Differences in endothelial function between patients with type 1 and type 2 diabetes: effects of red blood cells and arginase.

The mechanisms underlying endothelial dysfunction in type 1 and type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and 26 patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV), were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared to patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments whereas RBCs from patients with T1DM did not affect EDR nor EIDR. This study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms.

Standardising personalised diabetes care across European health settings: A person-centred outcome set agreed in a multinational Delphi study.

OBJECTIVE: Standardised person-reported outcomes (PRO) data can contextualise clinical outcomes enabling precision diabetes monitoring and care. Comprehensive outcome sets can guide this process, but their implementation in routine diabetes care has remained challenging and unsuccessful at international level. We aimed to address this by developing a person-centred outcome set for Type 1 and Type 2 diabetes, using a methodology with prospects for increased implementability and sustainability in international health settings. METHODS: We used a three-round questionnaire-based Delphi study to reach consensus on the outcome set. We invited key stakeholders from 19 countries via purposive snowball sampling, namely people with diabetes (N = 94), healthcare professionals (N = 65), industry (N = 22) and health authorities (N = 3), to vote on the relevance and measurement frequency of 64 previously identified clinical and person-reported outcomes. Subsequent consensus meetings concluded the study. RESULTS: The list of preliminary outcomes was shortlisted via the consensus process to 46 outcomes (27 clinical outcomes and 19 PROs). Two main collection times were recommended: (1) linked to a medical visit (e.g. diabetes-specific well-being, symptoms and psychological health) and (2) annually (e.g. clinical data, general well-being and diabetes self management-related outcomes). CONCLUSIONS: PROs are often considered in a non-standardised way in routine diabetes care. We propose a person-centred outcome set for diabetes, specifically considering psychosocial and behavioural aspects, which was agreed by four international key stakeholder groups. It guides standardised collection of meaningful outcomes at scale, supporting individual and population level healthcare decision making. It will be implemented and tested in Europe as part of the H2O project.

High prevalence of prediabetes in a Swedish cohort of severely obese children.

OBJECTIVE: In this cohort of severely obese children and adolescents in Sweden we investigate the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance, (IGT) and silent type 2 diabetes (T2D), in relation to insulin resistance, insulin secretion, disposition index and cardio respiratory fitness. METHODS: A total of 134 obese children and adolescents [57 females, 77 males, age 13.7 ± 2.7, body mass index (BMI) standard deviation score (SDS) 3.6 ± 0.6] consecutively referred to the National Childhood Obesity Centre performed an oral glucose tolerance test (OGTT), frequently sampled intravenous glucose tolerance test (fs-IVGTT), dual X-ray absorptiometry (DEXA), bicycle ergometer test and fasting levels of glucose, insulin and c-peptide were obtained and homeostatic model of insulin resistance (HOMA-IR) was calculated. RESULTS: Isolated impaired fasting glucose (i-IFG) were present in 35.8 and 6% had isolated IGT. Combined IGT and IFG were present in 14.2%. The subjects with combined IGT/IFG had significantly lower acute insulin response (AIR) compared with subjects who had normal glucose metabolism or i-IFG (p < 0.05). Among the prepubertal children (n = 24), 25% (6/24) had i-IFG and 25% (6/24) had IGT/IFG and it was predominantly males. Disposition index was the major determinant of 2-h glucose levels (ß = -0.49, p = 0.0126). No silent diabetes was detected. CONCLUSION: In this cohort of severely obese children and adolescents the prevalence of prediabetes was very high. IFG was two times higher in this cohort of severely obese children than in a recently published unselected cohort of obese children in Sweden. In spite of the high prevalence of prediabetes, no subjects with silent diabetes were found.

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.

OBJECTIVES: 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.

HOMA-IR and QUICKI: decide on a general standard instead of making further comparisons.

AIM: To limit further comparisons between the two fasting indices Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI), and to examine their robustness in assessing insulin sensitivity. METHODS: A total of 191 obese children and adolescents (age 13.9 ± 2.9 years, BMI SDS 6.1 ± 1.6), who had undergone a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), were included. Receiver operating characteristic curve (ROC) analysis was used to compare indices in detecting insulin resistance and Bland-Altman plots to investigate agreement between three consecutive fasting samples when compared to using single samples. RESULTS: ROC analysis showed that the diagnostic accuracy was identical for QUICKI and HOMA-IR [area under the curve (AUC) boys 0.80, 95%CI 0.70-0.89; girls 0.80, 0.71-0.88], while insulin had a nonsignificantly lower AUC (boys 0.76, 0.66-0.87; girls 0.75, 0.66-0.84). Glucose did not perform better than chance as a diagnostic test (boys 0.47, 0.34-0.60; girls 0.57, 0.46-0.68). Indices varied with consecutive sampling, mainly attributable to fasting insulin variations (mean maximum difference in HOMA-IR -0.8; -0.9 to -0.7). CONCLUSIONS: Using both HOMA-IR and QUICKI in further studies is superfluous as these indices function equally well as predictors of the FSIVGTT sensitivity index. Focus should be on establishing a general standard for research and clinical purposes.

[One steroid injection in combination with HIV-medication resulted in a total adrenal insufficiency]. / Steroid­injektion i kombination med hivläkemedel gav total binjure­barkssvikt - Fallbeskrivning visar på risken för interaktion.

This case report describes a woman living with HIV on treatment including ritonavir-boosted darunavir, who suffered complete secondary adrenal insufficiency after a single intra-articular injection of the corticosteroid triamcinolone. There is a known pharmacological interaction between ritonavir and those corticosteroids which are metabolised by the CYP3A4 pathway. This interaction may lead to complete adrenal insufficiency, which is a life-threatening condition. Adrenal insufficiency must be promptly diagnosed and hydrocortisone replacement started. People living with HIV should be on lifelong antiretroviral treatment, and corticosteroids are common in the treatment of many different conditions seen by various specialists. This case highlights that not only physicians engaged in HIV treatment need to be aware of this important interaction.

Adiposity measures as indicators of metabolic risk factors in adolescents.

AIM: To examine the relation between adiposity assessment methods (percentage body fat (%BF), BMI, and waist circumference (WC)) and individual metabolic risk factors (f-insulin, HDL cholesterol, triglycerides) and a combined measure of metabolic risk. METHODS: Crosssectional study of 300 males (BMI 20.8 +/- 3.0 kg/m(2)) and females (BMI 21.3 +/- 2.9 kg/m(2)) 17 years of age. F-insulin and components of the metabolic syndrome defined by the International Diabetes Federation (IDF) were used as metabolic risk indicators, with samples stratified into BMI, %BF, and WC groups, respectively. Diagnostic accuracy was expressed as the area under the ROC curve (AUC). RESULTS: In males, diagnostic accuracy for HDL and f-insulin was poor to fair for BMI (AUC 0.70, p = 0.001; 0.60, p = 0.22), WC (0.68, p = 0.003; 0.63, p = 0.11), and %BF (0.65, p = 0.009; 0.66, p = 0.04). The diagnostic accuracy for triglycerides was greater for all three measures (BMI 0.92, WC 0.95, %BF 0.87; all p < 0.001). For females, neither test performed better than chance for f-insulin and HDL, and only %BF performed better than chance for triglycerides (0.65, p = 0.08). All three measures exhibited higher accuracy for presence of > or =2 metabolic risk factors (AUCs 0.76-0.91, p < 0.001) in both sexes. CONCLUSION: %BF was not superior to BMI and WC for detecting metabolic risk in the general adolescent population.

Alternative methods of insulin sensitivity assessment in obese children and adolescents.

OBJECTIVE: To validate fasting indexes against minimal model analysis (MMOD) of the frequently sampled intravenous glucose tolerance test (FSIVGTT) in an obese pediatric population. RESEARCH DESIGN AND METHODS: FSIVGTT-MMOD results were compared with homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin with the sample stratified by sex, puberty, and sensitivity index (S(i)) median in 191 children (82 males and 109 females, 13.9 +/- 2.9 years of age, BMI 36.9 +/- 6.2 kg/m(2), BMI SD score 6.1 +/- 1.6). RESULTS: Across pubertal groups, correlation coefficients between S(i) and HOMA-IR ranged from -0.43 to -0.78 in males and from -0.53 to -0.57 in females (age and BMI adjusted, P < 0.05 in all instances). Similar results were seen for fasting insulin. In females, the relationship was significantly weaker in more-insulin-resistant subjects. CONCLUSIONS: The validity of fasting indexes in explaining S(i) was sex dependent, varied with pubertal stage, and in females was influenced by degree of insulin sensitivity. In obese pediatric populations, we generally discourage the use of fasting indexes, although the validity varies within subgroups.

Transthyretin constitutes a functional component in pancreatic beta-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 beta-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 beta-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 beta-cell function. Conversion of TTR tetramer to monomer may be involved in the development of beta-cell failure/destruction in type 1 diabetes.