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.

<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.

Diabetic nephropathy is a chronic kidney disease and one of the more severe complications from diabetes mellitus type 2. The glomerular and tubular dysfunctions usually lead to end stage renal disease and the treatments of these patients (dialysis, kidney transplants) are a huge economic burden for the society. Due to an epidemiologic increase of type 2 diabetes, conventional diagnostic markers like creatinine and albumin are not sufficient, since they are only able to identify already existing kidney damage. With targeted metabolomics, the analysis of small molecules produced from metabolism, this project aimed at finding novel and more sensitive metabolic biomarkers from several different classes of metabolites. The different assays were performed with flow injection analysis, high performance liquid chromatography, gas chromatography and mass spectrometry, and with principal component analysis and discriminant analysis, up-and down-regulated metabolites could be identified and their respective biochemical pathways, if possible, explained. In diabetics significantly elevated concentrations of very long chain fatty acids (impaired peroxisomal β-oxidation), urinary sugars and acylcarnitines in plasma could be recognized. Markers indicating kidney damage included significantly increased plasma concentrations of asymmetric dimethylarginine (inhibition of nitric oxide synthase resulting in decreased endothelial functionality) and histamine (indication of uremic pruritus). Oxidative stress was also found to be a potential prognostic marker as indicated by the raised methionine-sulfoxide to methionine ratio in nephrotic patients. To summarize, this project succeeded in identifying metabolic biomarkers both for diabetes type 2 and nephropathy, which in the future might become important tools in slowing down progression or diagnosing these diseases.

I Sverige är 365 000 personer drabbade av sjukdomen diabetes mellitus typ 2. Sjukdomen kan bero på ärftliga eller miljömässiga faktorer. Sjukdomen börjar med insulinresistens i muskler, lever och fettvävnad som kan leda till allvarliga komplikationer. Patienter har behov av stöd från sjukvårdspersonalen för att hantera de egenkontroller och livsstilsförändringar som är nödvändiga. Genom empowerment kan patienter ta kontroll över sjukdomen. Litteraturstudiens syfte var att undersöka hur patienter med diabetes mellitus typ 2 beskriver sitt behov av stöd. Litteraturstudien består av 10 vetenskapliga artiklar, sex kvalitativa, två kvantitativa och två artiklar som är både kvalitativa och kvantitativa. Resultatet redovisas i fem teman: patientens behov av information som stöd, patientens behov av kunskap som stöd, patientens behov av undervisning som stöd, patientens behov av socialt stöd, patientens behov av stöd från sjukvårdspersonal. Patienter önskar information om blodsockerkontroller, medicinering, kost och motion från sjukvårdspersonalen för att kunna genomföra egenvård. Utbildning i grupp uppskattades av patienter, särskilt tillsammans med patienter med samma sjukdom och erfarenheter som de själva. Stöd från patientens omgivning kan stärka patientens livskvalitet. Upplevs behovet av stöd från sjukvårdspersonalen som tillräckligt upplevs sjukdomen hanterbar av patienterna. Det är därför relevant att sjuksköterskeprogrammet lyfter fram behov av stöd för patienter med diabetes mellitus typ 2 redan i utbildningen. Blivande sjuksköterskor kan då överföra kunskapen till vårdverksamheten. För vidare forskning inom ämnet vore det intressant att fler studier i Sverige undersöker patienternas behov av stöd och hur de upplever att deras behov blir bemötta i dagens sjukvård. / There are 365 000 people in Sweden who suffer from diabetes mellitus type 2. The disease is caused by factors that are genetic or environmental. The disease occurs from insulin resistance in the cells of the muscle, liver or fat tissue. The disease can result in serious complications. The patient has a need for support from the healthcare professionals to be able to manage self-management and the life- style changes that are necessary. The patient can through empowerment take charge over the disease. The aim of this study was to define how patients who suffer from diabetes mellitus type 2 describe their need for support. The literature study consists of ten scientific articles, six qualitative, two quantitative and two articles that were both qualitative and quantitative. The result is presented as five themes: the patient’s need for information as support, the patient’s need for knowledge as support, the patient’s need for education as support, the patient’s need for social support, the patient’s need for support from healthcare professionals. The patients desired information from the healthcare professionals about self- monitoring of blood glucose, medications, diets and exercise to be able to perform self-management. Peer education was appreciated by patients, particularly with patients with the same disease and experience as their own. The support from the surroundings could strengthen patient’s quality of life. If the need for support from the healthcare professionals was experienced as adequate the disease seemed more manageable by the patients. Therefore it is relevant, already in the beginning of the nursing program, to emphasize the need for support with diabetes mellitus type 2. Registered nurses can then include the knowledge within the clinic. Further research within healthcare is recommended, especially studies within Sweden that investigate the patient’s need for support.

<p>Diabetic nephropathy is a chronic kidney disease and one of the more severe complications from diabetes mellitus type 2. The glomerular and tubular dysfunctions usually lead to end stage renal disease and the treatments of these patients (dialysis, kidney transplants) are a huge economic burden for the society. Due to an epidemiologic increase of type 2 diabetes, conventional diagnostic markers like creatinine and albumin are not sufficient, since they are only able to identify already existing kidney damage. With targeted metabolomics, the analysis of small molecules produced from metabolism, this project aimed at finding novel and more sensitive metabolic biomarkers from several different classes of metabolites. The different assays were performed with flow injection analysis, high performance liquid chromatography, gas chromatography and mass spectrometry, and with principal component analysis and discriminant analysis, up-and down-regulated metabolites could be identified and their respective biochemical pathways, if possible, explained. In diabetics significantly elevated concentrations of very long chain fatty acids (impaired peroxisomal β-oxidation), urinary sugars and acylcarnitines in plasma could be recognized. Markers indicating kidney damage included significantly increased plasma concentrations of asymmetric dimethylarginine (inhibition of nitric oxide synthase resulting in decreased endothelial functionality) and histamine (indication of uremic pruritus). Oxidative stress was also found to be a potential prognostic marker as indicated by the raised methionine-sulfoxide to methionine ratio in nephrotic patients. To summarize, this project succeeded in identifying metabolic biomarkers both for diabetes type 2 and nephropathy, which in the future might become important tools in slowing down progression or diagnosing these diseases.</p>

The aim of the present thesis was to assess the occurrence of early lower extremity arterial disease (LEAD) in patients with diabetes and to assess novel potential risk markers for development or worsening of LEAD in the same patients. In parallel different measures of impaired peripheral circulation were evaluated. The measurement of ankle-to- brachial blood pressure index (ABI) to screen for asymptomatic LEAD in diabetic subjects is unreliable since a large proportion of patients have stiff ankle arteries (mediasclerosis) and thus may display a too high ABI. We studied type 1-, type 2 diabetic and non-diabetic subjects without a previous history of LEAD and a composite variable of ankle – plus toe blood pressures and indices was compared to ABI alone in detecting LEAD. Significantly more subjects with reduced peripheral circulation were detected using the composite variable compared to ABI alone. This was particularly true in diabetic subjects, about 30% of whom had signs of impaired peripheral circulation. Thus, it was found that toe blood pressure measurements, alone or in combination with ankle blood pressure measurements, increase the sensitivity for finding early asymptomatic LEAD in diabetic subjects. No significant difference in reproducibility between measurements of absolute ankle- and toe blood pressure and indices was found, but a correlation between systemic (brachial) and toe blood pressure variations over time may suggest that indices are more correct in assessing peripheral arterial circulation. Furthermore, toe blood pressure measurements can be performed using either the great toe or dig II and a strong concordance is found between these measurements. In addition, since the pole-test, another non-invasive method to measure peripheral blood pressure which is less sensitive to the presence of mediasclerosis compared to ABI, correlated significantly with toe blood pressure measurements this method may be used as an alternative screening method in subjects with previously known LEAD. Age, hypertension and glycemic control are well known risk factors and, in addition, high tissue plasminogen activator (tPA) activity turned out to be a novel early marker for asymptomatic LEAD in diabetic subjects, particularly in patients with type 2 diabetes. Age and hyperglycemia are the most important risk factors for development and progression of subclinical lower extremity arterial disease in type 2 diabetic subjects. No independent associations between markers of inflammation, such as CRP, interleukin-6 and TNF-α and early asymptomatic LEAD were seen among non-diabetic or diabetic subjects. In conclusion, impaired arterial circulation in the lower extremities is common in diabetic subjects even in the absence of symptoms. Including toe blood pressure measurement when screening for asymptomatic LEAD in diabetic subjects improves the ability to detect reduced peripheral circulation and this method avoids falsely elevated blood pressures readings due to mediasclerosis in the ankle arteries. Moreover, an altered fibrinolytic activity should be further evaluated as an early marker of atherosclerosis and LEAD.

Insulin pump treatment (CSII) is considered the most physiological way to imitate the healthy body’s insulin profile in adolescents with diabetes. However, despite the use of CSII, achieving the recommended disease control is difficult for adolescents. The aim of this thesis was to explore aspects of self-management of diabetes in adolescents using insulin pumps in order to describe conditions contributing to the recommended disease control. Three methods of bolusing (normal, dual-wave and square-wave) in connection with pasta meals were tested in a crossover study among 15 adolescents with diabetes to assess whether one method was superior in managing glucose levels. A cross-sectional study among 90 adolescents being treated with CSII was conducted to investigate the management of CSII, including the administration of bolus doses. Two qualitative interview studies, based on the grounded theory method, were performed to gain insight into the processes involved in taking bolus doses and to investigate reasons for missed bolus doses and strategies for avoiding missing them. Twelve adolescents, four parents and one diabetes specialist nurse were interviewed. No method of bolusing was found to be superior in managing the glucose levels after these meals. The post-prandial glucose peaks were &lt;10 mmol/L, in 48% of the cases, regardless of bolus methods. This indicates that adolescents can be encouraged to individually test which bolus method gives them the most normal post-prandial glucose levels. The cross-sectional study showed that adolescents were satisfied with CSII, but that 38% had missed more than 15% of the bolus doses the day under study. The frequency of bolus doses correlated with the disease control. Findings from the interview study revealed the need to clarify the responsibility for diabetes self-management in continuous negotiation between adolescents and parents to avoid insulin omission. The main reason for missed boluses was lost focus, and the strategies for remembering them were agreements involving reminders. The thesis describes that individual dose testing, clarification of responsibility and agreements involving reminders are conditions contributing to the recommended disease control. The thesis also describes that lost focus and a lack of responsibility can lead to insulin omission and be a hindrance to achieving disease control. / Anna Kernell avled maj 2010.