Methodological and Clinical Studies on Insulin Resistance in Childhood

Insulin resistance is a condition in which adequate amounts of insulin fail to give an adequate response in target tissues. This thesis is based on five different studies, aiming to investigate different aspects of insulin resistance and the assessment methods thereof in children and in adults. The rationale for performing these studies is that insulin resistance is a key component of the metabolic syndrome and crucial in the development of type 2 diabetes. Concomitant with the increase in obesity worldwide, insulin resistance has become an important and increasingly more common pathological condition, which needs to be efficiently diagnosed and treated. In Study I we investigated proxy measures of insulin sensitivity assessment as compared to the reference standard Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) in obese children and adolescents. The Homeostasis model assessment (HOMA-IR), the Quantitative Insulin Sensitivity Check Index (QUICKI) and fasting insulin were compared to the Sensitivity index (Si) of the FSIVGTT with the sample stratified by sex, puberty status and median of Si. This study demonstrated that fasting indices have a low validity in identifying insulin resistance in this group, and we generally discourage the use of these methods. Study II was performed in the same obese pediatric population with the aim of showing that HOMA-IR and QUICKI are interchangeable. The numerous comparisons between these methods should thus be avoided. Also, the high physiologic fluctuations in insulin levels further undermine the robustness of these methods. Studies I-II provide evidence that fasting indices as simple screening tools for insulin resistance in children and adolescents should, if used at all, be interpreted with caution. The third and fourth studies were performed with the aim of developing and validating models for the kinetics of C-peptide and Nonesterified fatty acids (NEFAs) respectively during an intravenous glucose challenge. An insulin modified FSIVGTT was performed on healthy normal weight young adults, with sampling of C-peptide and NEFAs included at all sampling points. In Study III a model was developed which assesses first phase C-peptide secretion, indirectly also estimating insulin secretion. Assessing insulin secretion is useful in understanding diabetes development, in assessing progression to a diabetic state and in monitoring the effect of therapeutic regimens. In Study IV a novel NEFA model was validated on a subject level, with curves well fitting the diverse range of NEFA responses to a glucose challenge. Validation of the model using static parameters derived from the dynamic counterparts showed high correlation of the model’s dynamic parameters to static parameters. NEFA levels are elevated in insulin resistance and affect glucose homeostasis on both the short and long term. This NEFA model may provide a complementary way of estimating insulin sensitivity, with focus on the lipotoxic aspect of diabetes development. Study V provides a clinical perspective on insulin sensitivity by examining metabolic features of a cohort of long-term cancer survivors treated with stem cell transplantation including total body irradiation, as compared to healthy controls matched for age and sex. The study shows an intact β-cell function, but decreased insulin sensitivity, after a median follow-up of 18 years. An adverse body composition with higher proportion fat mass than in controls was seen in cancer survivors. Lower levels of growth hormone, higher levels of leptin and lower levels of adiponectin were found, all of which may explain the adverse body composition and the reduced insulin sensitivity. In summary, several aspects of insulin resistance and insulin secretion have been studied. Existing methods of insulin secretion and sensitivity assessment have been investigated and implemented, and new methods described. We hope this will contribute further knowledge on diabetes development and treatment strategies

Which diabetes specific patient reported outcomes should be measured in routine care? A systematic review to inform a core outcome set for adults with Type 1 and 2 diabetes mellitus: The European Health Outcomes Observatory (H2O) programme

Diabetes mellitus; Patient reported outcome measures; Type 1Diabetis mellitus; Mesures de resultat informades pel pacient; Tipus 1Diabetes mellitus; Medidas de resultado informadas por el paciente; Tipo 1Objectives The objective was to identify candidate patient reported outcomes with potential to inform individual patient care and service development for inclusion in a digital outcome set to be collected in routine care, as part of an international project to enhance care outcomes for people with diabetes. Methods PubMed, COSMIN and COMET databases were searched. Published studies were included if they recommended patient reported outcomes that were clinically useful and/or important to people with diabetes. To aid selection decisions, recommended outcomes were considered in terms of the evidence endorsing them and their importance to people with diabetes. Results Twenty-seven studies recommending 53 diabetes specific outcomes, and patient reported outcome measures, were included. The outcomes reflected the experience of living with diabetes (e.g. psychological well-being, symptom experience, health beliefs and stigma) and behaviours (e.g. self-management). Diabetes distress and self-management behaviours were most endorsed by the evidence. Conclusions The review provides a comprehensive list of candidate outcomes endorsed by international evidence and informed by existing outcome sets, and suggestions for measures. Practice implications The review offers evidence to guide clinical application. Integrated measurement of these outcomes in care settings holds enormous potential to improve provision of care and outcomes in diabetes.H2O has received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No 945345-2. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, EFPIA, Trial Nation and JDRF International. The funding source was not involved in the study design; the collection, analysis, and interpretation of data; the writing of the report, or the decision to submit the article for publication. The manuscript reflects only the author's view. The IMI, the European Union, EFPIA, or any Associated Partners are not responsible for any use that may be made of the information it contains

Transthyretin constitutes a functional component in pancreatic β-cell stimulus-secretion coupling

Transthyretin (TTR) is a transport protein for thyroxine and, in association with retinol-binding protein, for retinol, mainly existing as a tetramer in vivo. We now demonstrate that TTR tetramer has a positive role in pancreatic β-cell stimulus-secretion coupling. TTR promoted glucose-induced increases in cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) and insulin release. This resulted from a direct effect on glucose-induced electrical activity and voltage-gated Ca(2+) channels. TTR also protected against β-cell apoptosis. The concentration of TTR tetramer was decreased, whereas that of a monomeric form was increased in sera from patients with type 1 diabetes. The monomer was without effect on glucose-induced insulin release and apoptosis. Thus, TTR tetramer constitutes a component in normal β-cell function. Conversion of TTR tetramer to monomer may be involved in the development of β-cell failure/destruction in type 1 diabetes