Iron Metabolism and Type 2 Diabetes Incidence

OBJECTIVE: Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D. RESEARCH DESIGN AND METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. RESULTS: Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01). CONCLUSIONS: The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.We thank all EPIC participants and staff for their contribution to the study. We thank Nicola Kerrison (MRC Epidemiology Unit, Cambridge) for managing the data for the InterAct Project. We thank Dr Felix Day (MRC Epidemiology Unit, Cambridge) for assistance with figures. Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: IS, JWJB and YTvdS: Verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht (The Netherlands); HBBdM, AMWS and DLvdA: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); FLC: Cancer Research UK; PWF: Swedish Research Council, Novo nordisk, Swedish Heart Lung Foundation, Swedish Diabetes Association; JH, KO and AT: Danish Cancer Society; RK: Deutsche Krebshilfe; SP: Associazione Italiana per la Ricerca sul Cancro; JRQ: Asturias Regional Government; MT: Health Research Fund (FIS) of the Spanish Ministry of Health; the CIBER en Epidemiología y Salud Pública (CIBERESP), Spain; Murcia Regional Government (Nº 6236); RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government. Biomarker measurements in the EPIC-InterAct subcohort were partially funded by a grant from the UK Medical Research Council and British Heart Foundation (EPIC-Heart: G0800270). Clara Podmore is funded by the Wellcome Trust (097451/Z/11/Z).This is the author accepted manuscript. The final version is available at http://care.diabetesjournals.org/content/early/2016/01/29/dc15-0257.abstract

FADO: A statistical method to detect favored or avoided distances between occurrences of motifs using the Hawkes' model

article n° 24International audienceWe propose an original statistical method to estimate how the occurrences of a given process along a genome, genes or motifs for instance, may be influenced by the occurrences of a second process. More precisely, the aim is to detect avoided and/or favored distances between two motifs, for instance, suggesting possible interactions at a molecular level. For this, we consider occurrences along the genome as point processes and we use the so-called Hawkes' model. In such model, the intensity at position t depends linearly on the distances to past occurrences of both processes via two unknown profile functions to estimate. We perform a non parametric estimation of both profiles by using B-spline decompositions and a constrained maximum likelihood method. Finally, we use the AIC criterion for the model selection. Simulations show the excellent behavior of our estimation procedure. We then apply it to study (i) the dependence between gene occurrences along the E. coli genome and the occurrences of a motif known to be part of the major promoter for this bacterium, and (ii) the dependence between the yeast S. cerevisiae genes and the occurrences of putative polyadenylation signals. The results are coherent with known biological properties or previous predictions, meaning this method can be of great interest for functional motif detection, or to improve knowledge of some biological mechanism

FADO: A Statistical Method to Detect Favored or Avoided Distances between Occurrences of Motifs using the Hawkes' Model

We propose an original statistical method to estimate how the occurrences of a given process along a genome, genes or motifs for instance, may be influenced by the occurrences of a second process. More precisely, the aim is to detect avoided and/or favored distances between two motifs, for instance, suggesting possible interactions at a molecular level. For this, we consider occurrences along the genome as point processes and we use the so-called Hawkes' model. In such model, the intensity at position t depends linearly on the distances to past occurrences of both processes via two unknown profile functions to estimate. We perform a non parametric estimation of both profiles by using B-spline decompositions and a constrained maximum likelihood method. Finally, we use the AIC criterion for the model selection. Simulations show the excellent behavior of our estimation procedure. We then apply it to study (i) the dependence between gene occurrences along the E. coli genome and the occurrences of a motif known to be part of the major promoter for this bacterium, and (ii) the dependence between the yeast S. cerevisiae genes and the occurrences of putative polyadenylation signals. The results are coherent with known biological properties or previous predictions, meaning this method can be of great interest for functional motif detection, or to improve knowledge of some biological mechanisms.

Exploring the treatment gap among patients with osteoporosis-related fractures in France

