Ziele der hier vorliegenden Arbeit waren eine immunhistochemische Analyse von GFAP (‚glial fibrillary acidic protein’) und GLUT-1 (Glukosetransporter-1) nach fokaler zerebraler Ischämie sowie deren mögliche Beeinflussung durch eine intravenöse Transplantation autologer mononukleärer Knochenmarkzellen (mKMZ) im Schafmodell. Eine differenzierte Analyse der Zielstrukturen in grauer und weißer Substanz (GS bzw. WS) sollte Aufschluss über eventuell unterschiedliche Reaktionsmuster liefern. Das Gehirnmaterial von zehn Tieren der bereits 2006/2007 stattgefundenen Studie, welche mit PET und MRT-Untersuchungen sowie der Durchführung von Verhaltenstests einherging, wurde retrospektiv im Rahmen der vorliegenden Arbeit untersucht. Je fünf gehörten zu einer Kontroll- bzw. Therapiegruppe (KG bzw. TG). Bei allen Versuchstieren wurde durch die permanente Okklusion der linken mittleren Zerebralarterie (pMCAO) eine fokale zerebrale Ischämie im Bereich des Neokortex hervorgerufen. Die Tiere der Therapiegruppe erhielten 24 Stunden nach dem Eingriff eine Transplantation autologer mKMZ (4x106/kg KGew). Nach sieben Wochen wurden die Versuchstiere getötet, ihre Schädel perfundiert und ihre Gehirne fixiert. Eine Lamelle der Gehirne wurde für die anschließende histologische Untersuchung in 30% Saccharose konserviert. Nach der Etablierung der Antikörper GFAP und GLUT-1 wurden vier Regionen der Gehirn-lamellen immunhistochemisch markiert und abschließend qualitativ und quantitativ analysiert. Die Regionen I (infarktnah) und III (infarktfern) lagen in der ipsilateralen Hemisphäre, die Regionen II (korrespondierend zu Region I) und IV (korrespondierend zu Region III) in der kontralateralen Hemisphäre. Durch den höheren Substanzverlust an Gehirnmasse in der ipsi-lateralen Hemisphäre der KG, wurden in dieser Tiergruppe die Regionen III und IV nicht ausgewertet. Vor der Analyse sind die physiologischen Markierungsmuster der vier Regionen in grauer und weißer Substanz an zwei gesunden Tieren (Prozesskontrolle) aufgezeigt worden. Durch die elektronenmikroskopische Untersuchung von Präparaten und anhand von GFAP/GLUT-1 doppelmarkierten Präparaten konnte festgestellt werden, dass die Astrozytenendfüßchen durch den hier verwendeten GLUT-1 Antikörper nicht markiert wur-den, sondern dass alleinig die gefäßständige, 55 kDa schwere Isoform detektiert worden ist. Die fokale zerebrale Ischämie führte in beiden Gruppen zu einer hochgradigen reaktiven Astrogliose mit Ausprägung einer Glianarbe in Region I. Protoplasmatische Astrozyten der grauen und fibrilläre Astrozyten der weißen Substanz zeigten hypertrophe Veränderungen. Die reaktive Astrogliose von Region I spiegelte sich in einer erhöhten GFAP-Dichte wider (p<0,05 in der Therapiegruppe). Region III hatte die gleiche GFAP-Dichte wie die Regionen II und IV. Der direkte Vergleich zwischen den Regionen I der beiden Gruppen zeigte Veränderungen der GFAP-Dichte durch die Zelltherapie auf: In der GS der Therapiegruppe lag eine geringere GFAP-Dichte vor, in der WS eine höhere (≠ p<0,05; GS und WS). Die Ergebnisse der GLUT-1-Analyse sind denen der GFAP-Analyse sehr ähnlich. Durch den Schlaganfall ist es zu einer erhöhten GLUT-1-Expression in GS und WS (p<0,05 WS) von Region I der Kontrollgruppe gekommen. Auch in Region I der Therapiegruppe konnten er-höhte GLUT-1-Dichten in GS und WS (p<0,05 WS) detektiert werden, zusätzlich dazu lag in der GS von Region III der Therapiegruppe eine erhöhte GLUT-1-Dichte vor (p<0,05). Der