.35, P=0.02), and triglyceride concentration (R-s=0.35, P=0.02), and an inverse association with insulin sensitivity (R-s=-0.33, P=0.03).<br/> Conclusions<br/> In normoglycaemic adults cutaneous microvascular vasodilatory capacity is associated with features of insulin resistance syndrome, particularly with plasminogen activator inhibitor type 1. A strong family history of Type 2 diabetes alone does not result in impairment in the maximum hyperaemic response

Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium

Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. RWK was funded by a STAR Award Novo Nordisk co-financed PhD fellowship. The work undertaken by PWF was supported in part by programme grants from the ERC-2015-CoG_NASCENT_681742 and the Swedish Research Council; strategic funding for Lund University Diabetes Centre, where some of the work described herein was performed, was provided by the Swedish Research Council, Strategic Research Area Exodiab, (Dnr 2009-1039), the Swedish Foundation for Strategic Research (IRC15-0067), the Swedish Research Council, Linnaeus grant (Dnr 349-2006-237). EP holds a Wellcome Trust Investigator award (grant reference 102820/Z/13/Z). Contributions to this work by SBru. were co-financed by the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001).published version, accepted version (12 month embargo), submitted versio

Analysis of radiation-induced cell death in head and neck squamous cell carcinoma and rat liver maintained in microfluidic devices

Objective The aim of this study was to investigate how head and neck squamous cell carcinoma (HNSCC) tissue biopsies maintained in a pseudo in vivo environment within a bespoke microfluidic device respond to radiation treatment. Study Design Feasibility study. Setting Tertiary referral center. Subjects and Methods Thirty-five patients with HNSCC were recruited, and liver tissue from 5 Wistar rats was obtained. A microfluidic device was used to maintain the tissue biopsy samples in a viable state. Rat liver was used to optimize the methodology. HNSCC was obtained from patients with T1-T3 laryngeal or oropharyngeal SCC; N1-N2 metastatic cervical lymph nodes were also obtained. Irradiation consisted of single doses of between 2 Gy and 40 Gy and a fractionated course of 5×2 Gy. Cell death was assessed in the tissue effluent using the soluble markers lactate dehydrogenase (LDH) and cytochrome c and in the tissue by immunohistochemical detection of cleaved cytokeratin18 (M30 antibody). Results A significant surge in LDH release was demonstrated in the rat liver after a single dose of 20 Gy; in HNSCC, it was seen after 40 Gy compared with the control. There was no significant difference in cytochrome c release after 5 Gy or 10 Gy. M30 demonstrated a dose-dependent increase in apoptotic index for a given increase in single-dose radiotherapy. There was a significant increase in apoptotic index between 1×2 Gy and 5×2 Gy. Conclusion M30 is a superior method compared with soluble markers in detecting low-dose radiation-induced cell death. This microfluidic technique can be used to assess radiation-induced cell death in HNSCC and therefore has the potential to be used to predict radiation response

The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes

Aims/hypothesis Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual’s probability of having MODY, as a crucial tool for rational genetic testing. Methods We developed prediction models using logistic regression on data from 1,191 patients with MODY (n0594), type 1 diabetes (n0278) and type 2 diabetes (n0319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. Results The models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA1c, parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA1c, parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic0 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic00.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis <25 years and an affected parent. The models are now available online at www.diabetesgenes.org. Conclusions/interpretation We have developed clinical prediction models that calculate an individual’s probability of having MODY. This allows an improved and more rational approac

Le secteur des télécommunications surfe-t-il de bulle en bulle ?

Le secteur des télécommunications a connu un développement rapide qui s’est accéléré à partir de la deuxième moitié des années 1990, avec l’apparition du GSM et de l’Internet. Mais la croissance réelle du secteur s’est rapidement transformée en une gigantesque bulle financière qui a été à l’origine de l’une des pires crises sectorielles qu’aient connu les économies modernes. Dans cet article, nous essayons d’identifier les facteurs qui ont conduit à une telle valorisation financière des entreprises de télécommunications ainsi que ceux qui ont conduit au retournement des marchés financiers. Enfin, à la veille de la mise en place de l’UMTS, certains éléments nous amènent à penser qu’une nouvelle bulle pourrait se former dans les années à venir. En annexes, nous simulons la rentabilité financière de l’UMTS et évaluons l’impact macroéconomique de ce projet sur les composantes de la croissance française.The telecommunication sector has recently undergone a fast development which accelerated from the second half of the 1990s, with the rise of the GSM and the Internet. But the actual growth of the sector turned into a gigantic financial bubble which was at the origin of one of the worst sector-based crises that the modern economies had seen. In this article, we try to identify the factors driving such a financial valuation of the telecommunications companies as well as those leading to the reversal of financial markets. Finally, on the verge of the implementation of the UMTS in France, some elements let us think that a new bubble might appear in the coming years. In the appendices, we simulate the financial profitability of the UMTS and estimate the macroeconomic impact of this project on the constituents of French economic growth

Recruitment, augmentation and apoptosis of rat osteoclasts in 1,25-(OH)2D3 response to short-term treatment with 1,25-dihydroxyvitamin D3in vivo

