Background: Type 2-diabetes is now a public health problem, which constitutes 85-90 percent of diabetes care. The district nurse´s role in treating a diabetic (/person with diabetes) does not only comprise pure medical treatment but also support, advice and training to the individual. In our profession as nurses, we have found that medical knowledge in patients with Typ 2-diabetes is not always enough to obtain changes in lifestyles. Aim: The purpose of this study was to investigate the illness perceptions in patients with Type 2-diabetes and their impact on health behavior. Method: This qualitative study used grounded theory as a method. Results: The informants described in the interviews, their perceptions of living with Type 2-diabetes. The analysis revealed the main category periodic health behavior built up on and related to five categories developed in data: preventive health awareness, guilt, confidence in medical treatment, motivational problems and periods of insight. Conclusion: This study contributes to understanding of patients with Type 2 - diabetes their beliefs about illness and how it affects everyday lives. Keywords: Believes, District nurses, Groundey Theory, Illness perception, Type 2-diabetes

Bakgrund: I dagens samhälle flödar information från många olika håll. Kunskap förmedlas till patienter och anhöriga av olika professioner utan samordning, vilket kan leda till missförstånd. För patienter med diabetes typ 2 är det viktigt att få information som kan förstås och som är relevant för deras sjukdom. Genom patientutbildning kan patienten sedan bedriva egenvård och ta kontroll över sjukdomen. Syfte: Syftet med studien var att se hur patienter med nydiagnostiserad typ 2 diabetes förstår egenvård efter besök hos diabetessköterskan. Metod: En empirisk, kvalitativ intervjustudie genomfördes och innehållet analyserades med kvalitativ innehållsanalys inspirerad av Graneheim och Lundman. Resultat: Det framkom under intervjuerna att ungefär hälften av deltagarna förväntade sig att drabbas av diabetes, då det fanns i släkten. Diabetes var naturligt att få vid en viss ålder, med eller utan egenvård. De flesta hade gjort förändring av kostvanor och rökning under de första månaderna efter diagnosen och fått bekräftat att egenvården gjort nytta. Många kände oro inför att inte orka fortsätta med de förändringar, men var ändå inte oroliga för framtiden. Andra hade fortsatt stor tillförsikt och visste att resultatet berodde på dem själv. Slutsats: Med eller utan tidig egenvård hade sjukdomen kommit ändå. Den första tiden efter diagnosen genomfördes förändringar och egenvården kändes viktig. När sedan känslan av att ”må bra” återkom, dalade motivationen. Med täta besök hos diabetessköterskan motiverades patienterna att fortsätta. / Background: In today's society, information flowing from many different directions. Knowledge communicated to patients and families of different professions, without coordination, which can lead to misunderstandings. For patients with diabetes type 2, it is important to get information that is understandable and relevant to their illness. Through patient education, the patient may then engage in self-care and take control of the disease. Aim: The purpose of this study was to see how patients with newly diagnosed type 2 diabetes understand self-care after visiting the nurse. Method: An empirical, qualitative interviews were carried out and contents were analyzed using qualitative content analysis inspired by Granheim and Lundman. Results: It emerged during the interviews that about half of the participants expected to suffer from diabetes, when there was a family history. Diabetes was natural to get at a certain age, with or without self-care. Most patients had made changes in diet and smoking during the first months after being diagnosed and confirmed that self-care was useful. Many felt concerned about not being able to continue with the changes, but was not worried about the future. Others had continued very confident and knew that the outcome depended on themselfs. Conclusion: With or without early self-care the disease would had come anyway. The first time after beeing diagnosed, change and self-care feelt important. When the sense of "feel good" reappeared, the motivation faded. With frequent visits to the nurse, the patients were motivated to continue.

Obesity and specifically central obesity is related to insulin resistance, type 2 diabetes and other components of the so-called metabolic syndrome. The aim of this study was to elucidate the interplay between hormones, nutrients and adipose depots in normal and insulin-resistant fat cell metabolism. High levels of free fatty acids (FFAs) induce insulin resistance in muscle and liver in vivo. In the present study, rat adipocytes were treated with high physiological levels of oleic or palmitic acid in vitro for 4-24 h. This treatment had no effect on basal or insulin-stimulated glucose uptake capacity in these cells, neither did it affect the levels of the insulin signalling proteins; insulin receptor substrate (IRS)-1 or –2, phosphatidylinositol 3-kinase (PI3-K), protein kinase B (PKB) or glucose transporter (GLUT) 4, or the regulation of lipolysis rate. Visceral adiposity is considered to be more harmful than peripheral adiposity with respect to metabolic and cardiovascular complications. In adipose biopsies from subjects undergoing abdominal surgery, we found that glucose uptake capacity was elevated in omental as compared to subcutaneous adipocytes. The sensitivity (EC50) or maximum relative response to insulin, measured as % of basal, did however not differ between the depots. In women, subcutaneous adipocytes displayed a higher lipolysis rate following cAMP-stimulation than omental adipocytes, whereas there was a tendency towards the opposite in adipocytes from men. No differences were found between depots or sexes in the ability of insulin to inhibit lipolysis or in the levels of the lipolysis regulating proteins, i.e. protein kinase A (PKA), hormone sensitive lipase (HSL) and perilipin. Glucocorticoids, e.g. cortisol, exert pronounced insulin-antagonistic effects and are associated with redistribution of fat from peripheral to central fat depots in humans. Treatment of human subcutaneous and omental adipocytes in vitro, with the cortisol analogue dexamethasone, resulted in a dose dependent down-regulation of basal and insulin-stimulated glucose uptake capacity in omental, but not in subcutaneous cells. Concomitantly, the levels of IRS-1 and PKB were decreased only in omental adipocytes after dexamethasone treatment. The relative effect of insulin to stimulate glucose uptake was however not altered by dexamethasone treatment. The cAMP-stimulated lipolysis rate was elevated by dexamethasone treatment in cells from the subcutaneous depot in women and tended to be elevated in omental cells from men. No alterations however, were seen in the levels of the assessed lipolysis regulating proteins. Subcutaneous as well as omental fat cell size correlated negatively to insulin action in subcutaneous fat cells in vitro after adjusting for age, sex and body fat parameters in non-diabetic, but not in type 2 diabetic, subjects. Large subcutaneous fat cell size was strongly related to plasma leptin levels in non-diabetic and in type 2 diabetic subjects. We conclude that 1) adipocytes seem to be less vulnerable to elevated levels of fatty acids than muscle and liver cells, 2) the interactions between glucocorticoids and insulin in the regulation of glucose uptake differ between adipose depots, 3) depot specific hormonal lipolysis regulation differs between sexes and 4) fat cell size is related to insulin action in subcutaneous fat cells and to circulating levels of leptin.

Patients with type II diabetes present alterations in glucose homeostasis due to insufficient amount of insulin (β-cell dysfunction) and inability to properly use the insulin that is secreted (insulin resistance). Combined genetical and environmental factors are believed to be responsible for these dysfunctions and the resulting impairment in glucose homeostasis. The pancreatic gland is composed of exocrine and endocrine tissues. The endocrine part of the organ couples glucose sensing to insulin release. Within this endocrine gland, also known as islets of Langerhans, the insulin secreting β-cell is the main player and therefore highly important for proper glucose metabolism. In this thesis, mice were developed in order to assess the role of BMP signaling molecule and Arsenite induced ATPase-1 (Asna1) for pancreas development and β-cell function. The mature β-cell responds to elevated glucose levels by secreting insulin in a tightly controlled manner. This physiological response of the β-cell to elevated blood glucose levels is critical for maintenance of normoglycaemia and impaired Glucose stimulated insulin secretion (GSIS) is a prominent feature of overt type 2 diabetes. Thus, the identification of signals and pathways that ensure and stimulate GSIS in β-cells is of great clinical interest. Here we show (Paper I) that BMPRIA and its high affinity ligand BMP4 are expressed in fetal and adult islets. We also provide evidence that BMPRIA signaling in adult β-cell is required for GSIS, and that both transgenic expression of Bmp4 in β-cells or systemic administration of BMP4 protein to mice enhances GSIS. Thus, BMP4-BMPRIA signaling in β-cells positively regulates the genetic machinery that ensures GSIS. Arsenite induced ATPase (Asna1), the homologue of the bacterial ArsA ATPase, is expressed in insulin producing cells of both mammals and the nematode Caenorhabditis elegans (C.elegans). Asna1 has been proposed to act as an evolutionary conserved regulator of insulin/insulin like factor signaling. In C.elegans, asna-1 has been shown to regulate growth in a non-cell autonomous and IGF-receptor dependent manner. Here we show that transgenic expression of ASNA1 in β-cells of mice leads to enhanced Aktactivity and β-cell hyperplasia (manuscript). ASNA1 transgenic mice develop, however, diabetes due to impaired insulin secretion. The expression of genes involved in secretion stimulus coupling and insulin exocytosis is perturbed in islets of these mice. These data suggest that activation of ASNA1, here mimicked by enhanced expression, positively influences β-cell mass but negatively affects insulin secretion.

A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population. Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development. Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar. The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment. The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population. The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs.

Typ 2 diabetes är den vanligaste diabetesformen i Sverige och har samband med vår vällevnad. Tidigare studier visar att sjukdomen är mer vanlig bland fysiskt inaktiva och bland människor med ett ökat energiintag. Syftet med studien var att kartlägga sjuksköterskans hälsofrämjande arbete i primärvården vid typ 2 diabetes. En kvalitativ intervjustudie användes för att samla data. Fem sjuksköterskor från olika vårdcentraler i gamla Skaraborgs län deltog. Analysen av intervjuerna resulterade i ett huvudtema och fem underteman. Resultatet visar på att sjuksköterskorna aktivt arbetar med att motivera patienterna till att ändra kostvanor och öka den fysiska aktiviteten i den icke- farmakologiska behandlingen. Sjuksköterskorna använde information, patientrelation, konkret arbete, patientens villkor och mål som verktyg för att få patienterna motiverade. Att förespråka kost och fysisk aktivitet anses vara mycket viktig uppgift för sjuksköterskorna och utgör en central del i deras arbete. / Type 2 diabetes is the most common form of diabetes in Sweden today and is related to our lifestyle. Previous studies indicate that the disease is more common among physical inactive people and in people with increased energy intake. The aim of this study was to survey how nurses´ in primary health care promote lifestyle change in patients with type 2 diabetes. A qualitative interview study was used for data collection. Five nurses from different primary health care settings in old Skaraborgs county participated. The analyses of the interviews resulted in one major theme and five sub themes. The result shows that nurses work actively to motivate patients to change dietary habits and start with daily physical activity as a part of non-drug therapy. The nurses´ used information, nurse- patient relationship, concrete work, goals and the patient terms as tools to get patients motivated. Promoting diet and physical activity is a central part of the nurses’ daily work.

