Type 1 Diabetes (T1D) is a serious chronic disease that results from an autoimmune destruction of the insulin-producing beta cells. Sweden has the second highest incidence of T1D in the world, and it affects more and more children each year. Genes controlling key functions of the immune system regulation of autoimmunity has been associated to T1D. Polymorphism in the Human Leukocyte Antigen (HLA) Class II is a major risk determinant for T1D but also Cytotoxic T lymphocyte Antigen 4 (CTLA-4) polymorphism can affect predisposition. Immune responses towards Glutamic Acid Decarboxylase 65 (GAD65), Insulin, insulinoma-associated antigen 2 (IA-2) and Heat Shock protein 60 have all been implicated in T1D pathogenesis. We aimed to study the effect and role of CTLA-4 and HLA Class II in the T1D immunity. By focusing on the immune responses associated to T1D in healthy children with risk genotypes we aimed to study immunological effects of T1D risk. We found that HSP60-peptide induced a higher IFN- response in subjects with risk associated CTLA-4 +49GG allele while GAD65 induced IL-4 secretion was lower in risk subjects. Individuals with T1D neutral HLA showed higher IFN- responses to GAD65 than DR3-DQ2 and DR4-DQ8 positive children. We did also detect that T1D patients have reduced IFN- responses to GAD65 compared to healthy children. Interestingly, HLA and CTLA-4 risk genotype seem to reduce those responses to become similar to responses of T1D patients. We also found that CTLA-4 and HLA risk is associated to reduced percentages of lymphocytes expressing intracellular CTLA-4 in healthy children. In another study we recorded maintained levels of CTLA-4 and TGF- mRNA responsiveness to GAD65 in recent onset T1D patients receiving ECP treatment although clinical outcome was certainly limited. In conclusion, HLA Class II risk genes but also CTLA-4 +49A/G to some extent, influence CTLA-4 capacity and T1D protective antigen-specific responses in a manner that might explain the genes’ predisposing and pathogenic capability. / Varför har Sverige näst efter Finland världens högsta incidens av barndiabetes? Typ 1 diabetes (T1D) är vanligare i norra Europa och särskilt i de nordiska länderna. Genetisk profil, infektioner och andra miljöfaktorer påverkar en individs mottaglighet för T1D. Hittills är det dock okänt vad som till slut utlöser den process som leder till att aktiverade immunförsvarsceller ”byter sida” och förstör kroppens egna insulinproducerande celler i bukspottskörteln. Ett grundläggande problem utifrån immunförsvarets perspektiv är att kunna skilja mellan vän och fiende, dvs skilja skadliga bakterie- eller virusfragment från fragment som tillhör kroppen själv. För att lära sig vad som är vad, utbildas immunförsvarets dirigenter, T-cellerna (en sorts vita blodkroppar) i thymus-körteln. Där sorteras överreagerande celler bort och de som blir kvar skickas ut i kroppen för att hjälpa oss att hålla oss friska. En förutsättning för att cellerna ska kunna göra den här åtskillnaden är att de nedbrutna bakterie- och virusfragment i form av äggviteämnen, visas upp för andra vita blodkroppar. HLA klass II molekylen fungerar som en serveringsbricka och håller upp det som ätarceller hittat och brutit ned. Variationer i konstruktionskoden för HLA gör att risken för att utveckla T1D ökar eller minskar. Möjligen sker detta genom att de HLA-varianter som finns i 95 % av T1D patienter serverar äggviteämnen på ett sätt som immunförsvaret missförstår som farligt. Vissa virus har identiska sektioner med äggviteämnen i de insulinproducerande cellerna vilket gör att immunförsvaret skulle kunna missta betacellerna för virusinfekterade celler och attackera dem. Det har på senare år visat sig att utbildningssystemet i thymus inte fungerar perfekt, utan faktiskt släpper igenom en del överreagerande celler, som skulle kunna starta reaktioner mot kroppens egna celler. För att hindra detta utnyttjar immunförsvaret ett kontrollsystem bestående av regulatoriska signaler och T-celler (T-reg celler). Treg celler har till uppgift att hålla eventuella självreaktiva immunprocesser i schack och undervisa immunförsvaret att tolerera ofarliga äggviteämnen. Ett viktigt äggviteämne i detta kontrollsystem är CTLA-4. Det är en ytmarkör som finns i och på T-celler, och framförallt T-reg celler. CTLA-4 fungerar som en sorts tröskel, så det krävs en tillräckligt stark (=säker) hotsignal för att komma över denna tröskel så att immunförsvaret sen kan gå till attack. CTLA-4 aktivitet tros vara väldigt viktigt i de mekanismer som kan bromsa eller hejda utvecklingen av T1D. Dessa skyddande mekanismer är målet för en del av forskningen kring framtida behandlingar av T1D. Konstruktionskoden för CTLA-4 varierar något mellan olika personer. Några varianter har visat sig vara sammankopplade med ökad risk för T1D och andra sjukdomar där immunförsvaret överreagerar och angriper kroppens egna vävnader (så kallade autoimmuna sjukdomar). Tidigare studier har visat att immunförsvarets signalmolekyler, cytokiner, driver in systemet mot i huvudsak två olika profiler, Typ1 och Typ2. De här profilerna är en viktig del i den normala kampen mot virus och bakterier, men i vissa sjukdomar visas en övervikt av den ena eller den andra profilen. Typ1 är vanligare bland personer som utvecklar typ 1 diabetes, medan Typ2 verkar skydda. Både immunprofil och Treg celler går att spåra med hjälp av signaler som är karakteristiska för celltyperna. Populärt förfarande vid utredning av T1D-immunologi och genetik är att man antingen studerar signalerna inom immunförsvaret och dess inbördes förhållanden, eller att man studerar hur stor andel av individerna med en viss genvariant som utvecklar sjukdomen. Detta är förstås värdefull information, men det lämnar en kunskapslucka i relationen mellan gen och immunförsvar. Det som är unikt med vår forskning är att vi studerat just vad för effekt de genetiska förändringarna får på immunförsvaret och särskilt det immunreglerande proteinet CTLA-4. Vår hypotes är att genom att gruppera friska och sjuka individer för olika kända riskgener - och sedan studera deras immunreaktioner – så kan vi identifiera delar av den process som riskgenerna verkar genom. Vi har fokuserat vår forskning på att försöka ta reda på hur de olika varianterna i HLA och CTLA-4 påverkar immunförsvaret så att de insulinproducerande cellerna angrips. Vi har observerat att immunsvaret i individer med den sjukdomsassocierade varianten av CTLA-4 har en större övervikt mot typ 1 när det retas med ett särskilt äggviteämne som är intressant inom diabetesforskning. Vi kunde även observera att friska barn med HLA klass II risk att utveckla T1D reagerade med svagare Typ1 svar än barn med neutrala gener när deras celler retades med ett äggviteämne som verkar vara aktivt i sjukdomsmekanismen av T1D. Intressant nog verkar barn med HLA risk ha en responsprofil som liknar de barn som redan utvecklat T1D. Observationer från ett annat projekt visar tecken på att barn med både CTLA-4 och HLA risk har försämrad förmåga till att uppreglera tolerans. Cellernas depåer av äggviteämnet CTLA-4 som är en viktig aktör i den toleransprocessen, är lägre i friska barn med genetisk risk. Inom avhandlingen har vi dessutom studerat effekter på toleranssystemen efter behandling med en tidigare föreslagen terapikandidat vid T1D, fotoferes. Behandlingen som i princip gick ut på att en andel av de vita blodkropparna bestrålades med UV-ljus, hade begränsade kliniska resultat men vi kunde se att behandlingen verkade stödja toleranssystemen. Genom att studera centrala immunologiska mekanismer och gener starkt förknippade med T1D har vi kunnat observera interaktioner mellan dessa system. Om vi drar oss till minnes att 95% av individerna som utvecklar T1D har HLA risk, kan vi nära nog säga att HLA risk är nästintill en förutsättning för att senare utveckla sjukdom. Vi visar att friska barn med HLA risk har en försämrad kapacitet att motverka ett självreaktivt immunförsvar. Kan det alltså vara så att T1D föregås av en försämring av kontrollsystemen? Det är viktigt att fortsätta undersöka hur CTLA-4 och framförallt HLA påverkar immunförsvaret och vad det betyder för personer med riskvarianter av dessa gener. I framtiden kanske vår forskning leder till att vi blir bättre på att se vem som riskerar att bli sjuk och hur detta går till. Det är också av yttersta vikt att vi får en tydligare bild av hur dessa centrala toleransmekanismer verkar när vi utvärderar den möjliga effekten av det nu aktuella T1D-”vaccinet” Diamyd och andra kliniska terapiförsök.

The aim of this thesis is to investigate different methods of improving the glycaemic control of diabetic out-patients, within the scope of the author's training both as a therapeutic dietitian and as a teacher. Evidence is presented from the literature, which indicates that high-carbohydrate, high-fibre diets are of benefit in diabetes, that supplements of viscous fibre improve glycaemic control, and that education of the diabetic patient may help to achieve good diabetic control, provided that the patient also complies with all parameters of therapy. Three main studies have been undertaken: - (1) An educational project, to investigate the effect of a mass-education programme on compliance and control in diabetic out-patients. (2) An investigation of the effect of long-term high-fibre diets in diabetic out-patients. (3) A study of the use of guar gum in the diabetic diet. In Study 1, a large random sample of patients attending a diabetes outpatient clinic were tested by means of a detailed questionnaire, in order to assess their existing knowledge of the disease. A suitable education programme was then devised and patients were exposed to this in the clinic situation. Another sample of patients was then re-tested with the same questionnaire and statistical analysis was used to assess the effect of this programme on knowledge, compliance and control. Results indicate that, while patients' knowledge scores improved, there was no improvement in dietary compliance and also no significant change in the standard of diabetic control in the clinic population. In Study 2 we investigated the practical aspects of administering a high-fibre diet to diabetic out-patients in Cape Town, in the light of the reported benefits of diets containing large amounts of dietary fibre (OF) in the control of diabetes. Readily-available, low-cost foodstuffs with a high OF content, were incorporated into suitable, individualised high-fibre meal plans for 10 selected diabetic out-patients. Patients were closely monitored over a period of 9 months, for 3 months of which the high-fibre diet was prescribed. Various parameters of glycaemic control were recorded and analysed, and the patients' compliance to the new regimen was assessed. Only 3 patients approached the projected fibre intake, but significant negative correlations were found between the dietary fibre increments and both mean plasma glucose and mean serum triglyceride changes. These findings suggest that, were it not for poor dietary compliance, a high-fibre diet might result in significant improvement in diabetic control, and that education and motivation are of prime importance when making major changes to patients' eating habits. Study 3 investigates the use of guar gum, when incorporated into the diabetic diet in both short- and medium-term studies. This viscous fibre has been shown by workers overseas to be effective in lowering postprandial glycaemia. In this study a palatable vehicle for the gum, a digestive-type biscuit, was tested for its effect on glycaemic control when incorporated into the usual meal plans of diabetic out-patients, and also against an oral glucose load as a reference standard. It was found to be effective in reducing the post-prandial rise in blood glucose, and in improving glycaemic control, as shown by reduced fasting blood glucose values and decreased 24-hour urinary glucose excretion. The biscuit proved to be palatable and acceptable to patients, and the guar gum was effective in much smaller quantities than have previously been tested. It may therefore prove a valuable adjunct to diabetes therapy. Results of these studies indicate that compliance to therapeutic recommendations is the crux of achieving good diabetic control. Increased diabetic knowledge alone does not lead to improved diabetic control, and compliance to altered eating habits is difficult to achieve unless prior education and motivation has taken place. The simplest means of achieving better glycaemic control of diabetes appears to be the use of a supplement of viscous fibre, which will improve the glycaemic response to the patients' usual meals.

No description available.

No description available.

Transplantation of insulin producing cells is currently the only cure for type 1 diabetes. However, even though the Edmonton protocol markedly increased the success rate of pancreatic islet transplantation, the long term insulin independence is still very poor. An adequate engraftment is critical for islet graft survival and function. In the present thesis, isolated islet endothelial cells were found to have a low proliferatory and migratory capacity towards vascular endothelial growth factor (VEGF), but this could be reversed by using neutralizing antibodies to the angiostatic factors thrombospondin-1, endostatin or alpha1-antitrypsin. In the adult islet endothelial cell, VEGF may act as a permeability inducer more than an inducer of angiogenesis. p38 MAP kinase activity has been shown to serve as a switch between these properties of VEGF. Inhibition of p38 MAP kinase by daily injections of SB203580 in the early posttransplantation phase lead to a redistribution of the islet graft blood vessels from the stroma into the endocrine tissue and this was accompanied by a higher oxygen tension. Besides transports of oxygen and nutrients, beta-cells may require signals from the endothelial cells for their growth and differentiation. It was demonstrated that islet endothelial cells secrete factors, including laminin, that have positive effects on beta-cell insulin release and insulin content. Our results suggest that improved revascularization of transplanted islets may be achieved by either inhibition of angiostatic factors, or by blocking p38 MAPkinase activity, in the implanted tissue. Islet endothelial cells have a supportive paracrine role for beta-cells that might be hampered by the normally poor revascularization.

The goal of this diploma thesis is to evaluate changes in the body structure, selected laboratory values and blood pressure for patients with prediabetes or diabetes mellitus of 2nd type who attended nutritional therapy in diabetic ambulance. The patients were divided in 2 groups based on their preferences. The first monitored group monitored energy intakes and expenditures on web page www.kaloricketabulky.cz. The first group had also an opportunity to be supervised or to communicate with its nutritional therapist on web page www.casprozdravi.cz. The second monitored group monitored energy intakes and expenditures manually in the diabetic notebook. The body changes were monitored by bioelectric impedance scale Tanita BC-545 N during each consultation. Laboratory values were taken on consultation 1 and 5. The blood pressure was measured on consultation 1 and 5. Rated values - overall body weight, waistline, percentage of body fat, glycemia, HbA1c, overall cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and blood pressure. The results of this research were weight reduction in both groups by an average of 3.2 %, waistline by 4.5 %, body fat by 1.7 %, glycemia by 16 %, HbA1C by 28.6 %, overall cholesterol by 15.1 %, HDL cholesterol by 6.5 %, LDL cholesterol by 23.6 %, triglycerides by...

<p>Individuals with diabetes and blindness meet problems in daily life that are related to both conditions. The aim was to study diabetes self-management, burden of diabetes, power, sense of coherence (SOC) and health among individuals with diabetes-related blindness. The aim was further to determine psychometric properties of a diabetes empowerment scale (DES) and to use it in the evaluation of an empowerment programme. The participants were 39 blind diabetic and non-diabetic individuals and 21 diabetic individuals with threat of blindness. A convenience sample of 195 diabetic patients completed DES and 9 blind diabetic individuals participated in the empowerment programme. Two reference groups from the Swed-qual population studies were also included. Data were collected by questionnaires, interviews and by scrutinizing medical records. Quantitative data were analyzed with parametric and non-parametric methods and qualitative data with content analysis. Blind diabetic individuals expressed more problems with self-management than did those with threat of blindness. In some health domains, blind diabetic individuals perceived significantly poorer health than did non-diabetic blind individuals. There were though individual differences in how blind individuals perceived their health as well as how burdensome they experienced their self-management. Individuals with power and strong SOC felt less burden and perceived better health when compared to those with weak SOC or non-power. The diabetes empowerment scale showed acceptable validity and reliability and was used, along with qualitative interviews, to evaluate the effect of the empowerment programme. Evaluation of the programme showed that the participants had improved knowledge and awareness of self-management. The programme seems suitable for blind individuals and creates an inspiring learning climate enhancing empowerment. It is concluded that blind individuals have problems in their diabetes self-management and perceive poor health but the experience of power is a factor of importance for health and an empowerment education programme may enhance power.</p>

Individuals with diabetes and blindness meet problems in daily life that are related to both conditions. The aim was to study diabetes self-management, burden of diabetes, power, sense of coherence (SOC) and health among individuals with diabetes-related blindness. The aim was further to determine psychometric properties of a diabetes empowerment scale (DES) and to use it in the evaluation of an empowerment programme. The participants were 39 blind diabetic and non-diabetic individuals and 21 diabetic individuals with threat of blindness. A convenience sample of 195 diabetic patients completed DES and 9 blind diabetic individuals participated in the empowerment programme. Two reference groups from the Swed-qual population studies were also included. Data were collected by questionnaires, interviews and by scrutinizing medical records. Quantitative data were analyzed with parametric and non-parametric methods and qualitative data with content analysis. Blind diabetic individuals expressed more problems with self-management than did those with threat of blindness. In some health domains, blind diabetic individuals perceived significantly poorer health than did non-diabetic blind individuals. There were though individual differences in how blind individuals perceived their health as well as how burdensome they experienced their self-management. Individuals with power and strong SOC felt less burden and perceived better health when compared to those with weak SOC or non-power. The diabetes empowerment scale showed acceptable validity and reliability and was used, along with qualitative interviews, to evaluate the effect of the empowerment programme. Evaluation of the programme showed that the participants had improved knowledge and awareness of self-management. The programme seems suitable for blind individuals and creates an inspiring learning climate enhancing empowerment. It is concluded that blind individuals have problems in their diabetes self-management and perceive poor health but the experience of power is a factor of importance for health and an empowerment education programme may enhance power.

Background/aim. The incidence of microvascular complications has been reported to be unchanged the last decades. However, in randomized clinical trials it has been shown that improved metabolic control can reduce the development of long term complications. It has been debated whether it is possible to achieve the same results in an unselected population. In a previous study we found a decreased incidence of overt nephropathy, but unchanged incidence of severe laser treated retinopathy in a population of patients with type 1 diabetes diagnosed in childhood. The aim of the present study was to investigate the incidence 10 years later in the same population and to analyse the importance of possible risk factors. In another previous study we found a high prevalence of subclinical neuropathy among young diabetic patients despite intensive insulin therapy since diagnosis. The aim of the present study was to examine if intensive treatment is more effective in preventing early diabetic complications other than neuropathy. The incidence of type 1 diabetes has doubled in Sweden the last decades. The reason must be environmental factors. These, as well as more intensive insulin regimens from onset of diabetes, might also lead to different disease process. We wanted to analyse if clinical characteristics at onset had changed the last 25 years and if there was any secular trend of C-peptide secretion. We also intended to investigate if longer persistence of C-peptide secretion could be of importance for prevention of long term complications. Methods. The whole study population consisted of all 478 patients with type 1 diabetes diagnosed before the age of 15 during the years 1961 - 2000, living in the catchment area of the Paediatric Clinic, University Hospital, Linköping, Sweden. For the statistical analysis the population was divided into five–year cohorts according to time of onset of diabetes. The cumulative proportion of severe retinopathy and overt nephropathy in 269 patients with onset of diabetes 1961 - 1985 was computed with survival analysis. Multivariable regression models were used to analyse the importance of metabolic control, diabetes duration, blood pressure, smoking, BMI, lipids and persisting C-peptide secretion. The prevalence of all grades of retinal changes, nephropathy and neuropathy, defined as abnormal nerve conduction, was estimated in the late 1990s in a subgroup of 80 children and adolescents with mean 13 years of diabetes duration. Clinical characteristics at onset, duration of partial remission and regularly measurements of fasting and stimulated C-peptide secretion the first five years after onset were analysed in 316 patients with onset of diabetes 1976 - 2000. Results. The cumulative proportion of severe laser treated retinopathy showed a significant declining trend the last decades. The decrease was significant between the oldest cohort with diabetes onset 1961 - 1965 and the cohorts with diabetes onset 1971 - 1975 and 1976 - 1980. The cumulative proportion of overt nephropathy also declined with a significant decrease between the oldest cohorts and all the following cohorts. After 25 years of diabetes duration it was 30% and 8% in the two oldest cohorts respectively and remained largely unchanged after 30 years. Diabetes duration and long term HbA1c were the only significant independent risk factors for both retinopathy and nephropathy. The risk of overt nephropathy increased substantially when HbA1c was above 8.5%, while the risk of severe retinopathy increased already when HbA1c exceeded 7.5%. The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% in the population of young patients after mean 13 years of diabetes duration. During the last 25 years the clinical characteristics at onset were unchanged as well as duration of partial remission and magnitude and persistence of C-peptide secretion. Conclusions. In this unselected population the cumulative proportion of severe retinopathy and overt nephropathy decreased over the last decades. Diabetic nephropathy has probably been prevented and not just postponed. Good glycaemic control was the most important factor to avoid complications, with the necessity of a lower level of HbA1c to escape retinopathy than nephropathy. Intensive insulin regimens from diabetes onset was not sufficient to entirely escape early diabetic complications after mean 13 years of diabetes duration, even if the prevalence of retinopathy and especially nephropathy was lower than usually reported. The clinical picture at onset of diabetes was unchanged the last 25 years. There was no secular trend of partial diabetes remission or C-peptide secretion during the first years after diagnosis.

The bank vole (Microtus arvalis) develops glucose intolerance both when kept in captivity and in the wild state. Glucose intolerant bank voles kept in captivity exhibited polydipsia, polyuria, hyperglycemia, hyperinsulinemia, islet autoantibodies and a markedly changed islet structure resembling so–called hydropic degeneration. Islets showing hydropic degeneration have reduced β–cell mass. However, the relative islet size to total pancreas area was not changed. Pancreatic islet isolated from glucose intolerant bank voles had an altered islet function showing signs of being exposed to an increased functional demand on their β–cells. Also, islets from male bank voles seem more affected than the islets from females. Islets isolated from glucose tolerant male bank voles cultured for 5 days at 28 mM glucose did not reveal any change in insulin gene expression or insulin biosynthesis rate. However, islets from female bank voles displayed a glucose concentration dependent response. This suggests that there is gender difference in that, islets of female more easily than islets of males adapt to elevated glucose concentration. Furthermore, islets isolated from glucose tolerant males had reduced insulin gene expression after exposure to proinflammatory cytokines for 48 hrs. This effect seemed to be NO-independent since only a minor elevation of nitrite accumulation in the medium was seen, and the use of iNOS inhibitor could not counteract the cytokine effect. The observed response seen in bank vole islets upon exposure to various glucose concentrations or proinflammatory cytokines is similar to those seen in studies of human islets. The bank vole may therefore represent a novel animal model for the study of diabetes. An unresolved issue is the role of the Ljungan virus which is found in the bank vole colony. Bank voles developing glucose intolerance display features of both human type 1 and type 2 diabetes, where environmental factors seems to play an important role as determinant. Our findings suggest that bank voles bred in the laboratory may develop more of a type 2 diabetes. However, bank voles caught in nature instead may rather develop a type 1 form of the disease.