Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906.

Aim: To report two phase I studies of the novel subcutaneous glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist BI 456906 versus placebo in healthy volunteers and people with overweight/obesity.

Materials And Methods: A phase Ia study (NCT03175211) investigated single rising doses (SRDs) of BI 456906 in 24 males with a body mass index (BMI) of 20-<30 kg/m . A phase Ib study (NCT03591718) investigated multiple rising doses (MRDs) of BI 456906 (escalated over 6 [Part A] or 16 [Part B] weeks) in 125 adults with a BMI of 27-40 kg/m .

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo.

Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.

Background: There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD.

Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial.

Patients with type 2 diabetes mellitus (T2DM) with a glycated haemoglobin (HbA1c) level ≥7 and ≤10% were randomized to receive empagliflozin 12.5 mg twice daily (n = 219), 25 mg once daily (n = 218), 5 mg twice daily (n = 219) or 10 mg once daily (n = 220), or placebo (n = 107) as add-on to stable-dose metformin immediate release (IR) twice daily for 16 weeks. The primary endpoint was change from baseline in HbA1c at week 16.

Sensitive troponins--which suits better for hemodialysis patients? Associated factors and prediction of mortality.

Background: In hemodialysis patients, elevated plasma troponin concentrations are a common finding that has even increased with the advent of newly developed sensitive assays. However, the interpretation and relevance of this is still under debate.

Methods: In this cross-sectional study, we analyzed plasma concentrations of sensitive troponin I (TnI) and troponin T (TnT) in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors and mortality.

Active depression is associated with regional adiposity in the upper abdomen and the neck.

Objective: In major depression, the incidence of overweight, the risk of type 2 diabetes, as well as cardiovascular disease is increased. Aim was to determine body fat distribution in depressive and healthy females using whole body Magnetic Resonance Imaging (MRI). Measurements of total adipose tissue (TAT), visceral (VAT), and subcutaneous adipose tissue (SCAT) at the trunk and the whole body fat distribution along the body axis were performed and compared.

In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor δ reflects donors' insulin sensitivity in vivo.

Background: Peroxisome proliferator-activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity.

Materials And Methods: Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR.

Cardiorespiratory fitness determines the reduction in blood pressure and insulin resistance during lifestyle intervention.

Objective: Lifestyle intervention is not always effective for improving arterial hypertension and other cardiovascular risk factors, and the parameters determining the outcome are not known. Because high cardiorespiratory fitness (CRF) protects from cardiovascular disease and mortality, we determined whether CRF at baseline predicts the improvement of blood pressure and other cardiovascular risk factors during a lifestyle intervention.

Methods: A total of 219 patients at risk for type 2 diabetes, who underwent a 9-month lifestyle intervention with diet modification and increase in physical activity, and had measurement of CRF, were studied.

Insulin sensitivity and liver fat: role of iron load.

Context: Increased liver fat (LF) is associated with insulin resistance. However, a considerable individual variability between LF and insulin sensitivity (IS) is observed, and at equal levels of LF, insulin-resistant as well as insulin-sensitive individuals are found.

Objective: Our objective was to study whether hepatic iron load (HIL) explains some of the variation between IS and LF.

Apelin serum levels are not associated with early atherosclerosis or fat distribution in young subjects with increased risk for type 2 diabetes.

Apelin is proposed to possess protective cardiovascular properties and may furthermore promote favorable effects on glucose metabolism. First data in humans seem to support this hypothesis. Therefore we aimed to assess the meaning of apelin as an early risk indicator in young subjects prone to atherosclerosis and type 2 diabetes.

Morning to evening changes of intramyocellular lipid content in dependence on nutrition and physical activity during one single day: a volume selective 1H-MRS study.

Object: Intramyocellular lipids (IMCL) were shown to be metabolically highly active. In order to get insight into short-term regulation of IMCL and to reveal related problems with standardization in metabolic studies using the common signal ratio IMCL/Cr3, relative concentration changes from morning to evening in the same day were examined under four different nutritional and exercise conditions.

Material And Methods: Twelve healthy male volunteers participated in an interventional program, comprising single days of fasting (F), low-caloric/low-fat diet (LC), or high-caloric/high-fat diet (HC), combined with low physical activity.

Acute, short-term hyperinsulinemia increases olfactory threshold in healthy subjects.

Objective: Smell plays an important role in feeding behavior. We therefore tested whether insulin as a postprandial signal is involved in the regulation of olfactory function.

Research Design And Methods: We assessed olfactory thresholds in eight lean subjects (age: 34 ± 7 years, M/F: 5/3) before and during a 2-h hyperinsulinemic (1 mU kg(-1) min(-1)) euglycemic clamp and in eight lean fasted subjects (age: 36 ± 6 years, M/F: 5/3) without insulin infusion at the same time of the day.

The impact of genetic variation in the G6PC2 gene on insulin secretion depends on glycemia.

Context: Single-nucleotide polymorphisms (SNPs) within the G6PC2 locus are associated with fasting glucose and insulin secretion. These SNPs are not associated with type 2 diabetes risk.

Objective: Our objective was to investigate whether the impact of the SNP on variables of glucose-stimulated insulin secretion is influenced by glucose tolerance status.

Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion.

Objective: Several single nucleotide polymorphisms (SNPs) in diabetes risk genes reduce glucose- and/or incretin-induced insulin secretion. Here, we investigated interactions between glycemia and such diabetes risk polymorphisms.

Research Design And Methods: Insulin secretion was assessed by insulinogenic index and areas under the curve of C-peptide/glucose in 1,576 subjects using an oral glucose tolerance test (OGTT).

Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes.

Purpose: To assess adipose body compartments with magnetic resonance (MR) imaging and MR spectroscopy during a lifestyle intervention program that included optimized nutrition and controlled physical activity in subjects at increased risk for type 2 diabetes to determine factors that may help predict an increase in insulin sensitivity following the intervention.

Materials And Methods: This prospective study was approved by the local review board. All participants gave written informed consent.

Reducing visceral adipose tissue mass is essential for improving endothelial function in type 2 diabetes prone individuals.

Objective: In obesity, particularly increased visceral- (VAT), but not total (TAT) adipose tissue mass is a major source of proinflammatory cytokine expression and secretion. VAT, more than TAT, is associated with endothelial dysfunction (ED), which is an accepted risk factor for atherosclerosis. Consequently, we hypothesized that during a lifestyle intervention specifically a decrease in VAT, rather than TAT, is associated with improved ED and vascular adhesion molecules in type 2 diabetes prone subjects.

Interscapular fat is strongly associated with insulin resistance.

Context: Subcutaneous abdominal adipose tissue (SCAAT), visceral adipose tissue (VAT), fat in the neck area [interscapular fat (IF)], and liver fat (LF) are associated with metabolic traits related to insulin resistance. Whole-body magnetic resonance imaging and spectroscopy offer a unique approach to quantify fat depots in larger cohorts.

Objective: The objective was to study 1) the impact of the aforementioned fat depots on insulin sensitivity in a cross-sectional design and 2) changes in these fat depots and in insulin sensitivity during a lifestyle intervention (LI).

Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion.

Background: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity.

The ENPP1 K121Q polymorphism determines individual susceptibility to the insulin-sensitising effect of lifestyle intervention.

Aims/hypothesis: The K121Q (rs1044498) single nucleotide polymorphism (SNP) in the ENPP1 gene has shown association with insulin resistance and type 2 diabetes in various ethnic populations. We hypothesised that K121Q may predict the success of lifestyle intervention in terms of improvement of insulin sensitivity.

Methods: We genotyped 1,563 participants with an increased risk of type 2 diabetes for K121Q and performed correlational analyses with anthropometric data and variables of insulin sensitivity.

Gene variants of TCF7L2 influence weight loss and body composition during lifestyle intervention in a population at risk for type 2 diabetes.

Objective: The impact of the diabetes risk gene transcription factor 7-like 2 (TCF7L2) on body weight is unclear. As TCF7L2 is expressed in adipose tissue and involved in Wnt-dependent regulation of adipogenesis, we studied the impact of TCF7L2 variants on body composition and weight loss during lifestyle intervention.

Research Design And Methods: We genotyped 309 German subjects at increased risk for type 2 diabetes for single nucleotide polymorphisms (SNPs) rs7903146, rs12255372, rs11196205, and rs7895340 in TCF7L2 and performed oral glucose tolerance tests before and after a 9-month lifestyle intervention.

Novel obesity risk loci do not determine distribution of body fat depots: a whole-body MRI/MRS study.

A recent meta-analysis of genome-wide association studies has identified six new risk-loci for common obesity. We studied whether these risk loci influence the distribution of body fat depots. We genotyped 1,469 nondiabetic subjects for the single-nucleotide polymorphisms (SNPs) TMEM18 rs6548238, KCTD15 rs11084753, GNPDA2 rs10938397, SH2B1 rs7498665, MTCH2 rs10838738, and NEGR1 rs2815752.

Correlation of fat distribution in whole body MRI with generally used anthropometric data.

Objectives: : Obesity is a commonly known risk for many diseases such as metabolic syndrome and cardiovascular disease. Especially important is the discrimination of the adipose tissue inside the abdomen and the subcutaneous adipose tissue. Aim of this study was to compare the whole body fat distribution, and the volume of different adipose tissue compartments respectively, with anthropometric data.

Impact of variation near MC4R on whole-body fat distribution, liver fat, and weight loss.

Polymorphisms near the melanocortin-4 receptor (MC4R) gene locus are associated with body weight. Recent studies have shown that they influence insulin sensitivity and incidence of the metabolic syndrome. Thus, we hypothesized that the candidate single-nucleotide polymorphism (SNP) rs17782313 near MC4R additionally influences body fat distribution and its change during lifestyle intervention.