Background: Type 2 diabetes is a serious disease that is increasing globally. The focus of diabetes care has been to prevent diabetes related complications and thereby reduce mortality. An older population, the disease progression and decreased ability to perform self-management activities increases the risk for complications. Group education and patient-centred care are recommended to improve self-management through increased patient empowerment. Despite these recommendations, professionals have been reluctant to adopt these methods referring to lack of knowledge, time and tools to deliver patient-centred care in diabetes. Focusing on the patient’s illness integration process has in the literature been suggested to improve self-management and metabolic balance. Aim: The overall aim of the thesis was to describe the experiences of illness integration, self-management and support in type 2 diabetes and to evaluate the metabolic effects of a nurse-led patient-centred model for self-management support. Methods: The study setting was primary health care in Västerbotten County, Sweden. In total, 21 diabetes nurses (Study I) and 257 patients (Studies II-IV) participated in the four studies (Study II, n=44; Study III, n= 18; Study IV, n= 195). Data consisted of focus group interviews (Study I), individual semi-structured interviews (Studies II-III) and laboratory measurements (Study IV). Methods for analyses were qualitative content analysis (Studies I-III) and statistics (Study IV). Results: Study I revealed that diabetes nurses found the ideal diabetes care complex to achieve. Conflicting paradigms, power relations and departmentalisation of work were described. Study II describes a process whereby illness integration and self-management in type 2 diabetes develop simultaneously. When a turning-point occurs, people view self-management as both necessary and feasible. In study III, turning points in self-management are illuminated. Turning-point transitions include existential and emotional aspects that increase inner motivation and power for lifestyle change. Study IV evaluates the effects of a nurse-led intervention in which haemoglobin A1c (HbA1c) was significantly decreased at 12 months’ follow-up. Group intervention and individual intervention were both effective compared to traditional diabetes care. Conclusions: There is a potential for improvement of type 2 diabetes care. Increased patient-centredness is important to support patients towards illness integration and self-management. Focusing on the patients’ illness experiences, including the existential and emotional aspects of having and managing type 2 diabetes, in counselling can lead to improved self-management and glycaemic control. Patients’ experiences of illness are central to their inner motives for change, and patient-centred self-management support and patient education preferably emanate from this perspective. / Bakgrund: Typ 2 diabetes är en allvarlig sjukdom som ökar globalt. Fokus i diabetesvården har varit att förebygga diabetesrelaterade komplikationer och därmed minska dödligheten. En åldrande befolkning, progression av sjukdomen samt en begränsad förmåga att utföra egenvårdsaktiviteter ökar risken för komplikationer. Grupputbildning och patientcentrerad vård rekommenderas för att förbättra egenvården genom ökad empowerment. Trots dessa rekommendationer har läkare och sjuksköterskor rapporterats vara tveksamma till dessa metoder och hänvisat till bristande kunskap, tidsbrist och avsaknad av verktyg. Att fokusera på patienters sjukdomsintegrationsprocess har i litteraturen föreslagits förbättra såväl egenvård som metabol balans. Syfte: Avhandlingens övergripande syfte var att beskriva erfarenheter av sjukdomsintegration, sjukdomshantering och support vid typ 2 diabetes samt att utvärdera effekter av en sjuksköterskeledd patientcentrerad modell för egenvårdssupport. Metod: Studierna genomfördes inom primärvården i Västerbottens läns landsting. Totalt deltog 21 diabetessjuksköterskor (Studie I) och 257 patienter (Studie II-IV), i de fyra studierna (Studie II, n=44; Studie III, n= 18; Studie IV, n= 195). Data bestod av fokusgruppsintervjuer (Studie I), individuella halvstrukturerade intervjuer (Studie II-III) och laboratoriemätningar (Studie IV). Analysmetoderna var kvalitativ innehållsanalys (Studie I-III) och statistik (Studie IV). Resultat: Studie I visade att en ideal diabetesvård är svår att uppnå enligt diabetessjuksköterskorna. Paradigmkrockar, maktrelationer och splittrade arbetsuppgifter beskrevs. Studie II beskriver en modell där sjukdomsintegration och sjukdomshantering utvecklas samtidigt. När en ”turning point” nåddes såg patienterna sjukdomshanteringen som både nödvändig och möjlig att genomföra. I studie III belystes ”turning points” och som omfattar både existentiella och emotionella aspekter som kan öka inre motivation och egenkraft att utföra livsstilsförändringar. Studie IV utvärderade 12-månaderseffekterna av en sjuksköterskeledd intervention och HbA1c sänktes signifikant. Gruppintervention och individuell intervention visades vara effektiva metoder i jämförelse med traditionell diabetesvård. Slutsatser: Det finns en förbättringspotential inom diabetesvården och ökad patientcentrering är viktig för att stödja patienter att integrera sjukdom och egenvård i livet. Att i diabetesvården fokusera på patienters sjukdomsupplevelser inklusive de existentiella och emotionella aspekterna av att leva med och hantera en sjukdom kan innebära förbättrad sjukdomshantering och metabol balans. Patienters sjukdomsupplevelser är centrala för deras inre motiv till förändring och patientcentrerad egenvårdssupport och patientutbildning bör utgå från detta perspektiv.

Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are the small-intestinal glucosidases responsible for catalyzing the last glucose-releasing step in starch digestion. MGAM and SI are each composed of duplicated catalytic domains, N- and C-terminal, which display complementary substrate specificities for the mixture of short linear and branch oligosaccharide substrates that typically make up terminal starch digestion products. As MGAM and SI are involved in post-prandial glucose production, regulating their activities with α-glucosidase inhibitors is an attractive approach to controlling blood glucose levels for the prevention and treatment of Type 2 diabetes. To better understand the complementary activities and mechanism of inhibition of these intestinal glucosidases, this thesis aims to characterize the individual N- and C-terminal MGAM and SI domains using a combination of X-ray crystallographic structural studies, enzyme kinetics, and inhibitor studies. First, the structure of the N-terminal domain of MGAM (ntMGAM) was determined in its apo form and in complex with the inhibitor acarbose. In addition to sequence alignments and kinetics studies, the structures provide insight into the preference of the N-terminal MGAM domain for short linear substrates and the C-terminal domain for longer substrates. Second, the structure of ntMGAM was determined in complex with various α-glucosidase inhibitors, including those currently on the market (acarbose and miglitol), a new class of inhibitors from natural extracts of Salacia reticulata (salacinol, kotalanol and de-O-sulfonated kotalanol) and chemically synthesized derivatives of salacinol. These studies reveal the features of the Salacia reticulata inhibitors that are essential for inhibitory activity and highlight their potential as future drug candidates. Third, the crystal structure of the N-terminal domain of SI (ntSI) was determined in apo-form and in complex with kotalanol. Structural comparison of ntSI and ntMGAM reveal key differences in active site architectures, which are proposed to confer differential substrate specificity.

Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are the small-intestinal glucosidases responsible for catalyzing the last glucose-releasing step in starch digestion. MGAM and SI are each composed of duplicated catalytic domains, N- and C-terminal, which display complementary substrate specificities for the mixture of short linear and branch oligosaccharide substrates that typically make up terminal starch digestion products. As MGAM and SI are involved in post-prandial glucose production, regulating their activities with α-glucosidase inhibitors is an attractive approach to controlling blood glucose levels for the prevention and treatment of Type 2 diabetes. To better understand the complementary activities and mechanism of inhibition of these intestinal glucosidases, this thesis aims to characterize the individual N- and C-terminal MGAM and SI domains using a combination of X-ray crystallographic structural studies, enzyme kinetics, and inhibitor studies. First, the structure of the N-terminal domain of MGAM (ntMGAM) was determined in its apo form and in complex with the inhibitor acarbose. In addition to sequence alignments and kinetics studies, the structures provide insight into the preference of the N-terminal MGAM domain for short linear substrates and the C-terminal domain for longer substrates. Second, the structure of ntMGAM was determined in complex with various α-glucosidase inhibitors, including those currently on the market (acarbose and miglitol), a new class of inhibitors from natural extracts of Salacia reticulata (salacinol, kotalanol and de-O-sulfonated kotalanol) and chemically synthesized derivatives of salacinol. These studies reveal the features of the Salacia reticulata inhibitors that are essential for inhibitory activity and highlight their potential as future drug candidates. Third, the crystal structure of the N-terminal domain of SI (ntSI) was determined in apo-form and in complex with kotalanol. Structural comparison of ntSI and ntMGAM reveal key differences in active site architectures, which are proposed to confer differential substrate specificity.

Bakgrund: Diabetes typ 2 utgör den vanligaste diabetesformen, och cirka 4 % av Sveriges befolkning uppskattades ha diabetes 2010, varav nästan 90 % av dessa utgjordes av diabetes typ 2. Sjuksköterskan har en viktig roll i att stödja och vägleda patienten utifrån dennes upplevelser och behov. Syfte: Att beskriva hur vuxna patienter upplever att diagnostiseras med diabetes typ 2. Metod: Denna studie är en litteraturstudie baserad på tidigare forskning kring diabetes typ 2, och kommer att fokusera på fenomen relaterat till patienters upplevelser av att få en diagnos. Författarna identifierade sex teman: Upplevelser och känslomässiga reaktioner vid diagnos, Information och kunskap, Lära sig leva med diabetes, Att förneka sin sjukdom, Eget ansvar och egenvård samt Syn på framtiden. Teoretisk referensram: Som teoretiskreferensram valdes  Afaf Meleis' Transitionsteori som bygger på tanken om att människor går igenom transitioner i livet av olika art. Resultat: Resultaten visade att deltagarna upplevde att få en diagnos som diabetes typ 2 på olika sätt beroende på hur deras liv sett ut tiden innan diagnos. Det framkom också att kunskapen kring diabetes varierade och att deltagarna hade olika behov av information och stöd vid tillfälle för diagnos. Diskussion: Att få en diagnos som diabetes typ 2 kan upplevas olika och vi har sett att det finns vissa faktorer som kan påverka upplevelsen. Faktorer som vi menar kan ha en inverkan är: den information och det stöd som ges vid diagnos, samt vilket bagage och vilken förförståelse personen i fråga har sedan tidigare. / Background: Type 2 Diabetes is the most common form of diabetes, and approximately 4 % of Sweden's population was estimated to have diabetes in 2010, and almost 90 % of these consisted of type 2 diabetes. The nurse has an important role in supporting and guiding the patient based on his experiences and needs. Aim: To describe how adult patients experience of being diagnosed with diabetes type two. Method: This study is a literature review based on previous research on type 2 diabetes, and the focus will be on the phenomenon related to patient experiences of being diagnosed with type 2 diabetes. The authors identified six themes: Experiences and emotional reactions at diagnosis, Information and knowledge, Learning to live with diabetes, To deny their illness, Personal responsibility and self-care and views of the future. Theoretical framework: The theoretical framework that was chosen for this study was Afaf Meleis' Transition Theory, which is based on the idea that people go through different transitions in life. Results: The results showed that patients experienced diagnosis of type 2 diabetes in different ways, depending on what their life looked like at the time before diagnosis. Findings also demonstrated that knowledge about diabetes varied among participants, and that they had different needs for information and support at the time of diagnosis. Discussion: To receive a diagnosis like type 2 diabetes, can be experienced in different ways, and we have seen that certain factors can have an impact on the experience. These factors that we have identified are: information and support at the time of diagnosis, and the baggage and pre-understanding the person have before diagnosis.