No description available.

Sammanfattning Bakgrund: Diabetes mellitus typ 2 (DMT2)är en av den vanligaste sjukdomarna och den ökar mer och mer på grund av ohälsosam livsstil. Faktorer som höjer risken för att utveckla DMT2 är livstillfaktorer som till exempel tobak, minskad fysisk aktivitet, stillasittande liv, matvanor och fetma. Sjukdomen behandlas med hälsosam kost, fysisk aktivitet och medicinering. Syftet: Syftet med studie var att beskriva personers upplevelser av att leva med DTM2. Metod: Litteraturstudie med en beskrivande design som bygger på 13 kvalitativa artiklar. Resultat: personerna upplever en psykologisk påverkan som visar sig som oro, rädsla, nedstämdhet och oro över framtiden. Personerna upplever också olika sociala begränsningar. Egenvården som främst består av medicinering, kost och fysisk aktivitet upplevs som mycket viktig. Kunskap och stöd av närstående och vårdpersonalen upplevs som viktig. Slutsats: Personer med DMT2 känner sig nedstämda och upplever oro. Genom att få stöd från närstående och vårdpersonal underlättas personernas självhantering av sjukdomen. Personerna upplever att umgänget med andra personer minskas på grund av sociala begränsningar. Olika copingstrategier samt egenvård spela stor roll för personer med diabetes typ 2. Mer kunskap inom området vore önskvärt för att ge ett adekvat bemötande. Nyckelord: diabetes mellitus typ 2, dagligt liv, upplevelser.

Background: Type 2 diabetes mellitus is a metabolic disorder characterized by the rise of fasting plasma glucose from its normal range (≥125mg/dl). It is marked by insufficient production of insulin from pancreatic β-cells as a result of failed compensation due to insulin resistance. Several treatments are available for the disorder, which mainly focus on improving the sensitivity of insulin in different body tissues. Recently, probiotics were suggested as candidate treatments for type 2 diabetes and for extending lifespan as well. This experiment aims to investigate such claims using Drosophila melanogaster as a disease model.   Results: Other than the observed low average weights in treated larva samples, probiotics did not show any other significant results in affecting the length, glucose, glycogen, and trehalose levels (One-Way ANOVA and Kruskal-Wallis, p>0.05). Real-time PCR was only carried out once. Thus, no statistical tests were reliable enough to analyse the data obtained. The longevity study, on the other hand, did show significance (Log-rank (Mantel-Cox) test and Gehan-Breslow-Wilcoxon test, p<0.0001), as the probiotic Bifidobacterium lactis extended the lifespan of adult flies feeding on a high sugar diet significantly when compared to the control ones feeding on only high sugar diet without probiotics.   Conclusion: Except for weight measurements, none of the other results was reliable enough to make a concrete conclusion on whether the treatments indeed worked in reversing type 2 diabetes symptoms or not. Real-time PCR results did show some effects of some of the treatments at different developmental stages. However, unless Real-time PCR is repeated at least once using the same protocol, no deduction can be made. Additionally, the data obtained hint that the dosage used (0.025 g) was too high for larvae and adult flies and might have caused malnutrition by blocking their midgut and decreasing food absorption. Hence, false significant or non-significant results were acquired instead.   Further studies are required using a much lower probiotic dosage if Drosophila is used as a disease model. Although, other models such as mice or rats are recommended in this case, in order to reach a solid conclusion about the effectiveness of probiotics in treating type 2 diabetes mellitus. Baring these thoughts in mind and based on the results of this experiment, the null hypothesis indicating that there is no significant relationship between the use of probiotics and reversing type 2 diabetes mellitus symptoms is therefore accepted.

Bakgrund: Diabetes typ 2 är en folkhälsosjukdom som har ökat markant i världen. Kroppen har svårt för att reglera och hålla sockerhalten i blodet vid diabetes typ 2. En behandling kan vara livsstilsförändring i form av ökad fysisk aktivitet samt ändrade matvanor. Livsstilsförändringar bidrar till en bättre hälsa och diabeteskomplikationer minskas. Studien fokuserar på livsstilsförändringar relaterat till fysisk aktivitet och kost. Hälsofrämjande omvårdnad kan användas för att stärka patientens möjlighet till att uppnå en god egenvård vid diabetes typ 2. Sjuksköterskan ska få en förståelse hur patienten upplever livsstilsförändringar vid diabetes typ 2.  Syfte: Syftet med studien var att beskriva patienters upplevelser av att genomföra livsstilsförändringar vid diabetes typ 2. Metod:Föreliggande studie genomfördes som en litteraturstudie. Den baserades på 9 kvalitativa vetenskapliga artiklar. Analysen genomfördes av inspiration från Graneheim och Lundman, en beskrivning av en kvalitativ innehållsanalys på manifest nivå. Resultat: Det framkom i föreliggande studie två kategorier och en underkategori; stöd och utmaningar i sociala relationer, upplevelser av att hitta motivation och en ny mening med livet. De sociala relationerna kunde bidra med både positiv och negativ inverkan vid genomförandet av livsstilsförändringar. Motivationen sågs som den avgörande faktorn vid genomförandet och kunde bidra till en positiv eller negativ effekt. Negativ motivation var ett stort hinder vid genomförandet och den positiva motivationen kunde resultera med en ny mening med livet. Slutsats: I föreliggande studie framkom det att genomförandet av livsstilsförändringar var utmanande och många reagerade olika. Trots svårigheterna att upprätthålla förändringarna upplevde patienterna välbefinnande. Patienten är i behov av en personcentrerad omvårdnad för att kunna hitta motivation för att finna sin egen väg till hälsa.