Background Although much is known about the regulation of osteoclast (OC) formation and activity, little is known about OC senescence. In particular, the fate of of OC seen after 1,25-(OH)2D3 administration in vivo is unclear. There is evidence that the normal fate of OC is to undergo apoptosis (programmed cell death). We have investigated the effect of short-term application of high dose 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on OC apoptosis in an experimental rat model. Methods OC recruitment, augmentation and apoptosis was visualised and quantitated by staining histochemically for tartrate resistant acid phosphatase (TRAP), double staining for TRAP/ED1 or TRAP/DAPI, in situ DNA fragmentation end labelling and histomorphometric analysis. Results Short-term treatment with high-dose 1,25-(OH)2D3 increased the recruitment of OC precursors in the bone marrow resulting in a short-lived increase in OC numbers. This was rapidly followed by an increase in the number of apoptotic OC and their subsequent removal. The response of OC to 1,25-(OH)2D3 treatment was dose and site dependent; higher doses producing stronger, more rapid responses and the response in the tibiae being consistently stronger and more rapid than in the vertebrae. Conclusions This study demonstrates that (1) after recruitment, OC are removed from the resorption site by apoptosis (2) the combined use of TRAP and ED1 can be used to identify OC and their precursors in vivo (3) double staining for TRAP and DAPI or in situ DNA fragmentation end labelling can be used to identify apoptotic OC in vivo

Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy

BACKGROUND: Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those in the Apolipoprotein E (ApoE), Lipoprotein Lipase (LPL), and most recently, the Apolipoprotein AV (ApoAV) gene. However, less is known about how variants in these genes alter triglyceride concentrations in pregnancy or affect fetal growth. We aimed to determine the effect of the recently identified ApoAV gene on triglycerides in pregnancy and fetal growth. We assessed the role of two ApoAV haplotypes, defined by the C and W alleles of the -1131T>C and S19W polymorphisms, in 483 pregnant women and their offspring from the Exeter Family Study of Childhood Health. RESULTS: The -1131T>C and S19W variants have rare allele frequencies of 6.7% and 4.9% and are present in 13.4% and 9.7% of subjects respectively. In carriers of the -1131C and 19W alleles triglyceride concentrations were raised by 11.0% (1.98 mmol/ l(1.92 – 2.04) to 2.20 mmol/l (2.01 – 2.42), p = 0.035; and 16.2% (1.97 mmol/l (1.91 – 2.03) to 2.29 mmol/l (2.12 – 2.48), p < 0.001 respectively. There is nominally significant evidence that the -1131T>C variant is having an effect on maternal height (164.9 cm (164.3 – 165.5) to 167.0 cm (165.2 – 168.8), p = 0.029). There was no evidence that ApoAV genotype alters any other anthropometric measurements or biochemistries such as High Density Lipoprotein Cholesterol (HDL-C) or Low Density Lipoprotein Cholesterol (LDL-C). There is nominally significant evidence that the presence of a maternal -1131C variant alters fetal birth length (50.2 cm (50.0 – 50.4) to 50.9 cm (50.3 – 51.4), p = 0.022), and fetal birth crown-rump length (34.0 cm (33.8 – 34.1) to 34.5 cm (34.1 – 35.0), p = 0.023). There is no evidence that ApoAV genotype alters fetal birth weight or other fetal growth measurements. CONCLUSION: In conclusion variation in the ApoAV gene raises triglyceride concentrations in pregnancy, as well as normolipaemic states and there is preliminary evidence that it alters fetal growth parameters

Monitoring the impacts of trade agreements on food environments

The liberalization of international trade and foreign direct investment through multilateral, regional and bilateral agreements has had profound implications for the structure and nature of food systems, and therefore, for the availability, nutritional quality, accessibility, price and promotion of foods in different locations. Public health attention has only relatively recently turned to the links between trade and investment agreements, diets and health, and there is currently no systematic monitoring of this area. This paper reviews the available evidence on the links between trade agreements, food environments and diets from an obesity and non-communicable disease (NCD) perspective. Based on the key issues identified through the review, the paper outlines an approach for monitoring the potential impact of trade agreements on food environments and obesity/NCD risks. The proposed monitoring approach encompasses a set of guiding principles, recommended procedures for data collection and analysis, and quantifiable ‘minimal’, ‘expanded’ and ‘optimal’ measurement indicators to be tailored to national priorities, capacity and resources. Formal risk assessment processes of existing and evolving trade and investment agreements, which focus on their impacts on food environments will help inform the development of healthy trade policy, strengthen domestic nutrition and health policy space and ultimately protect population nutrition.The following organizations provided funding support for the travel of participants to Italy for this meeting and the preparation of background research papers: The Rockefeller Foundation, International Obesity Taskforce (IOTF), University of Auckland, Deakin University, The George Institute, University of Sydney, Queensland University of Technology, University of Oxford, University of Pennsylvania Perelman School of Medicine, World Cancer Research Fund International, University of Toronto, and The Australian National University. The Faculty of Health at Deakin University kindly supported the costs for open access availability of this paper, and the Australian National Health and Medical Research Council Centre for Research Excellence in Obesity Policy and Food Systems (APP1041020) supported the coordination and finalizing of INFORMAS manuscripts

Investigation of eight candidate genes on chromosome 1p36 for autosomal dominant total congenital cataract

Purpose: To identify the causative gene for autosomal dominant total congenital cataract in a six-generation Australian family displaying linkage to chromosome 1p36. Methods: Eight candidate genes (HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2) from within the previously defined linkage interval were selected based on expression in lens and their known or putative function. The coding exons were sequenced in multiple affected family members and compared to the reference sequence. Results: No segregating mutations were identified in any of the eight genes. Thirty-one polymorphisms were detected, 20 of which were in the exons and 11 in the flanking introns. Conclusions: Coding mutations in HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2 do not account for congenital cataract in this family