International audienceThe use of anti-osteoporosis treatment following a diagnosis of osteoporosis with fracture or a relevant fragility fracture remains low in France. Initiating an anti-resorptive may reduce the incidence of a subsequent fracture by 60%. Purpose To describe real-world osteoporosis treatment patterns in individuals with a fragility fracture in France and to explore the impact of initiating treatment on the risk of subsequent fracture. Methods A retrospective cohort study, using the national French Health Insurance claims database. Males and females 50 years and over, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture between 2011 and 2014, were included and followed until death or the end of 2016, whichever came first. The primary outcome was the proportion of patients receiving anti-osteoporosis treatments prior to and post-index fracture. Change in fracture rates before and after treatment initiation was assessed in an exploratory analysis. Results A total of 574,133 patients (138,567 males, 435,566 females) had a qualifying index fracture. The proportion of patients receiving any anti-osteoporosis treatment increased pre-index fracture to post-index fracture from 2.2 to 5.6% among males, and from 11.8 to 18.2% among females. Oral bisphosphonates were the most prescribed anti-osteoporosis treatment for both males and females among post-index fractures (60.6% and 68.8% of patients initiating treatment). Following initiation of anti-resorptives, the incidence of subsequent fracture was reduced by 60% (rate ratio (RR): 0.40, 95% confidence interval [CI]: 0.34-0.45). Conclusion Anti-osteoporosis treatment following an index fracture in France remains low. Improved identification and pharmacologic management of patients at risk of fragility fractures are necessary to reduce the risk of subsequent fractures

Gonadal hormonal factors before menopause and incident type 2 diabetes in women: A 22-year follow-up of 83 799 women from the E3N cohort study

International audienceBackground In many populations the incidence of type 2 diabetes is higher in men than in women. This may be explained by exposure to female gonadal hormones, but so far, there is no consensus on their role over the life course in type 2 diabetes etiology. Methods Data are from 83 799 French women from the E3N (Etude epidemiologique de Femmes de la Mutuelle Generale de l'Education Nationale) cohort study, followed for 22 years. Multivariable Cox models including classical risk factors were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) between gonadal hormonal factors and incident type 2 diabetes. Results Older age at menarche, more menstrual cycles, older age at menopause, longer duration of exposure to gonadal hormones and breastfeeding were inversely associated with incident type 2 diabetes cases (n = 4806). While a longer duration of menstrual cycles (HR = 1.23 [95% CI: 1.07-1.41] comparing &gt;= 32 vs &lt;= 24 days) and use of contraceptive pills (HR = 1.33 [1.25-1.42]) were associated with a greater risk of type 2 diabetes. Conclusions In women, a longer exposure to endogenous gonadal hormones with a later menopause as well as breastfeeding were associated with a lower risk of developing type 2 diabetes, independently of classical diabetes risk factors. In contrast, the use of contraceptive agents was associated with incident diabetes, but the influence of each type of contraception and of exposure duration remain to be investigated

Growth trajectories of body mass index during childhood: associated factors and health outcome at adulthood

International audienceObjective To identify body mass index (BMI) trajectories from birth to age 10 years and to assess their association with child and parental characteristics and with adult nutritional status and metabolic risk factors. Study design Retrospective cohort study with 1188 subjects aged 20-60 years. Childhood growth was assessed using measured weight and height data collected retrospectively from health booklets, which also provided information on gestational age, birth weight, and early nutrition. Height, weight, waist circumference, fasting blood glucose, lipids profile, and blood pressure were measured at adulthood. Participants self-reported parental silhouette based on a 9-figural scale. Group-based modeling was applied to identify BMI trajectories. Associations were assessed using ANOVA and multiple logistic regression. Results Five growth trajectories following or crossing BMI percentiles emerged: stable-25th (15.3% of the sample), stable-50th (35.9%), stable-75th (28.0%), ascending-75th (19.2%), and ascending-obesity (1.6%). Overall, associated factors from early life were mother's corpulence (higher in the ascending-obesity group), gestational age (higher in the stable-50th, stable-75th, and in the ascending-obesity groups), and birth weight (higher in the ascending-obesity group) (all P < .05). Childhood trajectories were associated with adult BMI and waist circumference (higher in the stable-75th and in the ascending groups) (all P < .0001). Conclusions This study shows heterogeneity in patterns of growth trajectories. Specific trajectories were associated with greater BMI and waist circumference during adulthood. Monitoring growth trajectories may improve chronic disease prevention

Heme iron intake, dietary antioxidant capacity, and risk of colorectal adenomas in a large cohort study of french women

