Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus : A post-hoc analysis of a 52-week randomised trial

Aims: To compare the effects of long-term treatment with the GLP-1RA exenatide twicedaily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. Methods: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean +/- SD age 60 +/- 8 years, HbA1c 7.5 +/- 0.9%, eGFR 86 +/- 16 mL/min/1.73m(2), median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 mg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albuminexcretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. Results: HbA1c-reductions were similar with exenatide (mean +/- SEM -0.80 +/- 0.10%) and iGlar (-0.79 +/- 0.14%; treatment-difference 0.02%; 95% CI - 0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P <0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 +/- 2.1 mL/min/1.73 m(2); P = 0.069) and iGlar (-2.7 +/- 1.2 mL/min/1.73 m(2); P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P <0.001), but did not affect blood pressure, lipids or plasma uric acid. Conclusions: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Stable Isotope Metabolic Labeling with a Novel 15N-Enriched Bacteria Diet for Improved Proteomic Analyses of Mouse Models for Psychopathologies

The identification of differentially regulated proteins in animal models of psychiatric diseases is essential for a comprehensive analysis of associated psychopathological processes. Mass spectrometry is the most relevant method for analyzing differences in protein expression of tissue and body fluid proteomes. However, standardization of sample handling and sample-to-sample variability are problematic. Stable isotope metabolic labeling of a proteome represents the gold standard for quantitative mass spectrometry analysis. The simultaneous processing of a mixture of labeled and unlabeled samples allows a sensitive and accurate comparative analysis between the respective proteomes. Here, we describe a cost-effective feeding protocol based on a newly developed 15N bacteria diet based on Ralstonia eutropha protein, which was applied to a mouse model for trait anxiety. Tissue from 15N-labeled vs. 14N-unlabeled mice was examined by mass spectrometry and differences in the expression of glyoxalase-1 (GLO1) and histidine triad nucleotide binding protein 2 (Hint2) proteins were correlated with the animals' psychopathological behaviors for methodological validation and proof of concept, respectively. Additionally, phenotyping unraveled an antidepressant-like effect of the incorporation of the stable isotope 15N into the proteome of highly anxious mice. This novel phenomenon is of considerable relevance to the metabolic labeling method and could provide an opportunity for the discovery of candidate proteins involved in depression-like behavior. The newly developed 15N bacteria diet provides researchers a novel tool to discover disease-relevant protein expression differences in mouse models using quantitative mass spectrometry

One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients: A randomized, controlled trial

0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS: Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therap

c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines

It is widely accepted that the c-Fos gene has a role in proliferation and differentiation of bone cells. ATP-induced c-Fos activation is relevant to bone homeostasis, because nucleotides that are present in the environment of bone cells can contribute to autocrine/paracrine signalling. Gut hormones have previously been shown to have an effect on bone metabolism. In this study, we used the osteoblastic Saos-2 cell line transfected with a c-Fos-driven reporter stimulated with five gut hormones: glucose inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), ghrelin and obestatin, in the presence or absence of ATP. In addition, TE-85 cells were used to determine the time course of c-Fos transcript induction following stimulation with GLP-1, and GLP-2 with or without ATP, using reverse transcription qPCR. The significant results from the experiments are as follows: higher level of c-Fos induction in presence of GIP, obestatin (p = 0.019 and p = 0.011 respectively), and GIP combined with ATP (p < 0.001) using the luciferase assay; GLP-1 and GLP-2 combined with ATP (p = 0.034 and p = 0.002, respectively) and GLP-2 alone (p < 0.001) using qPCR. In conclusion, three of the gut peptides induced c-Fos, providing a potential mechanism underlying the actions of these hormones in bone which can be directed or enhanced by the presence of ATP

Profiling Trait Anxiety: Transcriptome Analysis Reveals Cathepsin B (Ctsb) as a Novel Candidate Gene for Emotionality in Mice

Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait “anxiety”. We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, and also show signs of comorbid depression-like behavior

Intimate partner violence against women in rural Vietnam - different socio-demographic factors are associated with different forms of violence: Need for new intervention guidelines?

Background: This population-based study investigated the different forms, magnitude and risk factors of men's violence against women in intimate relationships in a rural part of northern Vietnam and whether a difference in risk factors were at hand for the different forms of violence. Vietnam has undergone a rapid transition in the last 20 years, moving towards a more equal situation for men and women however, Confucian doctrine is still strong and little is known about men's violence against women within the Vietnamese family. Methods: This is a cross-sectional population-based study that used a questionnaire developed by the World Health Organisation for investigating women's health and violence against women in different settings. Face-to face structured interviewing was performed and 883 married women, aged 17 to 60 participated. Bi- and multivariate analyses was used for risk factor assessment. Results: The lifetime prevalence of physical violence was 30.9 percent and past year prevalence was 8.3 per cent, while the corresponding figures for physical and sexual violence combined was 32.7 and 9.2 percent. The lifetime prevalence was highest for psychological abuse ( 27.9 percent) as a single entity. In most cases the violence was of a severe nature and exercised as repeated acts over time. Woman's low educational level, husband's low education, low household income and the husband having more than one wife/partner were risk factors for lifetime and past year physical/sexual violence. The pattern of factors associated with psychological abuse alone was however different. Husband's low professional status and women's intermediate level of education appeared as risk factors. Conclusion: Men's violence against women in intimate relationships is commonly occurring in rural Vietnam. There is an obvious need of preventive and treatment activities. Our findings point at that pure psychological abuse is different from physical/sexual violence in terms of differing characteristics of the perpetrators and it might be that also different strategies are needed to reduce and prevent this violence

Enhanced Fear Expression in a Psychopathological Mouse Model of Trait Anxiety: Pharmacological Interventions

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias

Diabetic gastroparesis: Therapeutic options

Gastroparesis is a condition characterized by delayed gastric emptying and the most common known underlying cause is diabetes mellitus. Symptoms include nausea, vomiting, abdominal fullness, and early satiety, which impact to varying degrees on the patient’s quality of life. Symptoms and deficits do not necessarily relate to each other, hence despite significant abnormalities in gastric emptying, some individuals have only minimal symptoms and, conversely, severe symptoms do not always relate to measures of gastric emptying. Prokinetic agents such as metoclopramide, domperidone, and erythromycin enhance gastric motility and have remained the mainstay of treatment for several decades, despite unwanted side effects and numerous drug interactions. Mechanical therapies such as endoscopic pyloric botulinum toxin injection, gastric electrical stimulation, and gastrostomy or jejunostomy are used in intractable diabetic gastroparesis (DG), refractory to prokinetic therapies. Mitemcinal and TZP-101 are novel investigational motilin receptor and ghrelin agonists, respectively, and show promise in the treatment of DG. The aim of this review is to provide an update on prokinetic and mechanical therapies in the treatment of DG