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Characterizing the phase space distribution of particle beams in accelerators is a central part of understanding beam dynamics and improving accelerator performance. However, conventional analysis methods either use simplifying assumptions or require specialized diagnostics to infer high-dimensional (>2D) beam properties. In this Letter, we introduce a general-purpose algorithm that combines neural networks with differentiable particle tracking to efficiently reconstruct high-dimensional phase space distributions without using specialized beam diagnostics or beam manipulations. We demonstrate that our algorithm accurately reconstructs detailed 4D phase space distributions with corresponding confidence intervals in both simulation and experiment using a limited number of measurements from a single focusing quadrupole and diagnostic screen. This technique allows for the measurement of multiple correlated phase spaces simultaneously, which will enable simplified 6D phase space distribution reconstructions in the future.
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Future improvements in particle accelerator performance are predicated on increasingly accurate online modeling of accelerators. Hysteresis effects in magnetic, mechanical, and material components of accelerators are often neglected in online accelerator models used to inform control algorithms, even though reproducibility errors from systems exhibiting hysteresis are not negligible in high precision accelerators. In this Letter, we combine the classical Preisach model of hysteresis with machine learning techniques to efficiently create nonparametric, high-fidelity models of arbitrary systems exhibiting hysteresis. We experimentally demonstrate how these methods can be used in situ, where a hysteresis model of an accelerator magnet is combined with a Bayesian statistical model of the beam response, allowing characterization of magnetic hysteresis solely from beam-based measurements. Finally, we explore how using these joint hysteresis-Bayesian statistical models allows us to overcome optimization performance limitations that arise when hysteresis effects are ignored.
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Type 1 diabetes mellitus (T1DM) is associated with a high risk of cardiovascular (CV) complications, even after controlling for traditional CV risk factors. Therefore, determinants of the residual increased CV morbidity and mortality remain to be discovered. This prospective cohort of people living with T1DM in France (SFDT1) will include adults and children aged over six years living with T1DM, recruited throughout metropolitan France and overseas French departments and territories. The primary objective is to better understand the parameters associated with CV complications in T1DM. Clinical data and biobank samples will be collected during routine visits every three years. Data from connected tools, including continuous glucose monitoring, will be available during the 10-year active follow-up. Patient-reported outcomes, psychological and socioeconomic information will also be collected either at visits or through web questionnaires accessible via the internet. Additionally, access to the national health data system (Health Data Hub) will provide information on healthcare and a passive 20-year medico-administrative follow-up. Using Health Data Hub, SFDT1 participants will be compared to non-diabetic individuals matched on age, gender, and residency area. The cohort is sponsored by the French-speaking Foundation for Diabetes Research (FFRD) and aims to include 15,000 participants.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Adulto , Glucemia , Automonitorización de la Glucosa Sanguínea , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Niño , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Estudios Prospectivos , Factores de RiesgoRESUMEN
AIMS: Interindividual variability in capacity to reabsorb glucose at the proximal renal tubule could contribute to risk of diabetic kidney disease. Our present study investigated, in patients with diabetes, the association between fractional reabsorption of glucose (FRGLU) and degree of renal disease as assessed by urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR). METHODS: FRGLU [1-(glucose clearance/creatinine clearance)] was assessed in 637 diabetes patients attending our tertiary referral centre, looking for correlations between FRGLU and UAE (normo-, micro-, macro-albuminuria) and Kidney Disease: Improving Global Outcomes (KDIGO) eGFR categories: >90 (G1); 90-60 (G2); 59-30 (G3); and<30-16 (G4) mL/min/1.73 m2. Patients were stratified by admission fasting plasma glucose (FPG) into three groups: low (<6mmol/L); intermediate (6-11mmol/L); and high (>11mmol/L). RESULTS: Median (interquartile range, IQR) FRGLU levels were blood glucose-dependent: 99.90% (0.05) for low (n=106); 99.90% (0.41) for intermediate (n=288); and 96.36% (12.57) for high (n=243) blood glucose categories (P<0.0001). Also, FRGLU increased with renal disease severity in patients in the high FPG group: normoalbuminuria, 93.50% (17.74) (n=135); microalbuminuria, 96.56% (5.94) (n=77); macroalbuminuria, 99.12% (5.44) (n=31; P<0.001); eGFR G1, 94.13% (16.24) (n=111); G2, 96.35% (11.94) (n=72); G3 98.88% (7.59) (n=46); and G4, 99.11% (2.20) (n=14; P<0.01). On multiple regression analyses, FRGLU remained significantly and independently associated with UAE and eGFR in patients in the high blood glucose group. CONCLUSION: High glucose reabsorption capacity in renal proximal tubules is associated with high UAE and low eGFR in patients with diabetes and blood glucose levels>11mmol/L.
