The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study.

Context: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood.

Objective: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D.

Methods: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D.

At any Level of Adiposity, Relatively Elevated Leptin Concentrations Are Associated With Decreased Insulin Sensitivity.

Context: The impact of obesity on glucose homeostasis has high interindividual variability, which may be partially explained by different adipokine concentrations. Leptin regulates energy balance and metabolism, and although its plasma levels are proportional to fat mass, they vary significantly across individuals with the same level of adiposity.

Objective: We tested whether glucose homeostasis differs in subjects with similar degrees of adiposity but different leptin levels.

The Cedar Project: Racism and its impacts on health and wellbeing among young Indigenous people who use drugs in Prince George and Vancouver, BC.

Racism continues to drive health disparities between Indigenous and non-Indigenous peoples in Canada. This study focuses on racism experienced by young Indigenous people who have used drugs in British Columbia (BC), and predictors of interpersonal racism. Cedar Project is a community-governed cohort study involving young Indigenous people who use drugs in Vancouver and Prince George, BC.

Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals.

Aims: Hypertriglyceridemia is associated with an increased risk of type 2 diabetes. We aimed to comprehensively examine the effects of hypertriglyceridemia on major glucose homeostatic mechanisms involved in diabetes progression.

Methods: In this randomized, cross-over, single-blinded study, two dual-labeled, 3-hour oral glucose tolerance tests were performed during 5-hour intravenous infusions of either 20 % Intralipid or saline in 12 healthy subjects (age 27.

Development and optimization of a fentanyl pharmacokinetic model for target-controlled infusion in anaesthetized dogs.

Objective: To investigate pharmacokinetics (PK) of fentanyl administered by target-controlled infusion (TCI), and to develop a PK model optimized by covariates for TCI in anaesthetized dogs.

Study Design: Prospective clinical study.

Animals: A group of 20 client-owned dogs with spinal pain undergoing anaesthesia for magnetic resonance imaging.

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study.

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.

Occupational exposure to crystalline silica in artificial stone processing.

Respirable Crystalline Silica (RCS) is a hazardous substance with known effects that can be well correlated with exposure levels that still persist in many traditional sectors, such as construction or stone processing. In the past decade, exposure scenarios for RCS have been found in the sector of artificial stone processing. The aim of this study is to evaluate the levels of RCS in facilities specialized in the production of artificial stone countertops and other accessories for the furnishing of kitchens, bathrooms, and offices after the introduction of some preventive technical measures such as wet processing or local exhaust ventilation systems.

New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms.

Objective: Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.

Mathematical Modeling for the Physiological and Clinical Investigation of Glucose Homeostasis and Diabetes.

Mathematical modeling in the field of glucose metabolism has a longstanding tradition. The use of models is motivated by several reasons. Models have been used for calculating parameters of physiological interest from experimental data indirectly, to provide an unambiguous quantitative representation of pathophysiological mechanisms, to determine indices of clinical usefulness from simple experimental tests.

Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study.

Objective: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).

Research Design And Methods: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression.

Upper and Lower Respiratory Signs and Symptoms in Workers Occupationally Exposed to Flour Dust.

A group of 142 bakers was studied in order to investigate the relationship between higher/lower respiratory signs/symptoms and inflammation biomarkers and occupational exposure to flour dust. A complete upper and lower respiratory tract evaluation was performed. Seven percent of bakers complained of lower respiratory symptoms, while 22% of them complained of upper respiratory symptoms.

Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk: An IMI DIRECT study.

Background: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D.

Occupational Exposure to Flour Dust. Exposure Assessment and Effectiveness of Control Measures.

The adverse effects associated with exposure to flour dust have been known since the 1700s. The aim of the study was to assess the occupational exposure to flour dust in Italian facilities, identify the activities characterized by the highest exposure, and provide information to reduce workers' exposure. The study was performed in different facilities such as flourmills ( = 2), confectioneries ( = 2), bakeries ( = 24), and pizzerias ( = 2).

