Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes

Aim: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo) B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. Materials and Methods: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on 1.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Results: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p <.0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p <.001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p <.001). Liraglutide also reduced VLDL1-triglyceride secretion (p = .017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (p = .015 and p <.001, respectively), but these associations were perturbed by liraglutide. Conclusions: In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins.Peer reviewe

Role of apolipoprotein C-III overproduction in diabetic dyslipidaemia

Aims To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. Materials and Methods Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5-H-2(3)]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. Results Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 +/- 198 vs. 652 +/- 196 mg/d, P = 0.03) and apoC-III levels (10.0 +/- 3.8 vs. 11.7 +/- 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 +/- 208 vs. 505 +/- 174 mg/d, P = 0.042). Conclusions The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III.Peer reviewe

Discovery of Species-unique Peptide Biomarkers of Bacterial Pathogens by Tandem Mass Spectrometry-based Proteotyping

Mass spectrometry (MS) and proteomics offer comprehensive characterization and identification of microorganisms and discovery of protein biomarkers that are applicable for diagnostics of infectious diseases. The use of biomarkers for diagnostics is widely applied in the clinic and the use of peptide biomarkers is increasingly being investigated for applications in the clinical laboratory. Respiratory-tract infections are a predominant cause for medical treatment, although, clinical assessments and standard clinical laboratory protocols are time-consuming and often inadequate for reliable diagnoses. Novel methods, preferably applied directly to clinical samples, excluding cultivation steps, are needed to improve diagnostics of infectious diseases, provide adequate treatment and reduce the use of antibiotics and associated development of antibiotic resistance. This study applied nano-liquid chromatography (LC) coupled with tandem MS, with a bioinformatics pipeline and an in-house database of curated high-quality reference genome sequences to identify species-unique peptides as potential biomarkers for four bacterial pathogens commonly found in respiratory tract infections (RTIs): Staphylococcus aureus; Moraxella catarrhalis; Haemophilus influenzae and Streptococcus pneumoniae. The species-unique peptides were initially identified in pure cultures of bacterial reference strains, reflecting the genomic variation in the four species and, furthermore, in clinical respiratory tract samples, without prior cultivation, elucidating proteins expressed in clinical conditions of infection. For each of the four bacterial pathogens, the peptide biomarker candidates most predominantly found in clinical samples, are presented. Data are available via ProteomeXchange with identifier PXD014522. As proof-of-principle, the most promising species-unique peptides were applied in targeted tandem MS-analyses of clinical samples and their relevance for identifications of the pathogens, i.e. proteotyping, was validated, thus demonstrating their potential as peptide biomarker candidates for diagnostics of infectious diseases

Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations

BACKGROUND. Apolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.METHODS. We investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.RESULTS. Compared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.CONCLUSION. These findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention. TRIAL REGISTRATION. ClinicalTrials.gov NCT04209816 and NCT01445730.Peer reviewe

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function

Childbearing – A way to improve marital life?

En förlossning kan påverka en kvinna när det gäller hennes självbild och hur hon fungerar i en relation. Det kan också förekomma fysiska förändringar hos kvinnan, framför allt i underlivet. Det finns mycket forskning om hur samlivet påverkas efter en förlossning. De flesta studier är genomförda 3-12 månader postpartum och beskriver ofta vilka problem som kan uppstå hos kvinnan när det gäller just samlivet. Syftet med detta arbete är att beskriva hur en vaginal förlossning kan ge ett förbättrat samliv 3-7 år efter förlossningen. En enkätundersökning genomfördes på Sahlgrenska sjukhuset, Göteborg. I denna uppsats analyseras kommentarerna till ett påstående i den enkäten. Metoden som valdes för att analysera materialet var kvalitativ innehållsanalys. Resultatet visar att det finns flera orsaker till att kvinnor upplever att samlivet förbättras efter en vaginal förlossning. De faktorer som framkom är den Sexuella funktionen, Samhörigheten med partnern, ökat Självförtroende, förändrad Kroppsuppfattning, ökad Självkänsla, Livserfarenhet och Fertilitet. Vi anser att det är viktigt att förmedla information om att samlivet kan förbättras då den mesta forskningen istället handlar om komplikationer efter förlossning. Genom denna studie har vi sett att den vaginala förlossningen kan ha stor betydelse för kvinnans mognad och hur hon betraktar sig själv och sin kropp, samt hur fysiska förändringar kan ge större njutning vid samlag

Central neuropeptide Y (NPH) expression and function : role in stress, experimental anxiety, and cognition