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Albuminuria/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Tasa de Filtración Glomerular , Glucosa/metabolismo , Glucosuria/metabolismo , Reabsorción Renal/fisiología , Adulto , Anciano , Glucemia/metabolismo , Diabetes Mellitus/metabolismo , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/metabolismoRESUMEN
Plasma wakefields can enable very high accelerating gradients for frontier high energy particle accelerators, in excess of 10 GeV/m. To overcome limits on single stage acceleration, specially shaped drive beams can be used in both linear and nonlinear plasma wakefield accelerators (PWFA), to increase the transformer ratio, implying that the drive beam deceleration is minimized relative to acceleration obtained in the wake. In this Letter, we report the results of a nonlinear PWFA, high transformer ratio experiment using high-charge, longitudinally asymmetric drive beams in a plasma cell. An emittance exchange process is used to generate variable drive current profiles, in conjunction with a long (multiple plasma wavelength) witness beam. The witness beam is energy modulated by the wakefield, yielding a response that contains detailed spectral information in a single-shot measurement. Using these methods, we generate a variety of beam profiles and characterize the wakefields, directly observing transformer ratios up to R=7.8. Furthermore, a spectrally based reconstruction technique, validated by 3D particle-in-cell simulations, is introduced to obtain the drive beam current profile from the decelerating wake data.
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AIMS: Copeptin, a surrogate of vasopressin, is elevated in type 1 diabetes (T1D) and predicts kidney disease and cardiovascular mortality. Given the cardiorenal protective effects of SGLT2 inhibition (SGLT2i), our aim was to examine: 1) the relationship between serum copeptin, metabolic, renal and systemic hemodynamic parameters in adults with T1D; and 2) serum copeptin after SGLT2i with empagliflozin. MATERIALS AND METHODS: In this post-hoc, exploratory analysis, serum copeptin, glomerular filtration rate (GFRInulin), effective renal plasma flow (ERPFPAH), plasma renin angiotensin aldosterone system markers, HbA1c, 24-hour urine volume and sodium excretion were measured in 40 participants with T1D (24.3±5.1 years) during eu- and hyperglycaemia before and after 8 weeks of 25mg of daily empagliflozin. RESULTS: Higher baseline copeptin correlated with higher HbA1c, lower 24-hour urine volume and sodium excretion, after correcting for age, sex, systolic blood pressure, and HbA1c. Copeptin concentrations increased in response to empagliflozin under euglycaemia (4.1±2.1 to 5.1±2.8pmol/L, P=0.0053) and hyperglycaemia (3.3±1.4 to 5.6±2.8pmol/L, P<0.0001). The rise in copeptin in response to empagliflozin correlated with change in 24-hour urine volume, but was independent of changes in fractional excretion of sodium and haematocrit. CONCLUSIONS: Elevated serum copeptin was associated with worse glycaemic control and lower diuresis and natriuresis. SGLT2i increased serum copeptin in adults with T1D, and the rise correlated with change in diuresis, but not natriuresis and hemo-concentration. Further work is required to evaluate the clinical implications of elevated copeptin with SGLT2i, including whether it is simply a marker of diuresis or may contribute to cardiorenal disease long-term.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glicopéptidos/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Adulto , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Hemoglobina Glucada/análisis , Control Glucémico , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Masculino , Natriuresis/efectos de los fármacos , Natriuresis/fisiología , Sistema Renina-Angiotensina/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Adulto JovenRESUMEN
AIM: In the D.E.S.I.R. cohort, higher consumption of dairy products was associated with lower incidence of hyperglycaemia, and dihydroceramide concentrations were higher in those who progressed to diabetes. Our aim here was to study the relationships between dairy consumption and concentrations of dihydroceramides and ceramides. METHODS: In the D.E.S.I.R. cohort, men and women aged 30-65 years, volunteers from West-Central France, were included in a 9-year follow-up with examinations every 3 years, including food-frequency questionnaires. Two items concerned dairy products (cheese, other dairy products except cheese). At each examination, dihydroceramides and ceramides were determined by mass spectrometry in a cohort subset; in the present study, the 105 people who did not progress to type 2 diabetes were analyzed, as the disorder per se might be a confounding factor. RESULTS: Higher consumption of dairy products (except cheese) was associated with total plasma dihydroceramides during the follow-up, but only in women (P=0.01 for gender interaction). In fact, dihydroceramide levels were lower in women with high vs low consumption (P=0.03), and were significantly increased during follow-up (P=0.01) in low consumers only. There was also a trend for lower ceramides in women with high dairy (except cheese) intakes (P=0.08). Cheese was associated with dihydroceramide and ceramide changes during follow-up (P=0.04 for both), but no clear trend was evident in either low or high consumers. CONCLUSION: These results show that, in women, there is an inverse association between fresh dairy product consumption and predictive markers (dihydroceramides) of type 2 diabetes.