We hypothesized that bone evolved, in part, to enable bony vertebrates to escape danger in the wild. In support of this notion we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents) and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Osteocalcin is also engaged in a complex cross talk with the other principal endocrine regulator of the ASR, the hypothalamic-pituitary-adrenal axis. Exogenous osteocalcin stimulates an increase in circulating adrenal steroids and Ocn-/- mice born of Ocn-/- mothers exhibit a severe developmental defect in adrenal steroidogenesis of corticosterone and aldosterone. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony vertebrate specific endocrine mediation of the ASR. Together these results demonstrate a role for bone in the physiology of danger.

No description available.

Obesity results from expansion of white adipose tissue. The inability of white adipose tissue to adequately store lipids leads to ectopic deposition of lipids in non-adipose tissue that can lead to systemic insulin resistance. It is well known that insulin resistance correlates with inflammation of adipose tissue in obese animals and humans. Decreasing inflammation in the adipose tissue has been proven as a therapeutic strategy for improvement of insulin sensitivity in vivo. Numerous factors secreted by immune cells, including macrophages, have been suggested as regulating adipose tissue insulin sensitivity. In the first part of my thesis, I describe the role of one such factor, CD40 in adipose tissue inflammation. The CD40-CD40L dyad acts as co-stimulation in the interaction of antigen-presenting cells, such as macrophages and dendritic cells, with effector cells, such as T cells, in adaptive immunity. We found that CD40 knockout mice were smaller but surprisingly more insulin resistant and glucose intolerant compared to wild-type mice when fed a high fat diet. Consistent with their metabolic phenotype, knockout mice displayed increased adipose tissue inflammation with infiltration of immune cells including macrophages and T cells. Consistent with increased inflammation, CD40 knockout adipose tissue displayed decreased lipid storage. Deficiency of CD40 also led to increased lipid deposition in liver, which may be due to increased lipid release into circulation from the adipose tissue as well as increased lipid synthesis in the liver. CD40 knockout mice had increased hepatic insulin resistance and increased gluconeogensis despite decreased hepatic inflammation. These findings suggest that CD40 is a novel regulator of adipose tissue inflammation in diet-induced obesity. In the second part of this thesis we examined perivascular adipose tissue and brown adipose tissue for the presence of inflammation. In contrast to visceral adipose tissue, macrophage infiltration was absent in perivascular and brown adipose tissue as defined by reduced F480+ cells by flow cytometry and immunohistochemistry. We also found that perivascular adipose tissue was similar to brown adipose tissue as shown by gross morphology and gene expression pattern. Inflammatory gene expression was not increased in brown or perivascular adipose tissue in obese mice as determined by microarray gene expression analysis. These findings suggest that perivascular adipose tissue is more similar to brown adipose tissue than white adipose tissue and that both perivascular and brown adipose tissue are resistant to inflammation. We conclude that, (1) CD40 protects against adipose tissue inflammation in diet-induced obesity, (2) the CD40 knockout mouse is an interesting model of hepatic steatosis with decreased inflammation and (3) perivascular adipose tissue is almost identical to brown adipose tissue in obese mice and that both are resistant to inflammation.

Obesity is the top risk factor for the development of type 2 diabetes mellitus in humans. Obese adipose tissue, particularly visceral depots, exhibits an increase in macrophage accumulation and is described as being in a state of chronic low-grade inflammation. It is characterized by the increased expression and secretion of inflammatory cytokines produced by both macrophages and adipocytes, and is associated with the development of insulin resistance. Based on these observations, we investigated the potential role of macrophage infiltration on whole body metabolism, using genetic and diet-induced mouse models of obesity. Using flow cytometry and immunofluorescence imaging we found that a significant percentage of macrophages proliferate locally in adipose tissue of obese mice. Importantly, we identified monocyte chemoattractant protein 1 (MCP-1) as the stimulating factor. We also found that ATMs can be targeted for specific gene silencing using glucan encapsulated siRNA particles (GeRPs). Knockdown of the cytokine osteopontin improved regulation of systemic glucose levels as well as insulin signaling in adipocytes. Conversely, targeting lipoprotein lipase (LPL) abrogated the buffering of lipid spillover from adipose tissue, resulting in increased hepatic glucose output. Finally, silencing of the master regulator of inflammation NF-κB in resident liver macrophages called Kupffer cells significantly improved hepatic insulin signaling. Thus this work demonstrates that macrophages can regulate whole body metabolism.

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Our lab and others have shown that a chronic low-grade inflammation takes place in skeletal muscles during diet-induced obesity, as evidenced by increased macrophage markers and pro-inflammatory cytokine levels. Interleukin (IL)-10 is a Th2-type cytokine that inhibits the synthesis and activity of pro-inflammatory cytokines and counteracts the Toll-like receptor-mediated inflammation. Our lab has previously demonstrated the preventive role of IL-10 against insulin resistance. Here, I have analyzed the effects of IL-10 on the skeletal muscle glucose metabolism and myogenesis in three different insulin resistant states (high fat diet-induced, leptin-deficiency-induced and aging-induced). The first model involved long-term (16 weeks) high-fat diet (HFD) feeding that resulted in markedly obese and hyperglycemic mice, representative of obese type 2 diabetic subjects. In mice overexpressing IL-10 specifically in the skeletal muscle (MIL10), we observed improved whole-body and skeletal muscle insulin sensitivity as compared to wild-types after long-term high fat diet feeding. The improved insulin sensitivity in the skeletal muscle was due to increased Akt signaling and decreased muscle inflammation. Leptin is an important adipocyte-derived hormone that is elevated in obesity, and it regulates numerous physiological functions including the energy balance and inflammation. Thus, my second model examined the effects of muscle-specific overexpression of IL-10 on glucose metabolism in the hyperphagic, leptin-deficient ob/ob mice. We detected improved whole-body insulin sensitivity compared to the control mice. My third model examined the effects of increased IL-10 expression using MIL10 mice during aging-induced insulin resistance. In 18-month old MIL10 mice, we found enhanced whole-body and skeletal muscle insulin sensitivity due to improved insulin signaling and decreased muscle inflammation as compared to wild-type mice. Last, to test whether direct signaling of IL-10 on skeletal muscle is responsible for the beneficial effects of IL-10 on muscle glucose metabolism, I generated mice lacking IL-10 receptor 1 type chain selectively in skeletal muscle (M-IL10R-/-). We observed more prominent muscle inflammation and whole-body insulin resistance in HFD-fed M-IL10R-/- mice as compared to wild-type mice. Interestingly, when studying insulin resistance in the IL-10 transgenic mouse models, we identified a consistent increased lean mass phenotype, and conversely decreased lean mass in the HFD-fed M-IL10R-/- mice. Quantitative RT-PCR on HFD-fed MIL10 group muscles to measure myogenesis-related gene expression identified a correlation between lean mass and both IL-10 and MyoD mRNA expression levels. In support of this, I showed that IL-10 caused an increase in in vitro cultured myoblast proliferation rates. Together, these results highlight the potential benefits of IL-10 expression not only in muscle glucose metabolism but also in maintaining muscle mass during insulin resistant states. Overall, these results demonstrate that selective expression of IL-10 in skeletal muscle suppresses inflammation, improves glucose metabolism and muscle growth in obese and aging mice, and further establishes that these effects are at least partially mediated by direct activation of IL-10 signaling in skeletal muscle.

abstract: Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine system leading to hypothalamic-pituitary-adrenal axis (HPA) dysregulation and increased affective disorders. Preliminary data indicate TBI causes neuroinflammation in the hippocampus, likely due to axonal damage, and in the paraventricular nucleus of the hypothalamus (PVN), where no axonal damage is apparent. Mechanisms regulating neuroinflammation in the PVN are unknown. Furthermore, chronic stress causes HPA dysregulation and glucocorticoid receptor (GR)-mediated neuroinflammation in the PVN. The goal of this project was to evaluate neuroinflammation in the HPA axis and determine if GR levels change at 7 days post-injury (DPI). Adult male and female Sprague Dawley rats were subjected to midline fluid percussion injury. At 7 DPI, half of each brain was post-fixed for immunohistochemistry (IBA-1) and half biopsied for gene/protein analysis. IBA-1 staining was analyzed for microglia activation via skeleton analysis in the hypothalamus and hippocampus. Extracted RNA and protein were used to quantify mRNA expression and protein levels for GRs. Data indicate increased microglia cell number and decreased endpoints/cell and process length in the PVN of males, but not females. In the dentate gyrus, both males and females have an increased microglia cell number after TBI, but there is also an interaction between sex and injury in microglia presentation, where males exhibit a more robust effect than females. Both sexes have significant decreases of endpoints/cell and process length. In both regions, GR protein levels decreased for injured males, but in the hippocampus, GR levels increased for injured females. Data indicate that diffuse TBI causes alterations in microglia morphology and GR levels in the hypothalamus and hippocampus at 7 DPI, providing a potential mechanism for HPA axis dysregulation at a sub-acute time point. / Dissertation/Thesis / Masters Thesis Biology 2019