László Barkai

Prospective assessment of severe hypoglycaemia in diabetic children and adolescents with impaired and normal awareness of hypoglycaemia

Summary To establish whether impaired hypoglycaemic awareness is associated with increased rate of severe hypoglycaemia and to assess clinical predictors of severe episodes without warning symptoms a prospective study of 130 insulin-dependent diabetic children and adolescents was undertaken for 1 year. Using a structured questionnaire, 48 patients reported impaired awareness and 82 reported normal awareness of hypoglycaemia at baseline of the study. The two groups did not differ regarding clinical and metabolic characteristics. Episodes of severe hypoglycaemia were recorded for 1 year. The rate of severe hypoglycaemia was higher in the group with impaired awareness than in the group with normal awareness (p < 0.0001). Of the severe hypoglycaemic episodes, 34.0 % developed without warning symptoms. Patients with impaired awareness experienced more severe episodes without warning symptoms than those with normal awareness (p = 0.0054). Severe hypoglycaemia occurred more frequently in patients with impaired awareness aged 6 years and less (p = 0.0041) than in older counterparts. Impaired awareness reported at baseline [adjusted odds ratio (OR): 5.8; p = 0.0021], age 6 years or less (3.4; p = 0.0121), previous severe episode (4.8; p = 0.0043) and more than 5 % of home blood glucose readings 3.3 mmol/l or less in the preceding month (4.2; p = 0.0211) proved to be independently predictive of severe hypoglycaemic events without warning symptoms. In conclusion, impaired hypoglycaemic awareness is associated with an increased rate of severe hypoglycaemia in diabetic children and adolescents. One third of severe episodes developed without warning symptoms. Impaired awareness, young age and recent biochemical or severe hypoglycaemias are independent risk factors for such episodes. Avoidance of hypoglycaemia should be a priority in pre-school children with diabetes. [Diabetologia (1998) 41: 898–903]

Cardiovascular autonomic dysfunction in diabetes mellitus.

The aim was to assess cardiovascular autonomic dysfunction in children and adolescents with diabetes mellitus. A total of 110 children and adolescents with type 1 (insulin dependent) diabetes (aged 6 to 18 years) and 130 non-diabetic controls were studied. Resting heart rate, heart rate variation to deep breathing, heart rate response to standing from a lying position, fall in systolic blood pressure on standing, and rise in diastolic blood pressure during sustained handgrip were measured. A reference range of results was obtained in the controls. Diabetic children had significantly increased resting heart rate [92.4 (SEM 2.5) v 84.2 (2.2) beats/min], decreased deep breathing heart rate variation [25.3 (0.9) v 32.8 (0.6) beats/min], and lower standing/lying heart rate ratio [1.23 (0.04) v 1.31 (0.03)] compared with controls. 46 diabetic children (42%) had at least one abnormal autonomic test result. Of these, 20 (15%) had only one abnormal test and 26 (24%) had two or more abnormal tests. Using multiple logistic regression analysis, longer diabetes duration and worse long term metabolic control were independently predictive of cardiovascular autonomic dysfunction as the dependent variable [adjusted OR (95% CI): 2.9 (1.1-5.9) and 3.3 (1.2-6.4), respectively]. Cardiovascular autonomic dysfunction is not rare in children with diabetes. Efforts should be made to maintain the best metabolic control to prevent or delay these complications.

Diabetes as a case study of chronic disease management with a personalized approach: The role of a structured feedback loop

As non-communicable or chronic diseases are a growing threat to human health and economic growth, political stakeholders are aiming to identify options for improved response to the challenges of prevention and management of non-communicable diseases. This paper is intended to contribute ideas on personalized chronic disease management which are based on experience with one major chronic disease, namely diabetes mellitus. Diabetes provides a pertinent case of chronic disease management with a particular focus on patient self-management. Despite advances in diabetes therapy, many people with diabetes still fail to achieve treatment targets thus remaining at risk of complications. Personalizing the management of diabetes according to the patients individual profile can help in improving therapy adherence and treatment outcomes. This paper suggests using a six-step cycle for personalized diabetes (self-)management and collaborative use of structured blood glucose data. E-health solutions can be used to improve process efficiencies and allow remote access. Decision support tools and algorithms can help doctors in making therapeutic decisions based on individual patient profiles. Available evidence about the effectiveness of the cycles constituting elements justifies expectations that the diabetes management cycle as a whole can generate medical and economic benefit.