Vergleich zwischen beiden Gruppen zeigte Veränderungen durch die Therapie für die Regio-nen I und II auf. Die GLUT-1-Dichte der WS war in beiden Regionen in der TG erhöht (p<0,05), die GS von Region I zeigte in der Therapiegruppe eine geringere GLUT-1-Dichte. Ein Schlaganfall führt zu einer Erhöhung der GFAP sowie GLUT-1-Dichten in WS und GS im infarktnahen Gebiet. Durch die Transplantation von 4x106 autologen mononukleären Knochenmarkzellen pro kg KGew 24 Stunden nach dem Schlaganfall können diese Strukturen in ihren Expressionsmustern beeinflusst werden, dabei reagieren graue und weiße Substanz unterschiedlich: Die GS mit einer Verringerung, die WS mit einer Erhöhung der GFAP- bzw. GLUT-1-Dichte (p<0,05 WS, GLUT-1). Die Funktionskreisläufe in infarktfernen Regionen sind sieben Wochen nach dem Schlaganfall auf Astrozytenebene normalisiert (vgl. Region III). Die erhöhte GLUT-1-Dichte (p<0,05) in der GS der infarktfernen Region ist möglicherweise mit einem erhöhten Glukosemetabolismus in Verbindung zu setzen. Dies kann jedoch erst durch die Auswertung der FDG-PET-Daten beantwortet werden. Ob die durch Transplantation autologer mKMZ festgestellten Veränderungen der GFAP- und GLUT-1-Dichte in der Therapiegruppe zusätzlich mit einer verbesserten motorischen Leistung der Tiere einhergingen, wird erst durch die Analyse der Daten aus den Verhaltenstests festgestellt werden können.

Parmi l’ensemble des désordres métaboliques retrouvés en insuffisance rénale chronique (IRC), la résistance à l’insuline demeure l’un des plus importantes à considérer en raison des risques de morbidité et de mortalité qu’elle engendre via les complications cardiovasculaires. Peu d’études ont considéré la modulation de transporteurs de glucose comme mécanisme sous-jacent à l’apparition et à la progression de la résistance à l’insuline en IRC. Nous avons exploré cette hypothèse en étudiant l’expression de transporteurs de glucose issus d’organes impliqués dans son homéostasie (muscles, tissus adipeux, foie et reins) via l’utilisation d’un modèle animal d’IRC (néphrectomie 5/6e). La sensibilité à l’insuline a été déterminée par un test de tolérance au glucose (GTT), où les résultats reflètent une intolérance au glucose et une hyperinsulinémie, et par les études de transport au niveau musculaire qui témoignent d’une diminution du métabolisme du glucose en IRC (~31%; p<0,05). La diminution significative du GLUT4 dans les tissus périphériques (~40%; p<0,001) peut être à l’origine de la résistance à l’insuline en IRC. De plus, l’augmentation de l’expression protéique de la majorité des transporteurs de glucose (SGLT1, SGLT2, GLUT1; p<0,05) au niveau rénal en IRC engendre une plus grande réabsorption de glucose dont l’hyperglycémie subséquente favorise une diminution du GLUT4 exacerbant ainsi la résistance à l’insuline. L’élévation des niveaux protéiques de GLUT1 et GLUT2 au niveau hépatique témoigne d’un défaut homéostatique du glucose en IRC. Les résultats jusqu’ici démontrent que la modulation de l’expression des transporteurs de glucose peut être à l’origine de la résistance à l’insuline en IRC. L’impact de la parathyroïdectomie (PTX) sur l’expression du GLUT4 a été étudié étant donné que la PTX pourrait corriger l’intolérance au glucose en IRC. Nos résultats démontrent une amélioration de l’intolérance au glucose pouvant être attribuable à la moins grande réduction de l’expression protéique du GLUT4 dans les tissus périphériques et ce malgré la présence d’IRC. L’excès de PTH, secondaire à l’hyperparathyroïdie, pourrait alors être à l’origine de la résistance à l’insuline en IRC en affectant l’expression du GLUT4. L’IRC partage de nombreuses similitudes avec le prédiabète quant aux défaillances du métabolisme du glucose tout comme l’hyperinsulinémie et l’intolérance au glucose. Aucune étude n’a tenté d’évaluer si l’IRC pouvait ultimement mener au diabète. Nos résultats ont par ailleurs démontré que l’induction d’une IRC sur un modèle animal prédisposé (rats Zucker) engendrait une accentuation de leur intolérance au glucose tel que constaté par les plus hautes glycémies atteintes lors du GTT. De plus, certains d’entre eux avaient des glycémies à jeun dont les valeurs surpassent les 25 mmol/L. Il est alors possible que l’IRC puisse mener au diabète via l’évolution de la résistance à l’insuline par l’aggravation de l’intolérance au glucose. / Of all metabolic disorders found in chronic renal failure (CRF), insulin resistance remains one of the most important to consider because of the risk of morbidity and mortality it causes via cardiovascular complications. Few studies have considered the modulation of glucose transporters as the mechanism underlying the emergence and progression of insulin resistance in CRF. We explored this hypothesis by studying the expression of glucose transporters from organs involved in its homeostasis (muscle , fat , liver and kidneys) through the use of an animal model reflecting CRF (5/6th nephrectomy). The insulin sensitivity was determined by a glucose tolerance test (GTT), where the results reflect glucose intolerance and hyperinsulinemia , and transport studies in muscle show a decrease in glucose uptake in CRF ratss (~31% , p<0.05). The significant decrease in GLUT4 in peripheral tissues (~40%, p<0.001) may be the cause of insulin resistance in CRF. Furthermore, increased protein expression of the majority of glucose transporters (SGLT1, SGLT2, GLUT1, p<0.05) within the kidney in CRF causes greater glucose reabsorption in which consequential hyperglycemia promotes a decrease in GLUT4 thus exacerbating insulin resistance. Elevated protein levels of GLUT1 and GLUT2 in the liver reflects an impaired glucose homeostasis in CRF. The results show that the modulation of the expression of glucose transporters may be responsible for insulin resistance in CRF. The impact of parathyroidectomy (PTX) on the expression of GLUT4 was studied since PTX is known to correct glucose intolerance in CRF. Our results show an improvement in glucose intolerance which may be due to less reduction of GLUT4 protein expression in peripheral tissues despite the presence of CRF. The excess of PTH, linked to secondary hyperparathyroidism, could be held responsible to the presence of insulin resistance in CRF by affectant GLUT4 expression. CRF shares many similarities with prediabetes in regards to impaired glucose metabolism such as hyperinsulinemia and glucose intolerance. No studies have attempted to assess whether CRF could lead to diabetes. Our results demonstrated that the induction of CRF in a predisposed animal model (Zucker rats) provoked greater glucose intolerance as evidenced by the highest blood glucose levels reached in the GTT. In addition, some of them had fasting blood glucose levels whose values exceeded 25 mmol/L. It is therefore possible that CRF can lead to diabetes through the evolution of insulin resistance by the worsening of glucose intolerance.

Parmi l’ensemble des désordres métaboliques retrouvés en insuffisance rénale chronique (IRC), la résistance à l’insuline demeure l’un des plus importantes à considérer en raison des risques de morbidité et de mortalité qu’elle engendre via les complications cardiovasculaires. Peu d’études ont considéré la modulation de transporteurs de glucose comme mécanisme sous-jacent à l’apparition et à la progression de la résistance à l’insuline en IRC. Nous avons exploré cette hypothèse en étudiant l’expression de transporteurs de glucose issus d’organes impliqués dans son homéostasie (muscles, tissus adipeux, foie et reins) via l’utilisation d’un modèle animal d’IRC (néphrectomie 5/6e). La sensibilité à l’insuline a été déterminée par un test de tolérance au glucose (GTT), où les résultats reflètent une intolérance au glucose et une hyperinsulinémie, et par les études de transport au niveau musculaire qui témoignent d’une diminution du métabolisme du glucose en IRC (~31%; p<0,05). La diminution significative du GLUT4 dans les tissus périphériques (~40%; p<0,001) peut être à l’origine de la résistance à l’insuline en IRC. De plus, l’augmentation de l’expression protéique de la majorité des transporteurs de glucose (SGLT1, SGLT2, GLUT1; p<0,05) au niveau rénal en IRC engendre une plus grande réabsorption de glucose dont l’hyperglycémie subséquente favorise une diminution du GLUT4 exacerbant ainsi la résistance à l’insuline. L’élévation des niveaux protéiques de GLUT1 et GLUT2 au niveau hépatique témoigne d’un défaut homéostatique du glucose en IRC. Les résultats jusqu’ici démontrent que la modulation de l’expression des transporteurs de glucose peut être à l’origine de la résistance à l’insuline en IRC. L’impact de la parathyroïdectomie (PTX) sur l’expression du GLUT4 a été étudié étant donné que la PTX pourrait corriger l’intolérance au glucose en IRC. Nos résultats démontrent une amélioration de l’intolérance au glucose pouvant être attribuable à la moins grande réduction de l’expression protéique du GLUT4 dans les tissus périphériques et ce malgré la présence d’IRC. L’excès de PTH, secondaire à l’hyperparathyroïdie, pourrait alors être à l’origine de la résistance à l’insuline en IRC en affectant l’expression du GLUT4. L’IRC partage de nombreuses similitudes avec le prédiabète quant aux défaillances du métabolisme du glucose tout comme l’hyperinsulinémie et l’intolérance au glucose. Aucune étude n’a tenté d’évaluer si l’IRC pouvait ultimement mener au diabète. Nos résultats ont par ailleurs démontré que l’induction d’une IRC sur un modèle animal prédisposé (rats Zucker) engendrait une accentuation de leur intolérance au glucose tel que constaté par les plus hautes glycémies atteintes lors du GTT. De plus, certains d’entre eux avaient des glycémies à jeun dont les valeurs surpassent les 25 mmol/L. Il est alors possible que l’IRC puisse mener au diabète via l’évolution de la résistance à l’insuline par l’aggravation de l’intolérance au glucose. / Of all metabolic disorders found in chronic renal failure (CRF), insulin resistance remains one of the most important to consider because of the risk of morbidity and mortality it causes via cardiovascular complications. Few studies have considered the modulation of glucose transporters as the mechanism underlying the emergence and progression of insulin resistance in CRF. We explored this hypothesis by studying the expression of glucose transporters from organs involved in its homeostasis (muscle , fat , liver and kidneys) through the use of an animal model reflecting CRF (5/6th nephrectomy). The insulin sensitivity was determined by a glucose tolerance test (GTT), where the results reflect glucose intolerance and hyperinsulinemia , and transport studies in muscle show a decrease in glucose uptake in CRF ratss (~31% , p<0.05). The significant decrease in GLUT4 in peripheral tissues (~40%, p<0.001) may be the cause of insulin resistance in CRF. Furthermore, increased protein expression of the majority of glucose transporters (SGLT1, SGLT2, GLUT1, p<0.05) within the kidney in CRF causes greater glucose reabsorption in which consequential hyperglycemia promotes a decrease in GLUT4 thus exacerbating insulin resistance. Elevated protein levels of GLUT1 and GLUT2 in the liver reflects an impaired glucose homeostasis in CRF. The results show that the modulation of the expression of glucose transporters may be responsible for insulin resistance in CRF. The impact of parathyroidectomy (PTX) on the expression of GLUT4 was studied since PTX is known to correct glucose intolerance in CRF. Our results show an improvement in glucose intolerance which may be due to less reduction of GLUT4 protein expression in peripheral tissues despite the presence of CRF. The excess of PTH, linked to secondary hyperparathyroidism, could be held responsible to the presence of insulin resistance in CRF by affectant GLUT4 expression. CRF shares many similarities with prediabetes in regards to impaired glucose metabolism such as hyperinsulinemia and glucose intolerance. No studies have attempted to assess whether CRF could lead to diabetes. Our results demonstrated that the induction of CRF in a predisposed animal model (Zucker rats) provoked greater glucose intolerance as evidenced by the highest blood glucose levels reached in the GTT. In addition, some of them had fasting blood glucose levels whose values exceeded 25 mmol/L. It is therefore possible that CRF can lead to diabetes through the evolution of insulin resistance by the worsening of glucose intolerance.

Orientador: Jaime Amaya-Farfán / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-21T17:15:26Z (GMT). No. of bitstreams: 1 Morato_PriscilaNeder_D.pdf: 813172 bytes, checksum: 96f9ce7da352faefcc39166ef5fe4fa9 (MD5) Previous issue date: 2012 / Resumo: As proteínas do soro do leite apresentam propriedades nutricionais e funcionais que influenciam a modulação de funções bioquímicas e fisiológicas.Estudos têm demonstrado que as proteínas do soro do leite (PSL), principalmente na forma hidrolisada (PSLH) possuem a capacidade de aumentar os níveis de glicogênio muscular. Considerando que a captação de glicose pela célula do músculo esquelético relaciona-se diretamente à atividade de proteínas transportadoras de glicose, este estudo se propôs realizar dois experimentos para conhecer os efeitos da PSL e da PSLH e de alguns dos seus produtos de hidrólise nos transportadores de glicose em músculos de ratos. No experimento 1, o objetivo foi verificar se o consumo de PSL e PSLH modulam a concentração de transportadores de glicose GLUT-1 e GLUT-4 na membrana plasmática (MP) de células musculares de animais sedentários e exercitados. Foram utilizados 48 ratos Wistar machos divididos em dois grupos: sedentários e exercitados, e cada um desses subdivididos em outros três, de acordo com a dieta, totalizando 6 grupos (n=8 por grupo). Os animais foram mantidos por 9 dias recebendo as dietas experimentais baseadas na AIN-93G, com as seguintes fontes protéicas: caseína (CAS), utilizada como controle, proteína do soro do leite (PSL), proteína do soro do leite hidrolisada (PSLH), e o animais exercitados foram submetidos a uma única sessão de exercício a 15m/min durante 60min um dia anterior ao sacrifício. Após o período experimental os animais foram sacrificados, os transportadores de glicose no músculo, GLUT-1 e GLUT-4, foram analisados por western blot. Adicionalmente, glicogênio, aminoácidos livres plasmáticos, insulina e indicadores bioquímicos de saúde foram determinados por métodos padrões. O consumo de PSLH elevou significativamente as concentrações de GLUT-4 na MP e de glicogênio, enquanto GLUT-1, insulina e os indicadores de saúde não apresentaram alterações. Baseado nas evidências do experimento 1, de que o consumo de PSLH eleva os estoques de glicogênio muscular e que também aumenta a concentração do transportador de glicose GLUT-4 na membrana plasmática, o experimento 2 teve como objetivo identificar quais componentes da PSLH poderiam modular a translocação do transportador de glicose GLUT-4 para a MP em músculo esquelético. Foram utilizados 49 ratos Wistar machos divididos em 7 grupos (n=7), que receberam soluções orais de glicose 30% mais 0,55 g/kg de peso corpóreo os seguintes componentes da PSLH: a) glicose (controle); b) PSLH; c) L-isoleucina; d) L-leucina; e) L-leucina mais L-isoleucina; f) peptídeo Lisoleucil- L-leucina; g) peptídeo L-leucil-L-isoleucina. Após receberem as soluções, os animais foram sacrificados, o transportador de glicose GLUT-4 no músculo foi analisado por western blot. Também foram analisados glicogênio, glicemia, insulina, aminoácidos livres plasmáticos e musculares, e indicadores bioquímicos de saúde por métodos clássicos. Entre os componentes testados da PSLH, o peptídeo leucil-isoleucina e o aminoácido isoleucina se mostraram mais eficientes em translocar GLUT-4 para a MP, favorecendo a captação de glicose pelo músculo esquelético. Os resultados obtidos nos experimentos indicam que o consumo da PSLH e de seus componentes ao aumentarem a translocação de GLUT-4 para a membrana plasmática, poderiam auxiliar no tratamento ou prevenção do diabetes do tipo II / Abstract: The milk whey proteins (WP) exhibit nutritional and functional properties which result in the modulation of the biochemical and physiological functions. Studies have shown that the WP, especially those in the hydrolyzed form (WPH),has the capacity to increase muscle glycogen levels. Considering that glucose uptake by the skeletal muscle cell is directly related to the activity of the glucose transporter proteins, the present study proposed to carry out two experiments to determine the effects of WP and WPH and of some of their hydrolysis products on the glucose transporters in rat muscles. The objective of experiment 1 was to verify if the consumption of WP and WPH are able to modulate the concentration of the glucose transporters GLUT-1 and GLUT-4 in the plasma membrane (PM) of muscle cells in sedentary and exercised animals. Forty-eight male Wistar rats were used, divided into sedentary and exercised groups, each of which was sub-divided into three sub-groups according to the diet, giving a total of 6 groups (n=8 per group). The animals were maintained for 9 days on experimental diets based on AIN-93G with the following protein sources: casein (CAS) used as the control, whey protein (WP) and whey protein hydrolysate (WPH). The exercised animals were submitted to a single exercise session for 60 min at 15m/min one day prior to euthanasia. After the experimental period, the animals were euthanized, and the muscle glucose transporters GLUT-1 and GLUT-4 analyzed by western blot. In addition, glycogen, free plasma amino acids, insulin and the biochemical health indicators were analyzed by standard techniques. The consumption of WPH significantly increased the concentrations of GLUT-4 in the PM and of glycogen, whereas GLUT-1, insulin and the health indicators remained unaltered. Based on evidence from experiment 1 that the consumption of WPH raised the muscle glycogen reserves and also the concentration of the glucose transporter GLUT-4 in the plasma membrane, the second experiment was designed to identify which WPH components could modulate translocation of the glucose transporter GLUT-4 to the PM in the skeletal muscle of the animals. Forty-nine male Wistar rats were used, divided into 7 groups (n=7), who were orally fed 30% glucose solutions plus 0.55 g/kg of body weight of the following WPH components: a) glucose (control); b) WPH; c) L-isoleucine; d) L-leucine; e) L-leucine plus L-isoleucine (50:50 mixture of both amino acids); f) L-isoleucyl-L-leucine peptide or g) L-leucyl-L-isoleucine peptide. After receiving the solutions, the animals were euthanized and the GLUT-4 determined by western blot. Glycogen, glycemia, insulin, free plasma and muscle amino acids, and the biochemical health indicators were also analyzed by classical methods. Of the WPH components tested, the peptide L-leucyl-L-isoleucine and the amino acid L-isoleucine were shown to be more efficient in translocating GLUT-4 to the PM, favoring the capture of glucose by the skeletal muscle. The results obtained from these experiments indicated that the consumption of WPH and its components increased GLUT-4 translocation to the plasma membrane, and could aid in the treatment and prevention of type ll diabetes / Doutorado / Nutrição Experimental e Aplicada à Tecnologia de Alimentos / Doutora em Alimentos e Nutrição

Cushing's syndrome and glucocorticoid therapy lead to central obesity, insulin resistance, and symptoms of altered energy regulation similar to those observed in the metabolic syndrome. We hypothesized that excess glucocorticoids alter energy sensing/signaling in skeletal muscle through mediation of the LKB1/AMPK signaling pathway. To test this hypothesis, three 100 mg pellets of corticosterone were implanted subcutaneously in each of nine rats for two weeks. Responses were compared with sham operated controls fed ad libitum or food restricted to produce the body weights similar to the treatment group rats. After the treatment period, animals were anesthetized and the right gastrocnemius-plantaris and soleus were removed for analysis. After tibial nerve stimulation for 5 min, the left gastrocnemius-plantaris and soleus were also removed. We assessed AMPK activity and subunit expression, as well as several metabolic indicators including ATP, creatine phosphate, creatine, glycogen, and malonyl-CoA levels in rested and stimulated gastrocnemius-plantaris and soleus muscles. We found that high levels of glucocorticoids decreased AMPKγ3 subunit expression in the gastrocnemius-plantaris. We also observed reduced AMPKα2 activity in the stimulated gastrocnemius-plantaris, but not the soleus; and that this decreased activity corresponded to a significant reduction in phosphorylated TBC1D1, a protein involved in signaling GLUT-4 translocation. Finally, in the gastrocnemius-plantaris, we also noted an increase in glycogen stores in the hypercorticosteronemic rats. Our data suggest that altered energy sensing/signaling associated with high levels of glucocorticoids may be due in part to inhibition of AMPKα2 activity and the high energy state produced by increased glycogen stores. We also conclude that high levels of glucocorticoids decrease the levels of AMPKγ3 and diminish insulin/contraction signaling through phosphorylated TBC1D1.

This paper evaluates the monetary and macroprudential policies that mitigate the procyclicality arising from the interlinkages between current account deficits and financial vulnerabilities. We develop a two-country dynamic stochastic general equilibrium (DSGE) model with heterogeneous households and collateralised debt. The model predicts that external shocks are important in driving current account deficits that are coupled with run-ups in house prices and household debt. In this context, optimal policy features an interest-rate response to credit and a LTV ratio that countercyclically responds to house price dynamics. By allowing an interest-rate response to changes in financial variables, the monetary policy authority improves social welfare, because of the large welfare gains accrued to the Savers. The additional use of a countercyclical LTV ratio that responds to house prices, increases the ability of borrowers to smooth consumption over the cycle and is Pareto improving. Domestic and foreign shocks account for a similar fraction of the welfare gains delivered by such a policy. (authors' abstract)

Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.

This paper evaluates the monetary and macroprudential policies that mitigate the procyclicality arising from the interlinkages between current account deficits and financial vulnerabilities. We develop a two-country dynamic stochastic general equilibrium (DSGE) model with heterogeneous households and collateralised debt. The model predicts that external shocks are important in driving current account deficits that are coupled with run-ups in house prices and household debt. In this context, optimal policy features an interest-rate response to credit and a LTV ratio that countercyclically responds to house price dynamics. By allowing an interest-rate response to changes in financial variables, the monetary policy authority improves social welfare, because of the large welfare gains accrued to the savers. The additional use of a countercyclical LTV ratio that responds to house prices, increases the ability of borrowers to smooth consumption over the cycle and is Pareto improving. Domestic and foreign shocks account for a similar fraction of the welfare gains delivered by such a policy. (authors' abstract) / Series: Department of Economics Working Paper Series

Teneurin C-terminal Associated Peptide (TCAP)-1 is postulated to play a critical role in cellular defense mechanisms as it is highly neuroprotective against alkalotic and hypoxic stress. Optimization of metabolic pathways is recognized as an essential survival tactic by alleviating energy deficits and meeting the demands to cope with the stressors. The aim of this research was to delineate the mechanism through which TCAP-1 confers protection. My findings show that TCAP-1 increases the overall expression of GLUT1 and enhances overall expression and membrane localization of GLUT3. With respect to metabolic parameters, chronic TCAP-1 application led to increased intracellular [ATP] with decreased intracellular [lactate], both in a dose-dependent manner, but did not alter tumourgenic glycolytic enzyme expression or mitochondrially associated apoptotic protein expression. Contrastingly, acute TCAP-1 led to decreased intracellular [ATP]. Indicative of increased cellular ATP production and physiological energy expenditure, TCAP-1 reduced serum insulin levels and subcutaneous adipocyte size in vivo.

Teneurin C-terminal Associated Peptide (TCAP)-1 is postulated to play a critical role in cellular defense mechanisms as it is highly neuroprotective against alkalotic and hypoxic stress. Optimization of metabolic pathways is recognized as an essential survival tactic by alleviating energy deficits and meeting the demands to cope with the stressors. The aim of this research was to delineate the mechanism through which TCAP-1 confers protection. My findings show that TCAP-1 increases the overall expression of GLUT1 and enhances overall expression and membrane localization of GLUT3. With respect to metabolic parameters, chronic TCAP-1 application led to increased intracellular [ATP] with decreased intracellular [lactate], both in a dose-dependent manner, but did not alter tumourgenic glycolytic enzyme expression or mitochondrially associated apoptotic protein expression. Contrastingly, acute TCAP-1 led to decreased intracellular [ATP]. Indicative of increased cellular ATP production and physiological energy expenditure, TCAP-1 reduced serum insulin levels and subcutaneous adipocyte size in vivo.