International audienceBackground: Nitrosylated and non-nitrosylated heme iron from red processed and nonprocessed meat have been associated with increased colorectal carcinogenesis. Mechanisms include oxidative processes. It has been hypothesized that dietary antioxidants could counteract the effects of heme iron. We investigated the relationships between heme iron intake and the risk of colorectal adenomas, and a potential interaction with the dietary antioxidant capacity, in the E3N prospective cohort study. Methods: The study included 17,397 women, who underwent at least one colonoscopy. Among them, 1,409 were diagnosed with at least one first colorectal adenoma during the 103,253 person-years of follow-up. Dietary intake was measured by a semiquantitative food history questionnaire. HR estimates and 95% confidence intervals (CI) were obtained from Cox proportional hazards models, adjusted for potential confounders. Results: Heme iron intake was positively associated with colorectal and colon adenoma risks [HR for the fourth vs. first quartile: HR4 = 1.36 (1.13-1.65), P-trend = 0.001 and HR4 = 1.49; 95% CI, 1.19-1.87; P-trend = 0.0003, respectively]. Nonnitrosylated and nitrosylated heme iron intakes were, respectively, associated with advanced distal and proximal adenoma risks. There was a dose-effect relationship between the heme iron to total dietary anti-oxidant capacity ratio and colorectal adenoma risk. Conclusion: In this prospective cohort study, the association between heme iron and colorectal adenoma risk was found to depend on site, nitrosylation or not, and the ratio with the NEAC. Impact: These results emphasize the need for a global assessment of diet when considering nutritional prevention of colorectal carcinogenesis

High baseline insulin levels associated with 6-year incident observed sleep apnea.: Hyperinsulinaemia precedes incident observed sleep apnea

Abstract: 250 words Text: 2938 words, 17 pages One on-line appendix 3 tables 22 referencesInternational audienceOBJECTIVE: Obstructive sleep apnea is common in patients with type 2 diabetes, and its association with insulin and insulin resistance has been examined in cross-sectional studies. We evaluate risk factors for incident observed sleep apnea in a general population not selected for sleep disturbances. RESEARCH DESIGN AND METHODS: A total of 1,780 men and 1,785 women, aged 33 to 68 years, from the cohort Data from an Epidemiologic Study on the Insulin Resistance Syndrome (D.E.S.I.R.) responded to the question, "Has someone said to you that you stop breathing during your sleep?" at baseline and 6 years. Anthropometric, clinical, and biological factors were recorded at both time points. RESULTS: At baseline, 14% of men and 7% of women reported having observed sleep apnea (positive response to question); 6-year incidences were 14 and 6%, respectively. Age, anthropometric parameters, blood pressure, and sleep characteristics were all associated with prevalent, observed apnea episodes, in both sexes. Baseline waist circumference was the strongest predictor of incident apnea: standardized odds ratio (OR), adjusted for age and sex, 1.34 (95% CI 1.19-1.52). After adjustment for age, sex, and waist circumference, the standardized ORs for incident observed apnea were identical for fasting insulin and the homeostasis model assessment of insulin resistance: 1.31 (1.13-1.51) and 1.24 (1.09-1.41) for triglycerides and 1.52 (1.12-2.05) for smoking. Observed apnea at baseline was not associated with changes in anthropometric or biological parameters over the 6-year follow-up. CONCLUSIONS: The most important baseline risk factor for incident apnea was adiposity. After accounting for adiposity, other risk factors were high insulin, insulin resistance, high triglycerides, and smoking, factors amenable to lifestyle intervention

Survival of patients with chronic acid sphingomyelinase deficiency (ASMD) in the United States: A retrospective chart review study

Background: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann–Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients. Methods: This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan–Meier survival analyses from birth until death. Results: The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD “non-type A'' (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications. Conclusion: Patients with chronic ASMD in the United States have poor survival and significant burden of illness

Data from: Should the WHO growth charts be used in France?

Background: Growth charts are an essential clinical tool for evaluating a child's health and development. The current French reference curves, published in 1979, have recently been challenged by the 2006 World Health Organization (WHO) growth charts. Objective: To evaluate and compare the growth of French children who were born between 1981 and 2007, with the WHO growth charts and the French reference curves currently used. Design: Anthropometric measurements from French children, who participated in 12 studies, were analyzed: 82,151 measurements were available for 27,257 children in different age groups, from birth to 18 years. We calculated and graphically compared mean z-scores based on the WHO and French curves, for height, weight and Body Mass Index (BMI) according to age and sex. The prevalence of overweight using the WHO, the French and International Obesity Task Force definitions were compared. Results: Our population of children was on average 0.5 standard deviations taller than the French reference population, from the first month of life until puberty age. Mean z-scores for height, weight and BMI were closer to zero based on the WHO growth charts than on the French references from infancy until late adolescence, except during the first six months. These differences not related to breastfeeding rates. As expected, the prevalence of overweight depended on the reference used, and differences varied according to age. Conclusion: The WHO growth charts may be appropriate for monitoring growth of French children, as the growth patterns in our large population of French children were closer to the WHO growth charts than to the French reference curves, from 6 months onwards. However, there were some limitations in the use of these WHO growth charts, and further investigation is needed