Coming dissertations at MedFak
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Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-517684
Gastric bypass surgery (GBP) leads not only to considerable and consistent weight loss but to a number of beneficial metabolic effects, often including a swift remission of type 2 diabetes (T2DM). Increases in the gut hormone GLP-1 are considered central to this effect, although several other mechanism are likely involved. One complication to GBP is post-bariatric hypoglycaemia (PBH), where the individual suffers from episodes of low blood sugar after meals. The mechanism behind this is incompletely understood.
Previous research has reported an attenuation of the counterregulatory response to hypoglycaemia in patients after GBP. Many hypoglycaemic episodes also appear to be asymptomatic. Together, this has led to the hypothesis that GBP and PBH may involve an adaptation to lower blood glucose levels, a lowered glycaemic set point. As much of hypoglycaemia counterregulation involves the central nervous system (CNS), such an adaptation would presumably involve neuroendocrine mechanism. Experimental treatment with GLP-1 receptor agonists (GLP-1RA) has been reported as successful against PBH, which is paradoxical as GLP-1RA stimulate insulin release.
The aim of this thesis is to further explore the metabolic changes after GBP that may influence glycaemic control. In Paper I, euglycaemic-hypoglycaemic clamps were used to assess whether infusion with GLP-1RA affects the counterregulatory response to hypoglycaemia after GBP. In Paper II, normoglycaemic-hypoglycaemic clamps were performed before and after GBP during simultaneous brain imaging with fMRI and FDG-PET techniques, cognitive testing and assessment of counterregulatory hormones. Paper III details the time course of metabolic changes after GBP in patients with previous T2DM with focus on adipose tissue, including gene expression, and possible anti-inflammatory effects. Paper IV approaches the same question as Paper I, this time in the setting of a standardized meal test. All papers include assessment of heart rate variability (HRV) as a potential reflection of autonomic nervous system (ANS) activity.
In Paper I, we do not find indications that GLP-1RA affects counterregulatory hormones, but that it may affect ANS activation during hypoglycaemia. In contrast, Paper IV reports higher cortisol levels with GLP1-RA after a meal, and indications of ANS effects, but no effect on post-prandial glucose levels. Results from Paper II support the hypothesis that GBP attenuates hormonal counterregulatory responses and affects how the CNS responds to hypoglycaemia. In Paper III we report sustained improvements in glucose uptake in adipocytes, potentially indications of decreased low-grade inflammation and signs of transient increases in parasympathetic activity.
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The role of hyaluronan and its CD44 receptor in inflammation and cancer
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-517801
Hyaluronan, an important extra-cellular matrix molecule, was thought to be interstitial connecting glue decades ago. However, recent evidence has revealed that hyaluronan and its binding proteins also play crucial roles in various pathophysiological conditions in humans, including inflammation and infection.
Study I focused on dengue virus infection and found that elevated serum hyaluronan levels during early infection phase was an independent predictor for occurrence of warning signs, and thus severe dengue. High circulating levels of the viral non-structural protein 1 (NS1) correlated with high concentrations of serum hyaluronan. NS1 exposure decreased the expression of CD44 in differentiating endothelial cells impairing the integrity of vessel-like structures and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1-induced disruption of endothelial integrity. Study II reports a negative correlation between the expression of genes encoding hyaluronan synthase HAS2, its natural antisense transcript HAS2-AS, the chromatin modulating factor HMGA2 and transforming growth factor-β (TGFβ), and survival of patients with invasive breast cancer. TGFβ induction of Hmga2, Has2as and Has2 in mouse mammary epithelial cells, and synthesis of hyaluronan were accompanied with activation of Akt and Erk1/2 MAP-kinase signaling and were required for breast cancer cell motility. Importantly, the hyaluronan receptor Cd44, but not Hmmr, was required for TGFβ-mediated epithelial-mesenchymal transition phenotype. Has2as was found to contribute to the maintenance of stem cell factors and breast cancer stemness. Study III explored the physical interaction between the inhibitor of the apoptosis-stimulating protein of p53 (iASPP) and the hyaluronan receptor CD44. The CD44 standard isoform (CD44s), but not the variant isoform, bound to iASPP via the ankyrin-binding domain in CD44s. iASPP was required for hyaluronan-induced CD44-dependent migration and adhesion of fibroblasts. CD44 altered the sub-cellular localization of the iASPP-p53 complex; thus, ablation of CD44 promoted translocation of iASPP from the nucleus to the cytoplasm, resulting in increased formation of a cytoplasmic iASPP-p53 complex in fibroblasts. Overexpression of iASPP decreased the level of intracellular reactive oxygen species, while overexpression of CD44 increased. Knock-down of CD44s, in the presence of p53, led to increased cell growth and cell density of fibroblasts by suppression of p27 and p53.
In summary, we investigated the interaction of hyaluronan and its transmembranous receptor, CD44, as well as the modulation of hyaluronan synthesis, in several different pathophysiological conditions.