Neuropeptide Y (NPY), a 36 amino acid peptide abundantly expressed throughout the mammalian nervous system, has been implicated in experimental anxiety and stress related responses, feeding, and learning and memory. These functions are mediated via different receptor subtype populations (Y1-Y6), all belonging to the G-protein coupled receptor superfamily. The Y1 -subtype has been shown to mediate the anxiolytic effects of NPY, while the Y2 subtype is involved in regulation of circadian rhythms and neuronal excitability in the hippocampus, and may, thus, be the receptor subtype involved in the peptide's effects on memory function. Stimulation of food-intake by NPY has been proposed to be mediated by Y5 and/or Y1-receptors within the hypothalamus. In this thesis, regulation of central NPY-expression has been examined in relation to stress, anxiety, and cognitive function in the rat. First, we examined the effects of acute or repeated restraint stress on NPY expression. A single restraint stress has been shown to be anxiogenic on the elevated plus-maze, an effect mediated through the central nucleus of the amygdala, while NPY is anxiolytic. A single restraint stress was shown to significantly decrease NPY mRNA and peptide expression in the amygdala, while repeating the restraint once per day for 10 consecutive days lead to an increase in amygdala NPY expression (mRNA and peptide), and to an endocrine and behavioral adaptation, i.e. an habituation, to the stressor. On the basis of these findings, we have proposed that NPY might be part of the mechanism regulating the behavioral responses to stress. A powerful way to examine the function of a gene and its product is to overexpress the gene in vivo. We used lipid-mediated gene transfer as a method for introducing genetic material, here cDNA for NPY, or, for optimization purposes, the enzyme chloramphenicol-acetyl-transferase (CAT) into the adult rat CNS. We were able to demonstrate the feasibility of in vivo gene transfer in the adult rat brain, and the production of functional protein measured as enzymatic activity. However, expression did not reach a sufficient level and / or distribution to be useful for our purposes. Instead, a rat overexpressing NPY was used to study the effects of NPY on experimental anxiety and response to restraint stress, cognitive function, locomotion, voluntary ethanol consumption and feeding. No effect of the genotype was seen on locomotion, voluntary ethanol consumption, food-intake, or anxiety related behavior on the elevated plus-maze under baseline (unstressed) conditions. However, the transgenic subjects displayed an insensitivity to the anxiogenic effects of a restraint stress when the stress preceeded behavioral testing on the elevated plus-maze. There was a marked release of punished responding in the punished drinking test in transgenic subjects compared to the wildtype litter-mate controls. Also, a highly significant impairment of spatial learning in transgenic subjects was seen in the acquisition-phase of testing on the Morris water-maze. Control experiments and previously published data indicate that anti-stress and memory impairment effects of NPY are independent. The work presented here supplies further evidence for the involvement of endogenous NPY in stress-related behaviors, experimental anxiety, and cognitive function

Om vägen till lönebidragsanställning för elever och unga vuxna med lindrig utvecklingsstörning

Syftet med denna studie är att beskriva och analysera framgångsfaktorer kring lönebidrags-anställningar för personer med lindrig utvecklingsstörning samt vilken typ av förberedande arbete som upplevs som gynnsamt. Studien är genomförd utifrån en kvalitativ forskningsmetod, där vi genomfört intervjuer med 15 informanter; sex unga vuxna med lindrig utvecklingsstörning som har eller snart skulle påbörja, en lönebidragsanställning samt nio nyckelpersoner, involverade i övergångsarbetet på olika sätt. Samtliga informanter beskrev positiva följder av möjligheten att få prova på praktik- och arbetsplatser med olika inriktningar. Nyckelpersonerna framhöll vikten av att tid läggs på matchningsarbetet utifrån individen kontra arbetsplatsens arbetsuppgifter och möjligheter till anpassningar. Elever och unga anställda uttryckte en stor vilja till självständighet och att begränsade arbetsuppgifter är en faktor för att möjliggöra detta. Bland elever och unga anställda fanns en stor medvetenhet kring deras funktionsnedsättning. Flera informanter framhöll att handledare behöver se och stötta samt inbjuda eleven/den unge anställde till delaktighet, även närstående är viktiga i det arbetet. Nyckelpersonerna betonade hur relationsskapandet mellan skola och arbetsplats är av stor vikt, liksom de ungas förståelse gällande arbetslivets krav och en väl avvägd plan för att möta dessa i ökande svårighetsgrad. Detta ökar möjligheten att lyckas vilket i sin tur leder till en ökad självkänsla. Utifrån studiens resultat konkluderas att det är av stor vikt att skolpersonal och andra berörda involverade i övergångsarbetet etablerar en god relation till arbetsplatsens handledare för att möjliggöra en nära samverkan och en öppen dialog. Både nyckelpersoner och elever/unga vuxna behöver ha kunskap om hur den enskilde individens funktionsnedsättning påverkar i olika sammanhang samt hur relationer och socialt samspel påverkar utveckling och lärande. Angeläget är att medvetet arbeta med psykologiska faktorer, vilka utvecklar och stärker individen både på ett personligt och yrkesmässigt plan, vilket i sin tur leder till ökade möjligheter att leva ett mer självständigt liv