Silicosis in finishing workers in quartz conglomerates processing.

Introduction: Outbreaks of silicosis have bene recently reported in artificial stone workers.

Aim: To describe the features of silicosis in quartz conglomerate workers in North-Eastern Italy.

Methods: Active search of pneumoconiosis was performed in 11 companies of North-Eastern Italy involved in the fabrication of quartz conglomerate countertops.

A pharmacokinetic model optimized by covariates for propofol target-controlled infusion in dogs.

Objective: To develop a population pharmacokinetic model for propofol target-controlled infusion (TCI) in dogs and to evaluate its performance for use in the clinical setting.

Study Design: Prospective clinical study.

Animals: A group of 40 client-owned dogs undergoing general anaesthesia for magnetic resonance imaging.

How to improve performance and prevent burnout in safety representatives.

Background: The present work is part of a greater research project, aimed to examine Safety Representatives' (SRs) role, twenty years after the appointment of this figure.

Objectives: The study aims to investigate the role of some personal and organizational dimensions in the promotion of SRs' well-being, in terms of reducing burnout and improving performance.

Methods: The study involved 455 SRs operating in North East Italy.

Multiorgan accelerated silicosis misdiagnosed as sarcoidosis in two workers exposed to quartz conglomerate dust.

Introduction: Clusters of silicosis cases have been reported in the fabrication of quartz conglomerate, a new high-silica-content artificial stone for kitchen and bathroom benchtops (countertops).

Aim: We describe two cases of accelerated-type silicosis with hepatic granulomas arising in workers exposed to artificial quartz conglomerates.

Methods: A confident diagnosis of multiorgan silicosis was based on high level of respirable silica in the workplace, typical radiological alterations in chest high-resolution CT, histological findings in the lung and liver, and detection of silica crystals in both tissues by phase-contrast polarising light microscopy and scanning electron microscopy and energy dispersive spectroscopy.

Sleeping oxygen saturation, rapid eye movement sleep, and the adaptation of postprandial metabolic function in insulin sensitive and resistant individuals without diabetes.

Aims: Sleeping oxygen saturation (SaO) and sleep stage duration have been linked with prediabetic alterations but the pathogenic pathways are not well understood. This study of insulin sensitive and resistant adults examined the effect on postprandial metabolic regulation of repeated mixed-meal challenges of different carbohydrate loading. The aim was to examine whether the relationship between lower sleeping oxygen saturation (SaO) and poorer fasting and postprandial metabolic function may be linked with reduced slow wave sleep (SWS) and rapid eye movement (REM) duration, independent of age, sex and total adiposity.

Analysis of variability in length of sleep state bouts reveals memory-free sleep subcomponents consistent among primary insomnia patients.

The statistical distributions of bout lengths for the different (macro) sleep states (wake, N1, N2, N3, and REM sleep) are essential to understanding whether any memory-free subcomponent ("micro state") is involved in the organization of sleep. Micro state detection can be prevented by the fusion of data including various sources of variability, in particular by the differences in sleep architecture between individuals, along sleep time (or nighttime), or between different nights. In this analysis, a mathematical model of sleep was adopted to disentangle these features and advance the understanding of the dynamics and mechanisms of sleep and its states.

Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors.

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg).

Effect of single-dose DPP-4 inhibitor sitagliptin on β-cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug-naïve, well-controlled type 2 diabetes subjects.

To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naïve, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-cell glucose sensitivity (the slope between glucose and insulin secretory rate).

GLP-1 response to sequential mixed meals: influence of insulin resistance.

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, =41) or insulin resistant (IR, =41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling.

PharmML in Action: an Interoperable Language for Modeling and Simulation.

PharmML is an XML-based exchange format created with a focus on nonlinear mixed-effect (NLME) models used in pharmacometrics, but providing a very general framework that also allows describing mathematical and statistical models such as single-subject or nonlinear and multivariate regression models. This tutorial provides an overview of the structure of this language, brief suggestions on how to work with it, and use cases demonstrating its power and flexibility.