Immunogenicity of different brands of human insulin and rapid‐acting insulin analogs in insulin‐naïve children with type 1 diabetes

Mianowska B, Szadkowska A, Pietrzak I, Zmys?owska A, Wegner O, Tomczonek J, Bodalski J, M?ynarski W. Immunogenicity of different brands of human insulin and rapid‐acting insulin analogs in insulin‐naïve children with type 1 diabetes. Aims: To determine (i) whether insulin preparations produced by three companies induce the same immune responses in insulin‐naïve children with type 1 diabetes (T1DM); (ii) if switching from human insulin to rapid‐acting insulin analogs influences this immune response; and (iii) if different insulin brands produce different clinical results during the first 2 yr after T1DM diagnosis. Methods: Insulin antibodies (IA) were measured for 140 patients aged 1.4–17.6 yr. Regular human insulin, neutral protamine Hagedorn (NPH) human insulin, and rapid‐acting insulin analogs (lispro or aspart) taken by the patients were produced by one of three companies: Bioton, Poland (A), Eli Lilly, USA (B) and NovoNordisk, Denmark (C). Results: Positive IA levels were found in 112 patients (80.0%) at baseline and in 137 (97.9%) at 6 and at 24 months after T1DM diagnosis. There was no difference in IA levels among patients taking insulin preparations produced by different companies at 6 months (mean ± SD, A 27.8 ± 15.7%; B 25.3 ± 15.4%; C 24.5 ± 14.2; p = 0.54) or at 24 months (A 25.6 ± 17.8%; B29.6 ± 17.0%; C 26.2 ± 17.0%; p = 0.52); HbA_1c and daily insulin dose did not differ significantly either. After 24 months, IA levels were similar for those who had used human insulin (mean ± SD, 25.7 ± 17.2%) and for those that had added rapid‐acting analogs (28.1 ± 17.3%, p = 0.41). Conclusions: Three brands of insulin preparations did not differ with respect to immunogenicity. Rapid‐acting analogs did not increase IA levels in patients previously treated with human insulin only. Patients using insulin preparations of different brands did not differ with respect to daily insulin dose or HbA_1c.     

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta‐analysis

This systematic review and meta‐analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity—following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non‐diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA‐IR]) were included in the meta‐analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA‐IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA‐IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA‐IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity.     

Childhood hypo‐adiponectinaemia but not hyper‐leptinaemia is associated with insulin insensitivity 6 years later

Kynde I, Heitmann BL, Bygbjerg IC, Andersen LB, Helge JW. Childhood hypo‐adiponectinaemia but not hyper‐leptinaemia is associated with insulin insensitivity 6 years later. Background: Biomarkers of metabolism and inflammation may predict children with increased diabetes risk. Objective: To study plasma adiponectin, leptin, IL‐8, and hepatocyte growth factor (HGF) in childhood and their independent associations with insulin insensitivity, cross‐sectional and in 6‐yr prospective. Subjects: Danish 8‐ to 10‐yr‐olds and 14‐ to 16‐yr‐olds from the European Youth Heart Studies I and II. Methods: Cross‐sectional (n = 386) and prospective (n = 246) linear regressions of baseline concentrations of plasma biomarkers and insulin insensitivity at baseline and 6 yr later. Adjustments were made at four progressive steps for sex, sexual maturity, body mass index (BMI), other biomarkers, physical activity, and school location as well as baseline insulin insensitivity in prospective analyses. Insulin insensitivity was measured using homeostasis model assessment standardized to the sample mean [homoestasis model assessment (HOMA) Z‐scores]. Plasma biomarkers were quantified using solid‐phase protein immunoassays. Overweight was defined as the highest BMI tertile. Results: Among overweight but not lean children at baseline, one SD difference in baseline plasma adiponectin was associated with ?0.41 SD difference in HOMA Z‐scores 6 yr later (p = 0.006). At baseline, one SD difference in plasma leptin was associated with 0.36 SD difference in HOMA Z‐scores (p =< 0.0001) among 8‐ to 10‐yr‐olds, but a prospective association was not found. Conclusions: We found a direct relationship between childhood hypo‐adiponectinaemia and insulin insensitivity in adolescence. This association was stronger for overweight than for normal weight children. Hyper‐leptinaemia was associated with concurrent insulin insensitivity at baseline but not 6 yr later.     

