Title: Physical education of individuals with type 2 diabetes mellitus Objectives: The aim of this thesis is to evaluate the effect of physical education of individuals with type 2 diabetes mellitus cured in diabetologic outpatient clinic of Genereal University Hospital in Prague. The physical education was focused on nordic walking. Methods: Eight patients of diabetological outpatient clinic were chosen by the doctor for this survey. The physical examination was carried out with seven patients. It involved anthropometrical measurements (weight, waist circumference) and blood collection for biochemical parameters assessment (glycemia, glycated hemoglobin). Two-minute step test was chosen for assessment of subject's physical fitness. Results: The physical activity education of individuals with type 2 diabetes mellitus doesn't increase the amount of their physical activity. The physical activity of type 2 diabetes mellitus individuals is rather low as well as their exercise adherence. Nordic walking exercise program can improve anthropometrical parametres (weight, waist circumference) and can reduce HbA1c levels. Lower health-related quality of life in physical and physological aspects wasn't proved in type 2 diabetes patients. Key words: nordic walking, physical activity, type 2 diabetes management,...

Detailed characterization of human pancreatic islets is key to elucidating the pathophysiology of all forms of diabetes, especially type 2 diabetes. However, access to human pancreatic islets is limited. Pancreatic tissue for islet retrieval can be obtained from brain-dead organ donors or from individuals undergoing pancreatectomy, often referred to as ‘living donors’. Different protocols for human islet procurement can substantially impact islet function. This variability, coupled with heterogeneity between individuals and islets, results in analytical challenges to separate genuine disease pathology or differences between human donors from experimental noise. There are currently no international guidelines for human donor phenotyping, islet procurement and functional characterization. This lack of standardization means that substantial investments from multiple international efforts towards improved understanding of diabetes pathology cannot be fully leveraged. In this Perspective, we overview the status of the field of human islet research, highlight the challenges and propose actions that could accelerate research progress and increase understanding of type 2 diabetes to slow its pandemic spreading.

Bakgrund: Diabetes typ 2 är en endokrin sjukdom och ett globalt hälsoproblem, där antalet insjuknande personer ökar kraftigt. Behandlingen vid diabetes typ 2 utgörs till största del av egenvård vilket ställer stora krav på patienten och på sjukvården. En bristande följsamhet till råd om egenvård kan leda till sämre hälsa för patienten och ökade kostnader för samhället. Syfte: Syftet med denna litteraturöversikt var att beskriva vilka faktorer som påverkar följsamheten till råd om egenvård hos patienter med diabetes typ 2. Metod: En litteraturöversikt baserad på 15 vetenskapliga artiklar där både kvalitativa och kvantitativa artiklar har granskats. Databaserna CINAHL och PubMed har använts. Resultat: Faktorer som påverkade följsamheten till råd om egenvård identifierades och resulterade i fem huvudkategorier: Information; Kunskap; Socialt stöd; Teknologiskt stöd och Livssituation. Dessa faktorer framkom som viktiga för en god följsamhet till råd om egenvård. Slutsats: Det är av stor betydelse att försöka identifiera varje individs olika förutsättningar, för att på så sätt ha möjlighet att anpassa både information, utbildning och egenvårdsplanering utifrån individen. / Background: Type 2 diabetes is an endocrine disorder and a global health problem, with the number falling ill persons greatly increases. Treatment of type 2 diabetes consists mainly of self-care, which places great demands on the patient and the healthcare system. A lack of compliance to advice on self-care can lead to poorer health for the patient and increased costs for society. Aim: The purpose of this literature review was to describe the factors that influence compliance to advice on self-care in patients with type 2 diabetes. Method: A literature review based on 15 scientific articles, both qualitative and quantitative articles were reviewed. The databases CINAHL and PubMed were used. Results: Factors affecting compliance to advice on self-care were identified and resulted in five broad categories: Information; Knowledge; Social support; technological support and Life situation revealed as important factors for low compliance to advice on self-care. Conclusion: It is very important to try to identify each individual's different conditions, in order to thus be able to cu

High circulating glucose and non-esterified free fatty acid (NEFA) levels can cause pancreatic β-cell failure. The molecular mechanisms of this β-cell glucolipotoxicity are yet to be established conclusively. In this thesis by exploring mitochondrial energy metabolism in INS-1E insulinoma cells and isolated pancreatic islets, a role of mitochondria in pancreatic β-cell glucolipotoxicity is uncovered. It is reported that prolonged palmitate exposure at high glucose attenuates glucose-stimulated mitochondrial respiration which is coupled to ADP phosphorylation. These mitochondrial defects coincide with an increased level of mitochondrial reactive oxygen species (ROS), impaired glucose-stimulated insulin secretion (GSIS) and decreased cell viability. Palmitoleate, on the other hand, does not affect mitochondrial ROS levels or cell viability and protects against the adverse effects of palmitate on these phenotypes. Interestingly, palmitoleate does not significantly protect against mitochondrial respiratory or insulin secretion defects and in pancreatic islets tends to limit these functions on its own. Furthermore, strong evidence suggests that glucolipotoxic-induced ROS are of a mitochondrial origin and these ROS are somehow linked with NEFA-induced loss in cell viability. To explore the mechanism of glucolipotxic-induced mitochondrial ROS and associated cell loss, uncoupling protein-2 (UCP2) protein levels and activity were probed in NEFA exposed INS-1E cells. It is concluded that UCP2 neither mediates palmitate-induced mitochondrial ROS production and the related cell loss, nor protects against these deleterious effects. Instead, UCP2 dampens palmitoleate protection against palmitate toxicity. Collectively, these data shed important new light on the area of glucolipotoxicity in pancreatic β-cells and provide novel insights into the pathogenesis of Type 2 diabetes.

Aim: To test the interactive effects of the constructs of Modified Social Learning Theory (MSLT) in relation to predicting health behaviour in Type 2 Diabetes. Methods: The study is mixed methods and employs an exploratory sequential design. Qualitative Phase: (N=12) Semi-structured interviews with adults with insulin-treated type 2 diabetes, explored how beliefs and values influence self-management behaviour. Interim Phase: Thematic analysis allowed development of an adapted Health Value Measure. Quantitative phase: (N=107) Valid questionnaires measured Health Value, Health Locus of Control (HLC) and Self-efficacy (SE). Health Value was measured pre and post diagnosis in order to compare any changes with time. Anxiety and depression was controlled for using the Hospital Anxiety and Depression(HAD) scale. Five subscales measured diabetes outcome behaviour: general diet, specific diet, exercise, blood sugar and foot care. Hierarchical Multiple Regression(HMR) analyses consisted of four blocks, including three two-way interaction terms and one three-way interaction term to test the interactive effects of the three-predictor variables on outcome behaviours. ANOVA’s were conducted in an effort to add support to HMR results. Results: The interviews suggest that people may hold terminal (beliefs about desired end states)/instrumental health values (beliefs about desired modes of action) pre-diagnosis but these are mainly instrumental post-diagnosis in order to meet their new needs and maintain quality of life. The qualitative data also drew attention to the way in which LOC and SE beliefs impact on behaviour. Additionally, differing dimensions of various emergent themes highlight the demands Type 2 diabetes places on a person and how this influences beliefs and values. Interim phase results resulted in the new items being removed from the adapted health value measure prior to the quantitative data analysis, as item 5 was deemed problematic. Sensitivity analysis was carried out to increase the robustness of the quantitative findings due to removing 29 cases with missing data from Dataset 1. Dataset 1 includes 78 complete cases and Dataset 2 contains 107 cases, 29 of which had missing values and were replaced using regression imputation. HMR analyses produced significant results that support MSLT when the three-way interaction variable was added to block 4. ANOVA results produced minimum support for MSLT. Conclusion: Support for MSLT has been found and can be used to inform interventions to change self-management behaviours of patients with poor diabetes control. Change in health value orientation post-diagnosis purports further investigation, as it is supported by qualitative results but not quantitative.

Background: Type 2 diabetes mellitus (T2DM) is a complex health condition that impacts multiple organ systems and contributes to both acute and chronic health problems. In the United States (U.S.), T2DM is a growing health concern with increasing prevalence among both adult and pediatric populations (American Diabetes Association [ADA], 2015; Dea, 2011). Developing a comprehensive plan of care that incorporates a multifaceted treatment and prevention plan is necessary to address this growing health concern and reduce overall morbidity and mortality. Problem: The Edmund Primary Care (EPC) practice data for routine annual diabetic foot exams, annual eye exams, annual urine microalbumin, smoking cessation education and recommendations for pneumococcal polysaccharide do not meet the ADA (American Diabetes Association, 2015) recommendations for patients with T2DM.Design: Quality improvement (QI) project applying the Plan-Do-Study-Act (PDSA) cycle to develop a process change to improve diabetic preventative care measures for hemoglobin A1C, urine microalbumin, diabetic foot exams, and optometry referrals. Setting: A small, nurse practitioner owned, family practice clinic targeting patients 18 years and older with a diagnosis of T2DM.Intervention: A fishbone diagram to conduct a root cause analysis led to identification of key factors contributing to the problem. A comprehensive process change integrating a Diabetic Assessment Flow Sheet (DAFS) and diabetic foot exam sheet was developed to address the problem. Expected Outcome: Increase in rates of completion to at least 90% over eight weeks. Results: Analyzed with run charts demonstrating an increase in rates of completion to 100% for A1C, urine microalbumin, diabetic foot exams, and optometry referrals. A positive percent of change for each measure is as follows: A1C 7%; urine microalbumin 43%; diabetic foot exams 150%; and referrals to optometrist 43%. Significance: This QI project emphasizes the importance of implementing a system to evaluate the quality of care being delivered. It also highlights the usefulness of the PDSA cycle as a method to implementing quality improvement measures in health care. Lastly, this QI project demonstrated the effectiveness of flow sheets in improving the quality of care delivered to patients with T2DM.

Type 2 diabetes (T2DM) has reached epidemic levels worldwide during the past two decades. It affects nearly 26 million adults in the U.S. Advances in both the treatments for T2DM and guidelines for its optimal management are extensive. Despite these advances, barely half of type 2 diabetics achieve recommended glycemic targets. Specific Aims: The specific aims were to: Describe the available research on clinical inertia and interventions that have been implemented to reduce it. Analyze various behavioral theories that explain and predict self-care practices in diabetes in order to develop a conceptual model on which to base an investigation of predictors of readiness to initiate insulin therapy in type 2 diabetics. Determine predictors of readiness to initiate insulin therapy in patients with T2DM when oral medications fail to control hyperglycemia using the conceptual model based on Self-Determination Theory (SDT) as a framework. Results: A review of research articles published from 1990 to 2010 concluded that clinical inertia of primary care providers treating T2DM resulted in a majority of patients experiencing unnecessary chronic uncontrolled hyperglycemia. Behavioral theories were analyzed for their ability to predict self-care behaviors in type 2 diabetics. A conceptual model was developed based on the major constructs of SDT in order to guide the design of study to investigate predictors of readiness to begin insulin therapy in T2DM. Finally, a descriptive, correlational study was performed to determine readiness to initiate insulin therapy in patients with T2DM when oral medications fail to control hyperglycemia. Results of the study revealed that participants who had a friend or family using insulin were 5.5 times more likely to rate their readiness to initiate insulin as high than those who had neither (p=.020). In addition, those with greater negative beliefs and attitudes toward insulin therapy were more likely to rate their readiness to initiate insulin as low (p=.012). A majority (58%) of participants rated their readiness to begin insulin therapy as immediate if it would give them better control over their hyperglycemia. The study also confirmed findings from previous studies that clinical inertia was present in this setting.

Given the high and increasing social, health and economic costs of type 2 diabetes, early diagnosis and prevention are critical. Insulin sensitivity and insulin secretion are important etiological factors of type 2 diabetes and are used to define an individual’s risk or progression to the disease state. The dynamic insulin sensitivity and secretion test (DISST) concurrently measures insulin sensitivity and insulin secretion. The protocol uses glucose and insulin boluses as stimulus, and the participant response is observed during a relatively short protocol via glucose, insulin and C-peptide assays. In this research, the DISST insulin sensitivity value was successfully validated against the gold standard euglycaemic clamp with a high correlation (R=0.82), a high insulin resistance diagnostic equivalence (ROC c-unit=0.96), and low bias (-10.6%). Endogenous insulin secretion metrics obtained via the DISST were able to describe clinically important distinctions in participant physiology that were not observed with euglycaemic clamp, and are not available via most established insulin sensitivity tests. The quick dynamic insulin sensitivity test (DISTq) is a major extension of the DISST that uses the same protocol but uses only glucose assays. As glucose assays are usually available immediately, the DISTq is capable of providing insulin sensitivity results immediately after the final blood sample, creating a real-time clinical diagnostic. The DISTq correlated well with the euglycaemic clamp (R=0.76), had a high insulin resistance diagnostic equivalence (ROC c-unit=0.89), and limited bias (0.7%). These DISTq results meet or exceed the outcomes of most validation studies from established insulin sensitivity tests such as the IVGTT, HOMA and OGTT metrics. Furthermore, none of the established insulin sensitivity tests are capable of providing immediate or real-time results. Finally, and most of the established tests require considerably more intense clinical protocols than the DISTq. A range of DISST-based tests that used the DISST protocol and varying assay regimens were generated to provide optimum compromises for any given clinical or screening application. Eight DISST-based variants were postulated and assessed via their ability to replicate the fully sampled DISST results. The variants that utilised insulin assays correlated well to the fully sampled DISST insulin sensitivity values R~0.90 and the variants that assayed C-peptide produced endogenous insulin secretion metrics that correlated well to the fully-sampled DISST values (R~0.90 to 1). By taking advantage of the common clinical protocol, tests in the spectrum could be used in a hierarchical system. For example, if a DISTq result is close to a diagnostic threshold, stored samples could be re-assayed for insulin, and the insulin sensitivity value could be ‘upgraded’ without an additional protocol. Equally, adding C-peptide assays would provide additional insulin secretion information. Importantly, one clinical procedure thus yields potentially several test results. In-silico investigations were undertaken to evaluate the efficacy of two additional, specific DISTq protocol variations and to observe the pharmacokinetics of anti-diabetic drugs. The first variation combined the boluses used in the DISTq and reduced the overall test time to 20 minutes with only two glucose assays. The results of this investigation implied no significant degradation of insulin sensitivity values is caused by the change in protocol and suggested that clinical trials of this protocol are warranted. The second protocol variant added glucose content to the insulin bolus to enable observation of first phase insulin secretion concurrently with insulin sensitivity from glucose data alone. Although concurrent observation was possible without simulated assay noise, when clinically realistic noise was added, model identifiability was lost. Hence, this protocol is not recommended for clinical investigation. Similar analyses are used to apply the overall dynamic, model-based clinical test approach to other therapeutics. In-silico analysis showed that although the pharmacokinetics of insulin sensitizers drugs were described well by the dynamic protocol. However, the pharmacokinetics of insulin secretion enhancement drugs were less observable. The overall thesis is supported by a common model parameter identification method. The iterative integral parameter identification method is a development of a single, simple integral method. The iterative method was compared to the established non-linear Levenberg-Marquardt parameter identification method. Although the iterative integral method is limited in the type of models it can be used with, it is more robust, accurate and less computationally intense than the Levenberg-Marquardt method. Finally, a novel, integral-based method for the evaluation of a-priori structural model identifiability is also presented. This method differs significantly from established, derivative based approaches as it accounts for sample placement, measurement error, and probable system responses. Hence, it is capable of defining the true nature of identifiability, which is analogous, not binary as assumed by the established methods. The investigations described in this thesis were centred on model-based insulin sensitivity and secretion identification from dynamic insulin sensitivity tests with a strong focus on maximising clinical efficacy. The low intensity and informative DISST was successfully validated against the euglycaemic clamp. DISTq further reduces the clinical cost and burden, and was also validated against the euglycaemic clamp. DISTq represents a new paradigm in the field of low-cost insulin sensitivity testing as it does not require insulin assays. A number of in-silico investigations were undertaken and provided insight regarding the suitability of the methods for clinical trials. Finally, two novel mathematical methods were developed to identify model parameters and asses their identifiability, respectively.

Placental insufficiency-induced intrauterine growth restriction (IUGR) increases risk of mortality and morbidity in newborn infants and domestic animals. IUGR fetuses are typically exposed to prolonged hypoxemia, hypoglycemia, and hypercatecholaminemia, which results in perinatal pancreatic β-cell dysfunction. Recent evidence indicates that chronic exposure to norepinephrine in utero suppresses insulin secretion through α2-adrenergic receptors (ARs), but if the adrenergic actions are blocked compensatory hyper insulin secretion response is observed in the IUGR sheep fetus. In the current studies, we demonstrate that chronic NE exposure alone can produce the compensatory enhancement of β-cell responsiveness following termination of a chronic NE infusion. In the fetus NE was continuously infused at 1-4 μg/min for seven days starting at 131 days of gestational age (term = 145 days). During treatment, NE infused fetuses had higher (P < 0.05) plasma NE concentrations and lower (P < 0.01) insulin concentrations than vehicle infused control fetuses. Glucose stimulated insulin secretion (GSIS), which measures β-cell function, prior to NE treatment was not different between treatments. However, insulin concentrations during hyperglycemic steady state period of GSIS studies and area under the curve of glucose-potentiated arginine-induced insulin secretion were higher (P < 0.01) than control values and this augmentation was confirmed at 3 hours, 24 hours, and five days in NE-infused fetuses after discontinuing the infusion. Pancreatic islets isolated within 10 hours post NE infusion had lower (P < 0.05) mRNA expression of α1D (58%), α2A (43%), α2C (42%), α1 (67%) adrenergic receptors (ARs), and uncoupling protein 2 (40%) compared to islets from controls. Isolated islets from NE-infused fetuses 5 days after NE treatment had lower (P < 0.05) inhibitory responsiveness from NE and a greater (P < 0.05) maximal insulin release with glucose simulation in static incubations compared to controls. These findings show that following chronic NE exposure insulin secretion responsiveness was augmented and was coupled with desensitized adrenergic signaling. Moreover, this compensatory β-cell enhancement persists for days indicating chronic NE exposure permanently alters β-cell responsiveness.

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.