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Ceramidas/sangre , Productos Lácteos , Diabetes Mellitus Tipo 2/epidemiología , Dieta , Adulto , Anciano , Diabetes Mellitus Tipo 2/sangre , Femenino , Humanos , Incidencia , Estudios Longitudinales , Persona de Mediana EdadRESUMEN
OBJECTIVE: Continuous glucose monitoring tends to replace capillary blood glucose (CBG) self-monitoring. Our aim was to determine the agreement between CBG and a flash glucose monitoring system (Flash-GMS) in treatment decision-making during pregnancy. RESEARCH DESIGN AND METHODS: Insulin-treated women with either type 1 (n=25), type 2 (n=4) or gestational diabetes (n=4) were included. A Flash-GMS sensor was applied for 14 days. Women scanned the sensor whenever they monitored their CBG. The primary endpoint was the proportion of discordant therapeutic decisions they would have made based on Flash-GMS rather than CBG results. Glucose averages, mean absolute difference (MAD), mean absolute relative difference (MARD) and Flash-GMS accuracy were also estimated. RESULTS: Data for forty 14-day periods were available. Preprandial Flash-GMS and CBG values were 93±42mg/dL and 105±45mg/dL, respectively (P<10-4), and 2-h postprandial (PP) values were 106±45mg/dL and 119±47mg/dL, respectively (P<10-4). MAD was 14±22mg/dL preprandial and 15±24mg/dL 2-h PP; MARD was 19%; and 99% of glucose value pairs were within the clinically acceptable A and B zones of the Parkes error grid. Concordance rate for therapeutic decision-making was 80-85% according to ADA targets and 65-75% according to a pragmatic threshold. At different time points of the day, 83-92% of discordant results were due to Flash-GMS values being lower than their corresponding CBG values. CONCLUSION: Flash-GMS tends to give lower estimates than CBG. Thus, in cases requiring therapeutic changes to treat or prevent hypo- or hyperglycaemia, 25-35% of choices would have been divergent if based on Flash-GMS rather than CBG.
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Glucemia/análisis , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Gestacional/sangre , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Adulto , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Gestacional/tratamiento farmacológico , Esquema de Medicación , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Sistemas de Infusión de Insulina , EmbarazoAsunto(s)
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
AIMS: To explore comparative glycaemic control and hypoglycaemia incidence with insulin degludec 100U/mL (IDeg) or insulin glargine 300U/mL (Gla-300) versus glargine 100U/mL (Gla-100) in trial-level meta-analyses of phase 3a clinical trials including people with type-2 diabetes. METHODS: Meta-analyses of HbA1c, fasting plasma glucose (FPG), average 24h self-measured plasma glucose (SMPG), pre-breakfast SMPG and hypoglycaemia incidence and rate, using data from the BEGIN (IDeg) and EDITION (Gla-300) insulin development programmes, were performed. RESULTS: In BEGIN, despite greater FPG reduction with IDeg than Gla-100, HbA1c reduction was greater with Gla-100 (mean difference [95% CI] in HbA1c change: 0.09 [0.01-0.18] %) whereas in EDITION, there was no difference in FPG and HbA1c reduction between Gla-300 and Gla-100. Risk of nocturnal confirmed (<3.1mmol/L [<56mg/dL]) or severe hypoglycaemia, but not anytime (24h) events, was lower with IDeg than Gla-100 (relative risk [RR] 0.79 [0.66-0.94]) whereas Gla-300 was associated with reduced risk of nocturnal (RR 0.75 [0.61-0.92]) and anytime (24h) (RR 0.81 [0.69-0.94]) confirmed (<3.0mmol/L [<54mg/dL]) or severe hypoglycaemia versus Gla-100. CONCLUSIONS: These trial-level meta-analyses suggest that despite greater reductions in FPG, IDeg was associated with less improvement in HbA1c versus Gla-100, with a hypoglycaemia benefit only evident at night. In contrast, Gla-300 showed similar HbA1c reduction to Gla-100, accompanied by lower risk of hypoglycaemia both at night and at any time of day. Gla-300 and IDeg appear more similar than dissimilar, but head-to-head trials are required.
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Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Insulina Glargina/efectos adversos , Insulina de Acción Prolongada/efectos adversos , Diabetes Mellitus Tipo 2/sangre , Humanos , Hipoglucemia/epidemiología , Hipoglucemiantes/uso terapéutico , Incidencia , Insulina Glargina/uso terapéutico , Insulina de Acción Prolongada/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
AIM: To compare steady state pharmacodynamic and pharmacokinetic profiles of insulin glargine 300U/mL (Gla-300) with insulin degludec 100U/mL (Deg-100) in people with type 1 diabetes. METHODS: This single-centre, randomized, double-blind crossover euglycaemic clamp study included two parallel cohorts with fixed once-daily morning dose regimens. For both insulins participants received 0.4 (n=24) or 0.6U/kg/day (n=24), before breakfast, for 8 days prior to the clamp. The main endpoint was within-day variability (fluctuation) of the smoothed glucose infusion rate (GIR) over 24 hours (GIR-smFL0-24). RESULTS: Gla-300 provided 20% less fluctuation of steady state glucose infusion rate profiles than Deg-100 over 24 hours at 0.4U/kg/day (GIR-smFL0-24 treatment ratio 0.80 [90% confidence interval: 0.66 to 0.96], P=0.047), while at the dose of 0.6U/kg/day the difference between insulins was not statistically significant (treatment ratio 0.96 [0.83 to 1.11], P=0.603). Serum insulin concentrations appeared more evenly distributed with both dose levels of Gla-300 versus the same doses of Deg-100, as assessed by relative 6-hour fractions of the area under the curve within 24 hours. Both insulins provided exposure and activity until 30 hours (end of clamp). CONCLUSION: Gla-300 provides less fluctuating steady state pharmacodynamic profiles (i.e. lower within-day variability) and more evenly distributed pharmacokinetic profiles, compared with Deg-100 in a once-daily morning dosing regimen of 0.4U/kg/day.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina Glargina/uso terapéutico , Insulina de Acción Prolongada/uso terapéutico , Adolescente , Adulto , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Insulina Glargina/administración & dosificación , Insulina Glargina/farmacocinética , Insulina de Acción Prolongada/administración & dosificación , Insulina de Acción Prolongada/farmacocinética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
People with chronic kidney disease (CKD) are at risk of severe outcomes, such as end-stage renal disease or cardiovascular disease, and CKD is a globally increasing health burden with a high personal and economic cost. Despite major progresses in prevention and therapeutics in last decades, research is still needed to reverse this epidemic trend. The regulation of water balance and the state of activation of the vasopressin system have emerged as factors tightly associated with kidney health, in the general population but also in specific conditions; among them, various stages of CKD, diabetes and autosomal dominant polycystic kidney disease (ADPKD). Basic science findings and also epidemiological evidence have justified important efforts towards interventional studies supporting causality, and opening therapeutic avenues. On the basis of recent clinical data, the blockade of V2 vasopressin receptors using tolvaptan in patients with rapidly progressing ADPKD has been granted in several countries, and a long-term randomized trial evaluating the effect of an increase in water intake in patients with CKD is on-going.