Severe hypoglycemia secondary to methimazole‐induced insulin autoimmune syndrome in a 16 year old African‐American male

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African‐American adolescent. A 16‐yr‐old healthy African‐American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio‐ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia.     

Relationship between resistin and aPAI‐1 levels with insulin resistance in Saudi children

Background: Association of resistin with insulin resistance (IR) in humans is still controversial and few studies have investigated the association of plasminogen activator inhibitor‐1 (PAI‐1) with IR in children. The purpose of the present study was therefore to evaluate serum levels of resistin and active PAI‐1 (aPAI‐1) in Saudi children and their association with the various obesity‐related complications. Methods: In this cross‐sectional study, 73 boys and 77 girls with varying body mass index (BMI) were recruited. They were assessed for anthropometric measures and fasting serum levels of glucose, insulin, lipid profile, resistin, angiotensin II (ANG II) and aPAI‐1. Results: Resistin was positively correlated with hips (r = 0.33, P < 0.01), waist (r = 0.23, P < 0.05) and BMI (r = 0.33, P < 0.01). The association of resistin with the markers of obesity was also significant in girls but lost significance in boys. aPAI‐1 was positively correlated with total cholesterol (r = 0.24; P < 0.01), triglycerides (r = 0.2, P < 0.05), HOMA‐IR (r = 0.26, P < 0.01) and insulin (r = 0.26, P < 0.01). The significant association of aPAI‐1 with IR was also true in girls but lost significance in boys. Conclusion: Resistin is not correlated with IR and further studies are needed to explore the role of resistin especially in childhood obesity. In contrast, increased levels of PAI‐1 may contribute to the risk of cardiovascular diseases related to obesity and insulin resistance in children. The observed gender‐related differences in the association between resistin, aPAI‐1 with obesity markers and IR could be attributed to sexual dimorphism in body fat distribution.     

Insulin resistance,role of metformin and other non‐insulin therapies in pediatric type 1 diabetes

Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents.     

Current practice of insulin pump therapy in children and adolescents – the Hannover recipe

Abstract:  Increasing evidence points to the importance of achieving low blood glucose variability and also a low hemoglobin A1c (HbA1c) to prevent diabetic late complications. Continuous subcutaneous insulin infusion (CSII) is associated with lower blood glucose variability in children. Frequent indications for starting CSII in youth are recurrent hypoglycemia, need for increased flexibility, poor glycemic control, dawn phenomenon, or needle phobia. At our center, about one-third of all patients across all age groups are currently on CSII. Although the average glycemic control is not very different from those on multiple daily injections, fewer patients are seen in the segment of very high and very low HbA1c with CSII. Across centers, the 'recipes' tailoring CSII treatment to individual patients and cultures are based more on experience than on evidence. However, several typical pediatric features have been identified. Patterns of the hourly basal rate and prandial insulin requirements vary with age. While many adolescents have increased requirements at dawn and dusk, young children show increasing needs in the second half of the day. Low insulin requirements, particularly in neonates, may need insulin dilution. The selection of catheters and needles has to be appropriate for the age. The opportunity to have an electronic memory read-out of all entries and alarms offers new possibilities of therapeutic monitoring, particularly in those youth not keeping good logbooks. This feature can be helpful, if a trustful relationship between the diabetes team and the family is established.     

Classifying insulin regimens – difficulties and proposal for comprehensive new definitions

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review – based on the experiences of the Hvidoere Study Group (HSG) – is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG – founded in 1994 – is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms ‘conventional’ and ‘intensified therapy’ were used consistently among all members. Besides the concepts ‘conventional’ and ‘intensified’, several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen.