The presentation and underlying pathophysiology of type 2 diabetes (T2d) is complex and heterogeneous. recent studies attempted to stratify T2d into distinct subgroups using data-driven approaches, but their clinical ...
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The presentation and underlying pathophysiology of type 2 diabetes (T2d) is complex and heterogeneous. recent studies attempted to stratify T2d into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2d based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2d etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired 1 beta cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2d can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.
Aims/hypothesis It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cy...
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Aims/hypothesis It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative diabetes research on Patient Stratification (IMI dIrECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N <= 920) or with recently diagnosed type 2 diabetes (cohort 2: N <= 435). Methods We defined a structural equation model that describes the TC and fitted this within the IMI dIrECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MrI, and physical activity through wrist-worn triaxial accelerometry. results are presented as standardised beta coefficients, SE and p values, respectively. results The TC and TC-PA models showed better fit than null models (TC: chi(2) = 242, p = 0.004 and chi(2) = 63, p = 0.001 in cohort 1 and 2, respectively;TC-PA: chi(2) = 180, p = 0.041 and chi(2) = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation These analyses partially support
development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (AdPKd) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes ass...
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development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (AdPKd) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes associated with the disease. Using a Pkd1 conditional knockout mouse, we demonstrate that subtly altering the timing and extent of Pkd1 deletion can have a significant impact on the origin and severity of kidney cyst formation. Pkd1 deletion on postnatal day 1 or 2 results in cysts arising from both the cortical and medullary regions, whereas deletion on postnatal days 3-8 results in primarily medullary cyst formation. Altering the extent of Pkd1 deletion by modulating the tamoxifen dose produces dose-dependent changes in the severity, but not origin, of cystogenesis. Limited Pkd1 deletion produces progressive kidney cystogenesis, accompanied by interstitial fibrosis and loss of kidney function. Cyst growth occurs in two phases: an early, rapid growth phase, followed by a later, slow growth period. Analysis of biochemical pathway changes in cystic kidneys reveals dysregulation of the cell cycle, increased proliferation and apoptosis, activation of Mek-Erk, Akt-mTOr, and Wnt-beta-catenin signaling pathways, and altered glycosphingolipid metabolism that resemble the biochemical changes occurring in human AdPKd kidneys. These pathways are normally active in neonatal mouse kidneys until repressed around 3 weeks of age;however, they remain active following Pkd1 deletion. Together, this work describes the key parameters to accurately model the pathological and biochemical changes associated with AdPKd in a conditional mouse model.
We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150 mg) on low density lipoprotein cholesterol (L...
We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150 mg) on low density lipoprotein cholesterol (LdL-C) reduction in patients with primary hypercholesterolemia on atorvastatin. A randomized, single ascending-dose study of alirocumab (100, 150, 250, or 300 mg) or placebo (3:1 ratio), administered subcutaneously, was conducted in 32 healthy Japanese men. The phase 2, randomized, double-blind, placebo-controlled, parallel-group study was performed in patients with primary hypercholesterolemia (defined as calculated LdL-C >= 100 mg/dl [2.6 mmol/l]) who were on a stable dose of atorvastatin (5 to 20 mg). Patients were randomized to alirocumab (50, 75, or 150 mg) or placebo (in single 1.0-m1 injection volumes) administered every 2 weeks (Q2W) for 12 weeks;the primary outcome was the mean percent change in calculated LdL-C from baseline to week 12. Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15 weeks andresulted in highest mean percent reductions in LdL-C from baseline of approximately 40% to 60%. In the multiple-dose study, least-square mean (SE) changes in calculated LdL-C concentrations from baseline to week 12 were -54.8% (3.1%) for alirocumab 50 mg, -62.3% (3.1%) for alirocumab 75 mg, and -71.7% (3.1%) for alirocumab 150 mg, with a least-square mean (SE) difference versus placebo of -52.2% (4.3%), -59.6% (4.3%), and -69.1% (4.3%), respectively (all p <0.0001). In conclusion, alirocumab was well tolerated and significantly reduced LdL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin. (C) 2016 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-Nd license (http://***/licenses/by-nc-nd/4.0/). (Am J Cardiol 2016;118:56-63)
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 (1...
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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 similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 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/m(2);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 charact
Background The rising prevalence of type 2 diabetes (T2d) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2d can be observed in easily acc...
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Background The rising prevalence of type 2 diabetes (T2d) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2d can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2d. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2d from the IMI-dIrECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2d. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-dIrECT cohort and evaluated with regard to stability, as well as preservation andrewiring in the cohort of individuals with T2d. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-dIrECT cohorts. results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2d status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals f
Low-molecular-weight heparins (LMWHs) are complex anticoagulant drugs, made from heparin porcine mucosa starting material. Enoxaparin sodium manufactured by sanofi is one of the most widely prescribed LMWHs and has be...
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Low-molecular-weight heparins (LMWHs) are complex anticoagulant drugs, made from heparin porcine mucosa starting material. Enoxaparin sodium manufactured by sanofi is one of the most widely prescribed LMWHs and has been used since 1993 in the USA. In 2010, US Food anddrug Administration approval for supplying generic enoxaparin was granted to Sandoz and subsequently to Amphastar. Little is known, however, of the differences in composition of these preparations. In this study, samples from several batches of generic enoxaparins were purchased on the US market and analyzed with state of the art methodologies, including disaccharide building blocks quantification, nuclear magnetic resonance (NMr), and a combination of orthogonal separation techniques. direct high-performance liquid chromatography analysis of the different enoxaparin batches revealeddistinct process fingerprints associated with each manufacturer. disaccharide building block analysis showeddifferences in the degree of sulfation, the presence of glycoserine derivatives, as well as in proportions of disaccharides. results were compared by statistical approaches using multivariate analysis with a partial least squares discriminant analysis methodology. The variations were statistically significant and allowed a cleardistinction to be made between the enoxaparin batches according to their manufacturer. These results were further confirmed by orthogonal analytical techniques, including NMr, which revealed compositional differences of oligosaccharides both in low- and high-affinity antithrombin fractions of enoxaparin. (C) 2015 The Authors. Published by Elsevier B.V.
Background & Aims: It remains unclear whetherdiabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a v...
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Background & Aims: It remains unclear whetherdiabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a vasopressin receptor antagonist that does not affect HE risk, in cirrhotic patients with ascites. Methods: The trials included 1198 patients, and we excluded those with HE before or at randomization and followed the remaining patients for the one yearduration of the trials. They were examined for HE regularly, and we comparedrates of first-time overt HE between diabetics and non-diabetic patients using Cox regression, adjusting for gender, age, ascites severity, cirrhosis etiology, Child-Pugh class, creatinine, bilirubin, INr, sodium, potassium, albumin, platelets, lactulose use, benzodiazepine/barbiturate use, spironolactone dose, furosemide dose, potassium-sparing diuretic dose, and CirCom comorbidity score. results: We included 862 patients of whom 193 (22%) haddiabetes. In total, they experienced 115 first-time episodes of overt HE during the follow-up. Fewerdiabetics than non-diabetic patients were in Child-Pugh class C at baseline (13% vs. 23%), yet they had higher cumulative risk of first-time overt HE (26.0% vs. 15.8% after 1 year), and their episodes of first-time overt HE were more likely to progress beyond grade 2 (64% vs. 42% of episodes progressed to grade 3 or 4, p = 0.01 for independence between diabetes and highest HE grade). After the confounder adjustment, the hazardratio of first-time overt HE fordiabetics vs. non-diabetic patients was 1.86 (95% CI 1.20-2.87). Conclusions: diabetes increased the risk of first-time overt HE among cirrhotic patients with ascites. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Background Phase II clinical trials are important milestones to determine whether a dose-effect exists and to decide on future doses to use in confirmatory studies. To take into account the overall shape of the dose r...
Background Phase II clinical trials are important milestones to determine whether a dose-effect exists and to decide on future doses to use in confirmatory studies. To take into account the overall shape of the dose response curve, modeling the relationship by linear or non-linear models is preferable to the classical pair-wise comparisons of the effect of each dose versus the placebo or the comparator. The multiple comparisons and modeling approach has been developed within the last 10 years to address this important question in the clinical development of drugs. despite some recent publications referring to this methodology, few detailed applications have been shown so far and several practical questions remain to be addressed. Methods Starting from a set of candidate models, model selection using classical methods criteria is possible. However, it suffers some limitations, not taking into account the uncertainty of the selection process itself. An attractive solution is to use model averaging, which applies appropriate weights to the parameters (e.g., the minimum effective dose) obtained from each model. results A discussion of the selection criteria is first presented. Through two real examples, how to proceed with model selection and model averaging is presented anddiscussed. Limitations The first multiple comparisons and modeling approach papers addressed normal responses. More recently, an extension of this methodology has been proposed to deal with other types of responses, in particular binary, time-to-event and longitudinal data. Questions that remain are concerned with the choice of the candidate models and of their parameters' guesstimates. Conclusions The analysis of clinical dose-finding studies using a modeling of the entire curve offers a promising alternative as compared with the classical multiple comparisons methods, while not compromising the necessary rigor of the analysis.
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