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Enfermedades Renales/fisiopatología , Vasopresinas/fisiología , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Biomarcadores/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/fisiopatología , Fluidoterapia , Glicopéptidos/sangre , Glicopéptidos/fisiología , Humanos , Riñón/fisiopatología , Enfermedades Renales/epidemiología , Enfermedades Renales/terapia , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/terapiaRESUMEN
AIMS: To document the family transmission of Type 2 diabetes to men and women. METHOD: The French D.E.S.I.R. cohort followed men and women over 9 years, with 3-yearly testing for incident Type 2 diabetes. First- and/or second-degree family histories of diabetes were available for 2187 men and 2282 women. Age-adjusted hazard ratios were estimated for various family members and groupings of family members, as well as for a genetic diabetes risk score, based on 65 diabetes-associated loci. RESULTS: Over 9 years, 136 men and 63 women had incident Type 2 diabetes. The hazard ratios for diabetes associated with having a first-degree family member with diabetes (parents, siblings, children) differed between men [1.21 (95% CI 0.80, 1.85)] and women [3.02 (95% CI 1.83, 4.99); Pinteraction =0.006]. The genetic risk score was predictive of diabetes in both men and women, with similar hazard ratios 1.10 (95% CI 1.06, 1.15) and 1.08 (95% CI 1.02, 1.14) respectively, for each additional at-risk allele. In women, the risk associated with having a family member with diabetes persisted after adjusting for the genetic score. CONCLUSION: Women with a family history of diabetes (paternal or maternal) were at risk of developing Type 2 diabetes and this risk was independent of a genetic score; in contrast, for men, there was no association. Diabetes screening and prevention may need to more specifically target women with diabetes in their family, but further studies are required as the number of people with diabetes in this study was small.
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Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Anamnesis , Adulto , Anciano , Estudios de Cohortes , Familia , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Síndrome Metabólico/genética , Persona de Mediana Edad , Factores de RiesgoAsunto(s)
Automonitorización de la Glucosa Sanguínea , Glucemia/análisis , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Adolescente , Adulto , Diabetes Mellitus Tipo 1/sangre , Femenino , Humanos , Hipoglucemia/sangre , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Adulto JovenRESUMEN
BACKGROUND: Greater renal function decline (RFD) in type 2 diabetes (T2DM) has been suggested in men compared with women, and imbalances in estrogen/androgen levels have been associated with cardiovascular disease mortality in elderly men, but it remains unclear whether sex hormone disequilibrium is related to diabetic nephropathy (DN) in men with T2DM. OBJECTIVE: This study examined the relationship between sex steroid concentrations and renal outcomes in male T2DM patients. POPULATION AND METHODS: Total testosterone (T), total estradiol (E2), sex hormone-binding globulin (SHBG), and total and calculated free (cf) E2/T ratios were compared in 735 male T2DM patients with (n=513) and without (n=222) DN, using a cross-sectional approach. Also, in a pilot complementary prospective nested case-control cohort, total E2/total T and cfE2/cfT were evaluated according to a hard renal outcome (HRO): end-stage renal disease/doubling of baseline serum creatinine (36 HRO cases, 72 HRO controls) and rate of eGFR decline (68 rapid vs 68 slow RFD). RESULT: With the cross-sectional approach, E2 and cfE2 were higher in DN cases vs DN controls (95.5 vs 86.8pmol/L [P=0.0246] and 2.59 vs 2.36pmol/L [P=0.005], respectively). The difference in E2 persisted on multivariate analysis. In the prospective approach, E2 and T concentrations, and total E2/total T and cfE2/cfT2 ratios did not differ in HRO cases vs controls or in patients with rapid vs slow RFD. CONCLUSION: Although positively related to DN in the cross-sectional analysis, progression of renal disease in male patients with T2DM was not related to either sex hormone levels or aromatase index as reflected by E2/T ratio.
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Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/sangre , Estradiol/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangre , Anciano , Estudios de Casos y Controles , Estudios Transversales , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
AIM: Adiponectin is an adipocyte-secreted protein associated with insulin sensitivity. T-cadherin is a receptor for high and medium molecular weight adiponectin. In GWAS, T-cadherin gene (CDH13) polymorphisms are associated with circulating adiponectin levels. This study investigated the associations between genetic variants of CDH13 and type 2 diabetes (T2D), and its related parameters, in a Caucasian population. METHODS: Two polymorphisms of CDH13 (rs11646213 and rs3865188) were genotyped in two French cohorts, a general population from the D.E.S.I.R. study (n=5212) and people with T2D in the DIABHYCAR study (n=3123). Baseline adiponectin levels were measured in D.E.S.I.R. participants who were normoglycaemic at baseline, but hyperglycaemic after 3 years (n=230), and in controls who remained normoglycaemic (n=226) throughout. RESULTS: In a cross-sectional analysis, CDH13 genotype distributions differed between those with and without T2D, with T2D odds ratios (OR) of 1.11 (95% CI: 1.04-1.18; P=0.001) and 0.92 (95% CI: 0.87-0.98; P=0.01) for rs11646213 and rs3865188, respectively. The rs11646213 variant, associated with a higher OR for T2D, was also associated with higher BMI (P=0.03) and HbA1c (P=0.006), and lower plasma adiponectin levels (P=0.03) in the D.E.S.I.R. PARTICIPANTS: Conversely, the rs3865188 variant, associated with a lower OR for T2D, was also associated with lower BMI (P=0.03), HbA1c (P=0.02) and Fatty Liver Index (FLI; P≤0.01), and higher plasma adiponectin levels (P=0.002). Associations with HbA1c, FLI and adiponectin levels persisted after adjusting for BMI. CONCLUSION: CDH13 polymorphisms are associated with prevalent T2D in this French population study. The association may be mediated through effects on BMI and/or plasma adiponectin.
