| 1. |
- Kristinsson, Hjalti
(författare)
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Effects of Free Fatty Acids on Insulin and Glucagon Secretion : – with special emphasis on the role of Free fatty acid receptor 1
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prevalence of type 2 diabetes mellitus (T2DM) is still rising and even so in the juvenile population. Obesity is highly associated with increased risk for developing T2DM. The development has been related to elevated fasting concentrations of the pancreatic islet hormones insulin and glucagon as well as to an increase in plasma lipids that occurs during obesity. Specifically, research has indicated that chronic exposure to high levels of saturated free fatty acids cause dysfunction in islet alpha- and beta-cells. Fatty acids can affect islet cells by various mechanisms one of which is the G-protein coupled receptor FFAR1/GPR40. The role of the receptor in the effects of fatty acids on pancreatic islet-cell function is not clear. The aim of this thesis was to clarify the role of FFAR1 in how fatty acids, and more specifically the long-chain saturated fatty acid palmitate, affect insulin and glucagon secretion.In children and adolescents with obesity elevated fasting levels of insulin and glucagon were positively correlated with lipid parameters. Specifically, plasma triglycerides and free fatty acids were positively correlated with insulin and glucagon at fasting as well as with visceral adipose tissue volume. Elevated glucagon levels at fasting were associated with worsening of glucose tolerance in the same population. In in vitro studies of isolated human islets palmitate stimulated basal insulin and glucagon secretion as well as mitochondrial respiration at fasting glucose levels. The effect was mediated by FFAR1 and fatty acid beta-oxidation. At higher glucose concentrations the receptor was involved in the potentiation of insulin secretion from isolated human islets and insulin-secreting MIN6 cells. Furthermore, we found that the effects of palmitate on hormone secretion were associated with enhanced mitochondrial respiration mediated by FFAR1 Gαq signaling and PKC activity as well as increased intracellular metabolism induced by the fatty acid. When islets were exposed to palmitate for long time periods and in the presence of FFAR1 antagonist, normalized insulin and glucagon secretion during culture and insulin response to glucose after culture were observed. In MIN6 cells chronic palmitate treatment increased mitochondrial uncoupling irrespective of FFAR1 involvement. However, FFAR1 antagonism during palmitate exposure resulted in elevated respiration and reduced apoptosis.In conclusion, children and adolescents with obesity have elevated fasting concentrations of insulin and glucagon that correlate with free fatty acids and fatty acid sources. High glucagon levels are linked to worsening of glucose tolerance in these subjects. In vitro the combination or synergy of FFAR1 activation and intracellular metabolism caused by palmitate is decisive for both the short-term enhancement effects and the negative chronic effects on insulin and glucagon secretion.
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| 2. |
- Manell, Hannes, 1987-
(författare)
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Impaired Glucose Tolerance in Childhood Obesity : Contribution of Glucagon, GLP-1 and Inflammation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the wake of increased obesity prevalence, impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in childhood and adolescence is increasingly common. Given the negative impacts these conditions have on health over time, understanding the pathophysiology in those affected early in life is important. Both the proglucagon-derived peptides and low-grade inflammation have been implicated in the development of obesity-related complications. The aim of this thesis was to study across the glucose tolerance spectrum in children and adolescents with obesity 1) proglucagon-derived peptides glucagon, GLP-1 and glicentin, 2) dipeptidyl peptidase-4 (DPP-4) and its degradation of GLP-1 and 3) novel inflammatory markers. To this end, children and adolescents of the Uppsala Longitudinal Study of Childhood Obesity were studied. Children and adolescents with obesity had higher fasting plasma glucagon concentrations than lean controls. In particular visceral adiposity, hyperinsulinemia, triglycerides and free fatty acids (FFAs) were associated with high plasma glucagon concentrations. In isolated islets elevated FFAs caused hypersecretion of glucagon. In children and adolescents with IGT or T2D, fasting plasma glucagon was further elevated and the GLP-1 and glicentin response to an oral glucose tolerance test (OGTT) was decreased. In T2D plasma glucagon increased during the first 15 minutes of OGTT. Plasma DPP-4 concentrations were elevated in obesity and associated with lower proportion of intact GLP-1 but not with IGT. Several pro-inflammatory markers were elevated in children and adolescents with obesity but not further elevated in IGT or T2D with the exception of low plasma Tumor necrosis factor-related weak inducer of apoptosis (TWEAK) levels, which were associated with IGT, hyperinsulinemia and hyperglucagonemia. High plasma hepatocyte growth factor (HGF) concentration was associated with increased risk of further weight gain in children and adolescents with obesity.In conclusion, elevated glucagon concentration at fasting, a hyperglucagonemic response to OGTT and reduced GLP-1 and glicentin are characteristics of IGT and T2D development in childhood obesity reflecting altered usage of the proglucagon gene. DPP-4 concentrations are elevated in childhood obesity but not associated with IGT. Reduced circulating TWEAK was identified as a novel marker of IGT early in life. Children with obesity and high HGF are less likely to respond well to lifestyle intervention.
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| 3. |
- Sol, E-ri Maria
(författare)
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Glucose, Palmitate and Apolipoprotein CIII-induced Effects on Insulin-Producing β-cells
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Type 2 diabetes mellitus results from complex interplay between genetic predisposition and environmental factors that together promote impairment of insulin-producing β-cells. Elevated levels of glucose, fatty acid palmitate and apolipoprotein CIII (apoCIII) are implicated in this process. To delineate effects of these factors, the role of enhanced carnitine palmitoyltransferase 1 (CPT1) expression in glucolipotoxic cells, glucose-dependency of the unfolded protein response (UPR) in palmitate-induced apoptosis and activation of mitogen activated protein kinases (MAPKs) in apoCIII-induced apoptosis were evaluated. In addition, protein profiles of β-cell exposed to elevated levels of glucose or palmitate were generated to identify proteins regulated by these nutrients. Methodology: INS-1E cells were cultured at different glucose concentrations in the absence or presence of palmitate or apoCIII for up to 48 hours. CPT1 was over-expressed with a Tet-ON regulated adenovirus. In cells exposed to apoCIII, inhibitors of MAPKs p38 or ERK1/2 were included during culture. After culture, apoptosis, insulin secretion, expression of UPR-markers and MAPKs and protein profiles were determined. Results: INS-1E cells exposed to elevated levels of glucose and palmitate showed deranged insulin secretion with increased insulin secretion at non-stimulatory glucose level, enhanced apoptosis and induced expression of UPR-markers. Over-expression of CPT1 reduced basal insulin secretion and attenuated apoptosis. Palmitate-induced apoptosis was accentuated by increasing the culture glucose concentration. Markers of UPR were not modulated by the glucose concentration in INS-1E cell exposed to palmitate, however. ApoCIII-induced apoptosis in INS-1E cells was accompanied by activation of p38 and ERK1/2. Protein profiling of INS-1E cells exposed to elevated levels of glucose or palmitate revealed changes in expression of multiple β-cell proteins implicated in glucose metabolism, defence against reactive oxygen species, protein translation/folding/degradation and insulin granular trafficking. Conclusions: Over-expression of CPT1 counteracts β-cell glucolipotoxicity. Activation of UPR is not a major determinant for palmitate-induced β-cell apoptosis. ApoCIII-induced β-cell apoptosis involves activation of MAPKs. The identified differentially expressed proteins indicate a central role of altered glucose metabolism and protein synthesis in gluco- and lipotoxic β-cells and may provide specific molecular mechanisms offering new ways of treating the disease.
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| 4. |
- Staaf, Johan, 1983-
(författare)
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Childhood Obesity and Islet Function
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prevalence of childhood obesity and Type 2 Diabetes Mellitus (T2DM) has increased during recent decades. T2DM is accompanied with functional changes in the islets of Langerhans, which can be identified early in the pathogenesis. The aim of this thesis was to explore how metabolic changes caused by obesity early in life relate to islet function prior to overt T2DM.To address this, Uppsala Longitudinal Study of Childhood Obesity (ULSCO) was established (paper I). Initially, the association between palmitate and insulin secretion was investigated using a translational approach with obese and lean normoglycemic juveniles and isolated human islets (paper II). Secondly, dynamics of islet-hormones insulin and glucagon, and gut-hormones glucagon like-peptide 1 (GLP-1) and glicentin (paper III) and magnetic resonance imaging of pancreatic fat fraction (PFF) (paper IV) were studied in association to glucose tolerance and beta-cell function. Finally, a novel method of analysing shape features of oral glucose tolerance test (OGTT) curves was introduced and evaluated (paper V).Obese subjects had high prevalence of prediabetes and metabolic syndrome (MetS) (paper I). In obese pre-pubertal children with elevated palmitate levels, hyperinsulinemia was observed (paper II). In contrast, obese pubertal adolescents with similar palmitate levels showed moderate insulin levels during OGTT with delayed first phase insulin response. To explore mechanisms for these variations, isolated human islets were exposed to palmitate for different time periods in vitro. After 2 days accentuated insulin response was observed. Impaired beta-cell function and apoptosis were evident after 7 days, however. Hyperglucagonemia and disturbed GLP-1 and glicentin levels were associated with obesity and glycaemic status, with fasting glicentin being predictive of prediabetes (paper III). Furthermore, PFF was increased in obese subjects and associated to MetS and visceral adipose tissue, but not to beta-cell function (paper IV). OGTT curves were converted into geometric centres, centroids, which correlated with differences in glucose tolerance (paper V).In conclusion, the islet function in obese children was associated with elevated levels of palmitate, but not pancreatic fat. Fasting palmitate and glicentin levels, as well as centroid analyses of OGTT curves, could potentially identify obese children at risk of prediabetes and subsequent T2DM.
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| 5. |
- Thörn, Kristofer, 1981-
(författare)
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Palmitate-induced Apoptosis in Insulin-producing β-cells
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes is a disease characterized by the inability of pancreatic β-cells to secrete sufficient amounts of insulin to maintain normoglycemia. Increased levels of saturated fatty acids such as palmitate are believed to contribute to β-cell failure and the development of the disease. In the present thesis, mechanisms behind palmitate-induced β-cell apoptosis were explored. Palmitate augmented insulin secretion after short exposure to the fatty acid, but attenuated the secretory response after longer exposure. Elevated levels of palmitate increased endoplasmic reticulum (ER) stress and induced apoptosis. When insulin secretion was inhibited by diazoxide, palmitate-induced ER stress and apoptosis were reduced. In comparison to palmitate, the mono-unsaturated fatty acid oleate increased neither ER stress nor apoptosis. Furthermore, shuttling of fatty acids into triglycerides and β-oxidation was favored in cells exposed to oleate compared to palmitate. When the levels of stearoyl-CoA desaturase 1 (SCD1), the enzyme responsible for conversion of saturated to mono-unsaturated fatty acids, were reduced, up-regulation of ER chaperones and components of the proteasome was observed. Cells with reduced levels of SCD1 showed increased sensitivity to palmitate, as exposure to the fatty acid increased levels of ER stress and apoptosis. Palmitate-induced apoptosis of the β-cell has been linked to alterations in sphingolipid metabolism. In cells with reduced levels of sphingosine kinase (SphK) 2, palmitate failed to induce apoptosis, and ER stress was reduced. Furthermore, SphK2 was required for the palmitate-induced activation of c-Jun N-terminal kinase (JNK). In contrast, knockdown of SphK1 sensitized the cell to palmitate-induced apoptosis independently of ER stress. In summary, palmitate induces β-cell apoptosis, which is partly dependent on the induction of ER stress. The mechanisms investigated support the notion that increased protein load on the ER, low degree of triglyceride formation and β-oxidation, and perturbations in sphingolipid metabolism contribute to palmitate-induced apoptosis in insulin-producing β-cells.
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| 6. |
- Bergqvist, Ewa, 1971-
(författare)
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Mathematics and mathematics education - two sides of the same coin : creative reasoning in university exams in mathematics
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Avhandlingen består av två ganska olika delar som ändå har en del gemensamt. Del A är baserad på två artiklar i matematik och del B är baserad på två matematikdidaktiska artiklar. De matematiska artiklarna utgår från ett begrepp som heter polynomkonvexitet. Grundidén är att man skulle kunna se vissa ytor som en sorts ”tak” (tänk på taket till en carport). Alla punkter, eller positioner, ”under taket” (ungefär som de platser som skyddas från regn av carporttaket) ligger i något som kallas ”polynomkonvexa höljet.” Tidigare forskning har visat att för ett givet tak och en given punkt så finns det ett sätt att avgöra om punkten ligger ”under taket”. Det finns nämligen i så fall alltid en sorts matematisk funktion med vissa egenskaper. Finns det ingen sådan funktion så ligger inte punkten under taket och tvärt om; ligger punkten utanför taket så finns det heller ingen sådan funktion. Jag visar i min första artikel att det kan finnas flera olika sådana funktioner till en punkt som ligger under taket. I den andra artikeln visar jag några exempel på hur man kan konstruera sådana funktioner när man vet hur taket ser ut och var under taket punkten ligger. De matematikdidaktiska artiklarna i avhandlingen handlar om vad som krävs av studenterna när de gör universitetstentor i matematik. Vissa uppgifter kan gå att lösa genom att studenterna lär sig någonting utantill ur läroboken och sen skriver ner det på tentan. Andra går kanske att lösa med hjälp en algoritm, ett ”recept,” som studenterna har övat på att använda. Båda dessa sätt att resonera kallas imitativt resonemang. Om uppgiften kräver att studenterna ”tänker själva” och skapar en (för dem) ny lösning, så kallas det kreativt resonemang. Forskning visar att elever i stor utsträckning väljer att jobba med imitativt resonemang, även när uppgifterna inte går att lösa på det sättet. Mycket pekar också på att de svårigheter med att lära sig matematik som elever ofta har är nära kopplat till detta arbetssätt. Det är därför viktigt att undersöka i vilken utsträckning de möter olika typer av resonemang i undervisningen. Den första artikeln består av en genomgång av tentauppgifter där det noggrant avgörs vilken typ av resonemang som de kräver av studenterna. Resultatet visar att studenterna kunde bli godkända på nästan alla tentorna med hjälp av imitativt resonemang. Den andra artikeln baserades på intervjuer med sex av de lärare som konstruerat tentorna. Syftet var att ta reda på varför tentorna såg ut som de gjorde och varför det räckte med imitativt resonemang för att klara dem. Det visade sig att lärarna kopplade uppgifternas svårighetsgrad till resonemangstypen. De ansåg att om uppgiften krävde kreativt resonemang så var den svår och att de uppgifter som gick att lösa med imitativt resonemang var lättare. Lärarna menade att under rådande omständigheter, t.ex. studenternas försämrade förkunskaper, så är det inte rimligt att kräva mer kreativt resonemang vid tentamenstillfället.
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| 7. |
- Bergsten, Lisa, 1990-
(författare)
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Housing tenures in Sweden; from rental to ownership and intermediate tenures
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The importance of housing tenures for a well-functioning housing market is repeatedly emphasized. Such suggestions include the need for balance between tenures, various tenures, mixed tenures in neighborhoods, et cetera. The development of new types of housing tenures has also been noticed as a tool or vehicle to make the housing market accessible to more people, either through creating more affordable housing or supporting homeownership. Since these tenures often combine attributes from both ownership and rental - and place somewhere in between rental and ownership on a continuum, they are often described as intermediate housing tenures. Intermediate tenures and concepts have been developed in Sweden as more people encounter difficulties accessing the housing market.As these new tenures and schemes develop, so does the need to increase the understanding of them, for example, in terms of the legal framework, rights, obligations, as well as risk exposure. This thesis examines the content of various tenures (established and new ones) and explores how and why intermediate tenures and concepts have been developed. This thesis includes two appended papers. The first paper is a comparative case study examining the design and content of the primary tenures in four Nordic countries. The second paper is a case study of four intermediate concepts in Sweden. As methods for data collection, document and literature studies were used for both papers, and paper 2 was supplemented with expert interviews with representatives from the concept developers.The findings imply significant similarities between the tenures in the four Nordic countries based on their design and content. Based on the literature, some attributes for overall tenures, such as ownership and rental, can be pointed out (although major differences still exist between tenure forms). In summary, attributes associated with ownership include far-reaching rights and responsibilities as well as risk-taking. In comparison, these rights are much more restricted for rentals, which do not include risk- taking. This also corresponds with the findings, showing that tenures within ownership have the most far- reaching rights, particularly regarding the right to transfer or let out the housing unit and the value therefrom. Furthermore, the rights are most restricted for rentals, while the tenures between ownership and rental also have bundles of rights in between. The studied intermediate tenures and concepts in Sweden were described to have evolved from the difficulties many faces in accessing the housing market (or the poor housing conditions that prevailed when they were created), like intermediate tenures in countries worldwide. Most of the studied concepts are new and, thus, still in the establishment phase. However, the developers see potential to scale up the concepts. Challenges identified in order to establish and scale up such concepts are to reach out with information to various actors and to achieve a certain degree of recognition, getting access to buildable land, and financial issues. The financial issues both concern the financial ability to initiate this type of project and to consider the current members' interest while scaling up the concepts.This thesis has contributed to the literature on intermediate housing tenures by providing examples of four cases of intermediate tenures from a Swedish context. This contribution can provide insights into the development of such tenures and concepts as well as some of the challenges the developers have met. These insights can also be a valuable practical contribution for actors, such as municipalities, policymakers, housing developers, and so forth, to understand some of the difficulties developers of new concepts meet.
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| 8. |
- Cen, Jing, 1985-
(författare)
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Free fatty acids and insulin hypersecretion studied in human islets
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Free fatty acid (FFA) levels are increased in many obese subjects. High FFA levels stimulate the pancreatic beta-cells but have negative long-term effects. In obese children with high FFA levels circulating insulin concentration is high early in life but decline with age precipitating the development of type 2 diabetes mellitus (T2DM). The present study aims at preventing this development of T2DM by defining underlying mechanisms of insulin hypersecretion. Such mechanisms will be identified by studying regulation of insulin secretion from human pancreatic islets and human EndoC-βH1 cells exposed to elevated FFA levels.We found that elevated concentrations of FFAs acutely stimulate insulin from human pancreatic islets at fasting blood glucose level, with mono-unsatured being more potent than saturated fatty acids. Enhanced secretion was associated with increased glycolytic flux and mitochondrial respiration. Continued exposure to elevated palmitate levels for up to 2 days accentuated insulin secretion, whereas 7 days’ exposure caused secretory decline. Metformin prevented insulin hypersecretion from human islets treated with palmitate for 2 days by decreasing mitochondrial metabolism. In islets exposed to palmitate for 7 days metformin improved insulin secretion by enhancing calcium binding protein sorcin levels and thereby reducing ER stress and apoptosis. Downregulation of sorcin had negative effects on insulin secretion, mitochondrial metabolism and ER stress in human islets and EndoC-βH1 cells. Specific cellular pathways involved in insulin hypersecretion and secretory decline were identified by microarray expression analysis and subsequent bioinformatics in human islets cultured with palmitate for 0, 4, 12 hours, 1, 2, and 7 days.In conclusion, beta-cells respond to elevated levels of FFAs by initially augmenting insulin release followed by declining secretory levels after prolonged exposure. Metformin normalizes these secretory aberrations. Specific signaling pathways and proteins including sorcin contribute to the secretory alterations induced by palmitate. When developing strategies for prevention of T2DM in obese children with elevated FFA levels, metformin should be considered as well as novel strategies involving sorcin and the identified specific pathways.
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| 9. |
- Frejd, Peter
(författare)
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Mathematical modelling in upper secondary school in Sweden : An exploratory investigation
- 2011
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The official curriculum guidelines for upper secondary school in Sweden emphasise the use of mathematical models and mathematical modelling in mathematics education. However, no explicit definitions or descriptions of the notions are given in the curriculum. This licentiate thesis is an exploratory study which investigates teachers’ and students’ conceptions of the notion of mathematical modelling as well as their attitudes and experiences of working with mathematical modelling in mathematics classrooms. One experience of mathematical modelling that faces both students and teachers which is investigated is the national course tests in mathematics. The thesis includes five papers and a preamble, where the papers are summarised, analysed, and discussed. Both quantitative and qualitative methods are being used in the thesis and theoretical aspects concerning mathematical modelling and conceptions are examined. The results indicate that mathematical modelling plays a minor role in the investigated mathematics classrooms. The students as well as the teachers were not familiar with the notion of mathematical modelling. Only 23% of the 381 students and 50 % of the 18 teachers had heard the notion before participating in the study. Both teachers and students participating in this study expressed a variety of different interpretations of the notion of mathematical modelling. Negative attitudes were expressed by the students as well as by some of the teachers concerning mathematical modelling. These negative attitudes may present obstacles for implementing mathematical modelling in the upper secondary mathematics classroom. However, these negative attitudes are related to the used test items, which may have had a negative impact on the research, especially, as the test items only test parts of the modelling process. One dominant conception found among the teachers was that mathematical modelling is related to physics or chemistry. The conclusion made from the investigation about national course tests in mathematics course D, is that there is a lack of holistic assessment of mathematical modelling. Intra-mathematical aspects of mathematical modelling are put in favour for extra-mathematical aspects. Researchers argue that if we want develop students’ modelling competency, than modelling has to be explicitly used and practised in the mathematics classrooms. However, for the Swedish upper secondary school this study concludes that this is not the case. A suggestion for future research is to focus on mathematical modelling in teacher education and design studies of incorporation of modelling activities into mathematics classrooms.
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| 10. |
- Frejd, Peter, 1973-
(författare)
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Modes of Mathematical Modelling : An analysis of how modelling is used and interpreted in and out of school settings
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The relevance of using mathematics in and for out-of-school activities is one main argument for teaching mathematics in education. Mathematical modelling is considered as a bridge between the mathematics learned and taught in schools and the mathematics used at the workplace and in society and it is also a central notion in the present Swedish mathematical syllabus for upper secondary school. This doctoral thesis reports on students’, teachers’ and modelling experts’ experiences of, learning, teaching and working with mathematical modelling in and out of school settings and their interpretations of the notion of mathematical modelling.The thesis includes five papers and a preamble, where the papers are summarised, analysed, and discussed. Different methods are being used in the thesis such as video analysis of students’ collaboration working with modelling problem, interview investigations with teachers and expert modellers, content analysis of textbooks and literature review of modelling assessment. Theoretical aspects concerning mathematical modelling and the didactic transposition of modelling are examined.The results presented in this thesis provide a fragmented picture of the didactic transposition of mathematical modelling in school mathematics in Sweden. There are significant differences in how modellers, teachers and students work with modelling in different practices in terms of the goal with the modelling activity, the risks involved in using the models, the use of technology, division of labour and the construction of mathematical models. However, there are also similarities identified described as important aspects of modelling work in the different practices, such as communication, collaboration, projects, and the use of applying and adapting pre-defined models. Students, teachers and modellers expressed a variety of descriptions of what modelling means. The variety of descriptions in the workplace is not surprising, since their working approaches are quite different, but it makes the notion difficult to transpose into school practise. Questions raised are if it is unrealistic to search for a general definition and if it is really necessary to have a general definition. The consequence, for anyone how uses the notion, is to always be explicit with the meaning.An implication for teaching is that modelling as it shows in the workplace can never be fully ‘mapped’ in the mathematical classroom. However, it may be possible to ‘simulate’ such activity. Working with mathematical modelling in projects is suggested to simulate workplace activities, which include collaboration and communication between different participants. The modelling problems may for example involve economic and environmental decisions, to prepare students to be critically aware of the use of mathematics in private life and in society, where many decisions are based on mathematical models.
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