Enhanced Progression of Urinary Albumin Excretion in IDDM During Puberty

OBJECTIVE To determine whether the progression of urinary albumin excretion rate (AER) is higher during puberty than before or after this period. RESEARCH DESIGN AND METHODS A prospective study was conducted in which normoalbuminuric prepubertal (n = 20), pubertal (n = 28), and postpubertal (n = 26) IDDM groups matched for diabetes duration and long-term metabolic control were followed for 3 years. At 6-month intervals, 24-h urine collection was used to determine AER. RESULTS AER increased significantly over a period of 3 years in the pubertal (P = 0.001) and postpubertal (P = 0.003) subjects but not in prepubertal subjects. The annual progression of AER was significantly higher in the pubertal group than in the prepubertal (P = 0.001) or postpubertal (P = 0.001) groups. Six pubertal, two postpubertal, and none of the prepubertal subjects developed microalbuminuria (AER ≥ 20 μg/min on two consecutive occasions) over a 3-year period (P = 0.047). Multiple logistic regression analysis showed that the risk of development of microalbuminuria was increased in pubertal subjects compared with the prepubertal and postpubertal subjects (adjusted relative risk [95% CI]: 4.3 [1.5–9.3], P = 0.012, and 2.1 [1.1–5.0], P = 0.023, respectively). CONCLUSIONS Puberty represents an independent risk of the development of microalbuminuria in diabetes. This findings suggests that the endocrine changes of puberty lead to an accelerated process of early kidney damage in diabetes. In pediatric diabetes care, screening for microalbuminuria is needed soon after the onset of puberty.

Peripheral sensory nerve dysfunction in children and adolescents with Type 1 diabetes mellitus

The aim of the present study was to investigate peripheral sensory nerve function in diabetic children and adolescents without neurological symptoms. Ninety‐two children and adolescents with Type 1 (insulin‐dependent) diabetes mellitus (mean ± SD age: 14.2 ± 2.1 years, diabetes duration: 5.8 ± 3.0 years) and 80 healthy control subjects (age: 13.8 ± 2.2 years) matched for age, sex, body mass index, and height standard deviation score were involved in the study. Using a sine‐wave transcutaneous stimulator, current perception threshold (CPT) testing at 2000, 250 and 5 Hz was performed on the left median and peroneal nerves. Diabetic children had increased CPT at 2000 Hz on both nerves as compared to the control group (median (interquartile range), median nerve: 2.43 (2.20–3.43) vs 1.80 (1.51–2.60) mA, p = 0.02; peroneal nerve: 3.51 (2.81–4.82) vs 2.70 (2.04–3.70) mA, p = 0.01). Twenty‐one (23 %) of patients had CPT values higher than that of any healthy individual. Of these, elevated CPT was observed in 9 (9.8 %) patients on the median nerve, in 8 (8.7 %) patients on the peroneal nerve, and in 4 (4.3 %) patients on both median and peroneal nerves. Using multiple logistic regression analysis, worse long‐term metabolic control and advanced puberty were independently predictive of peripheral sensory nerve dysfunction as the dependent variable (adjusted OR (95 % CI): 3.4 (1.2–6.2), p = 0.01, and 2.8 (1.1–5.6), p = 0.03, respectively). In conclusion, evidence of peripheral sensory nerve dysfunction is not rare in children and adolescents with diabetes and can be demonstrated by CPT testing in asymptomatic patients. Poor metabolic control is a risk factor for such subclinical neuropathy, and pubertal development may be involved in the pathogenesis of diabetic peripheral neuropathy.

Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma

BACKGROUND Ciclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning. OBJECTIVE This 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared the efficacy and safety of ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma. METHODS Seven hundred and forty-four patients (aged 6-11 years) were randomized to ciclesonide (80 or 160 microg once daily) or fluticasone propionate (88 microg twice daily), following a 2-4-week run-in. Efficacy measurements included forced expiratory flow in 1s (FEV(1)), morning peak expiratory flow (PEF), asthma symptom scores, rescue medication use and quality of life. Systemic effect was assessed by 24-hour urine free cortisol adjusted for creatinine. RESULTS FEV(1) and morning PEF increased from baseline in all groups (p<0.0001). Ciclesonide 160 microg was not inferior to fluticasone propionate 176 microg for FEV(1) (p=0.0030, one-sided). In all groups, asthma symptom score sums and rescue medication use significantly improved (p<0.0001). The percentages of asthma symptom-, rescue medication- and nocturnal awakening-free days were high, with no significant differences between treatments. Quality of life scores improved with all treatments (p<0.0001). A significant dose-response occurred between low and higher doses of ciclesonide for exacerbations and asthma control definitions. The incidences of adverse events were comparable across treatments. Urine free cortisol levels decreased significantly with fluticasone propionate (p=0.0103), but not with ciclesonide. CONCLUSION Once-daily ciclesonide has a clinical effect similar to that of fluticasone propionate, but does not suppress cortisol excretion, in children with moderate and severe asthma.

Reduced physical fitness in children and adolescents with type 1 diabetes

To evaluate motor performance and cardiorespiratory function in youths with type 1 diabetes in comparison with age‐matched control groups and to analyze the influence of physical activity level, anthropometric and physical fitness parameters on long‐term metabolic control.

Cardiometabolic risk factors and insulin resistance in obese children and adolescents: relation to puberty

The prevalence of obesity with concomitant increasing risk for having cardiometabolic diseases is rising in the childhood population. Insulin resistance has a key role in metabolic changes in these children. Insulin levels elevate as puberty commences in every individual.

Allosteric interactions within the AT1 angiotensin receptor homodimer: Role of the conserved DRY motif

G protein coupled receptor (GPCR) dimerization has a remarkable impact on the diversity of receptor signaling. Allosteric communication between the protomers of the dimer can alter ligand binding, receptor conformation and interactions with different effector proteins. In this study we investigated the allosteric interactions between wild type and mutant protomers of type 1 angiotensin receptor (AT₁R) dimers transiently expressed in CHO cells. In our experimental setup, one protomer of the dimer was selectively stimulated and the β-arrestin2 binding and conformation alteration of the other protomer was followed. The interaction between β-arrestin2 and the non-stimulated protomer was monitored through a bioluminescence resonance energy transfer (BRET) based method. To measure the conformational alterations in the non-stimulated protomer directly, we also used a BRET based intramolecular receptor biosensor, which was created by inserting yellow fluorescent protein (YFP) into the 3rd intracellular loop of AT₁R and fusing Renilla luciferase (RLuc) to its C terminal region. We have detected β-arrestin2 binding, and altered conformation of the non-stimulated protomer. The cooperative ligand binding of the receptor homodimer was also observed by radioligand dissociation experiments. Mutation of the conserved DRY sequence in the activated protomer, which is also required for G protein activation, abolished all the observed allosteric effects. These data suggest that allosteric interactions in the homodimers of AT₁R significantly affect the function of the non-stimulated protomer, and the conserved DRY motif has a crucial role in these interactions.

Self-Monitoring of Blood Glucose in Diabetes: From Evidence to Clinical Reality in Central and Eastern Europe—Recommendations from the International Central-Eastern European Expert Group

Self-monitoring of blood glucose (SMBG) is universally considered to be an integral part of type 1 diabetes management and crucial for optimizing the safety and efficacy of complex insulin regimens. This extends to type 2 diabetes patients on intensive insulin therapy, and there is also a growing body of evidence suggesting that structured SMBG is beneficial for all type 2 diabetes patients, regardless of therapy. However, access to SMBG can be limited in many countries in Central and Eastern Europe. A consensus group of diabetes experts from 10 countries in this region (with overlapping historical, political, and social environments)--Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Serbia, Slovakia, Slovenia, and Ukraine--was formed to discuss the role of SMBG across the spectrum of patients with diabetes. The group considered SMBG to be an essential tool that should be accessible to all patients with diabetes, including those with non-insulin-treated type 2 diabetes. The current article summarizes the evidence put forward by the consensus group and provides their recommendations for the appropriate use of SMBG as part of individualized patient management. The ultimate goal of these evidence-based recommendations is to help patients and providers in Central and Eastern Europe to make optimal use of SMBG in order to maximize the efficacy and safety of glucose-lowering therapies, to prevent complications, and to empower the patient to play a more active role in the management of their diabetes.