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Cadherinas/genética , Diabetes Mellitus Tipo 2/genética , Hígado Graso/genética , Adiponectina/análisis , Adulto , Anciano , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Hígado Graso/epidemiología , Femenino , Francia/epidemiología , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaAsunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 1 , Hipoglucemia , Adolescente , Adulto , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/epidemiología , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/sangre , Hipoglucemia/complicaciones , Hipoglucemia/epidemiología , Hipoglucemiantes/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND AND AIMS: GPR120 (encoded by FFAR4) is a lipid sensor that plays an important role in the control of energy balance. GPR120 is activated by long chain fatty acids (FAs) including omega-3 FAs. In humans, the loss of function p.R270H variant of the gene FFAR4 has been associated with a lower protein activity, an increased risk of obesity and higher fasting plasma glucose levels. The aim of this study was to investigate whether p.R270H interacts with dietary fat intake to modulate the risk of type 2 diabetes (T2D, 198 incident; 368 prevalent cases) and overweight (787 incident and 2891 prevalent cases) in the prospective D.E.S.I.R. study (n = 5,212, 9 years follow-up). METHODS AND RESULTS: The association of p.R270H with dietary fat and total calories was assessed by linear mixed models. The interaction between p.R270H and dietary fat on T2D and overweight was assessed by logistic regression analysis. The p.R270H variant had a minor allele frequency of 1.45% and was not significantly associated with total calories intake, fat intake or the total calories derived from fat (%). However, there was a significant interaction between p.R270H and dietary fat modulating the incidence of T2D (Pinteraction = 0.02) where the H-carriers had a higher risk of T2D than RR homozygotes in the low fat intake category only. The interaction between p.R270H and fat intake modulating the incidence and prevalence of overweight was not significant. CONCLUSION: The p.R270H variant of GPR120 modulates the risk of T2D in interaction with dietary fat intake in the D.E.S.I.R.
Asunto(s)
Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Grasas de la Dieta/efectos adversos , Interacción Gen-Ambiente , Variación Genética , Receptores Acoplados a Proteínas G/genética , Adulto , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Ingestión de Energía , Femenino , Francia/epidemiología , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Incidencia , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Obesidad/epidemiología , Obesidad/genética , Fenotipo , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
AIMS: To conduct a patient-level meta-analysis of the EDITION 1, 2 and 3 studies, which compared the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively. METHODS: The EDITION studies were multicentre, randomized, open-label, parallel-group, phase IIIa studies, with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large population with T2DM (Gla-300, n = 1247; Gla-100, n = 1249). RESULTS: No significant study-by-treatment interactions across studies were found, enabling them to be pooled. The mean change in glycated haemoglobin was comparable for Gla-300 and Gla-100 [each -1.02 (standard error 0.03)%; least squares (LS) mean difference 0.00 (95% confidence interval (CI) -0.08 to 0.07)%]. Annualized rates of confirmed (≤3.9 mmol/l) or severe hypoglycaemia were lower with Gla-300 than with Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with ≥1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low (<1 kg) in both groups, with less gain with Gla-300 [LS mean difference -0.28 kg (95% CI -0.55 to -0.01); p = 0.039]. Both treatments were well tolerated, with similar rates of adverse events. CONCLUSION: Gla-300 provides comparable glycaemic control to Gla-100 in a large population with a broad clinical spectrum of T2DM, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia.