Insulin resistance and its effects in children and adolescents / Inzulinrezisztencia és következményei gyermek- és serdülokorban.

Összefoglaló. Számos adat igazolja, hogy az inzulinrezisztencia gyakori jelenség gyermek- és serdülokorban, és szoros kapcsolatban áll a cardiovascularis kockázat növekedésével, ami miatt a kérdéskörre az életnek ebben a korai szakaszában is kiemelt figyelmet kell fordítani. Ma már egyre több ismerettel rendelkezünk a kockázati tényezoket illetoen, nincs azonban egységes álláspont az inzulinrezisztencia meghatározására vonatkozóan a klinikai gyakorlatban, és nem rendelkezünk megfelelo laboratóriumi markerekkel, melyek segítségével a veszélyeztetetteket széles körben eredményesen lehetne azonosítani. Mindezek alapján a laboratóriumi módszerrel történo szurés ebben az életkorban nem indokolt, azonban a társuló és következményes kórállapotok klinikai alapon történo felismerésére törekedni kell. A cardiovascularis kockázat megelozésére irányuló életmódbeli prevenció hatásos az inzulinrezisztencia csökkentésében, a gyakorlatban azonban kivitelezése és eredményessége korlátozott. A gyógyszeres intervenció jelenleg ebben az életkorban csak egyes szelektált esetekben kerülhet alkalmazásra. További klinikai kutatásokra van szükség az inzulinrezisztencia mérése, az életmódbeli és gyógyszeres intervenciós lehetoségek területén annak érdekében, hogy sikeres stratégiák legyenek kialakíthatók a cardiovascularis halálozás megelozése, csökkentése érdekében. Orv Hetil. 2021; 162(11): 403-412. Summary. Numerous data confirm that insulin resistance is a common phenomenon in children, and closely links to an increase in cardiovascular risk, therefore it is urgent to pay attention to this from early childhood. Today, we have more and more knowledge about risk factors, but there is no common position on the definition of insulin resistance in clinical practice and we do not have adequate laboratory markers to identify those at risk effectively. Based on all these factors, laboratory screening is not justified at this age, however, efforts should be made to recognize associated and consequent conditions on a clinical basis. Lifestyle prevention to prevent cardiovascular risk is effective in reducing insulin resistance, but in practice its implementation and effectiveness are limited. At present, pharmacological intervention can only be used in certain selected cases with this age group. Further clinical research is needed to measure insulin resistance, lifestyle and drug intervention options in order to develop successful strategies to prevent and reduce cardiovascular death. Orv Hetil. 2021; 162(11): 403-412.

[Correlation between insulin resistance and puberty in children with increased cardiometabolic risk]. / Inzulinrezisztencia és pubertás kapcsolata megnövekedett kardiometabolikus kockázatú gyermekekben.

UNLABELLED: Epidemiologic data provide evidence that the frequency of obesity and cardiometabolic risk factors shows an increasing tendency in childhood. Insulin resistance plays a central role in the pathogenesis of cardiovascular and metabolic consequences of obesity. Transient decrease in the insulin sensitivity during puberty is a well-known physiological process; however, the feature of this phenomenon is not clear in obese children with increased cardiometabolic risk. AIM: The aim of the present study was to assess the effect of puberty on insulin resistance and metabolic parameters in obese children with and without increased cardiometabolic risk. MATERIALS AND METHODS: Anthropometric data, insulin levels during oral glucose tolerance test and lipid status were analyzed of 161 obese children aged 4-18 years. Σinsulin/Σglucose ratio was obtained during glucose load and HOMA index was used to assess insulin resistance. Children were sorted into prepubertal (T1), pubertal (T2-4) and postpubertal (T5) cohorts according to Tanner staging criteria and metabolic and insulin resistance parameters were evaluated. Increased cardiometabolic risk was defined as the presence of any two risk factors (elevated fasting plasma glucose, blood pressure, triglyceride or decreased HDL-cholesterol) in addition to obesity. RESULTS: Out of 161 obese subjects, 43 (26.7%) had increased cardiometabolic risk. Decreased HDL-cholesterol and/or elevated triglyceride was observed in 101 (56.5%) cases. Impaired glucose tolerance and/or impaired fasting glucose was found in 23 (14.4%) cases. In subjects without increased cardiometabolic risk, the Σinsulin/Σglucose ratio in T1 stage was significantly lower than in T2-4 and T5 stages (p = 0.01). In children with increased cardiometabolic risk, the insulin/glucose ratio was similar in T1, T2-4 and T5 stages, however, it was significantly higher in T1 stage as compared to subjects without increased cardiometabolic risk (p = 0.04). In T2-4 and T5 stages, Σinsulin/Σglucose ratio did not differ between children with and without increased cardiometabolic risk. No difference was found in HOMA index between groups with and without increased cardiometabolic risk in T1 stage, however significantly higher levels were observed in subjects with increased cardiometabolic risk at T2-4 stages (p = 0.01), indicating the presence of fasting hyperinsulinemia in this cohort. Elevated HbA1c (≥6.0%) was found in 13 (16%) out of the 81 children investigated, of whom only two cases had abnormal oral glucose tolerance test. In cases having normal HbA1c, oral glucose tolerance test showed impaired glucose tolerance in 5 cases, impaired fasting glucose in 2 cases, both impaired glucose tolerance and impaired fasting glucose in 2 cases, and type 2 diabetes in 2 cases. CONCLUSION: Increased insulin resistance can be observed in obese children without increased cardiometabolic risk. In obese children with increased cardiometabolic risk, substantial insulin resistance occurs in prepuberty and it is present at similar level throughout puberty. Fasting insulin levels are elevated in obese subjects with increased cardiometabolic risk as compared to those without increased cardiometabolic risk. To reveal type 2 diabetes cases, HbA1c and oral glucose tolerance test results should be assessed parallel.

Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a Basal-bolus insulin regimen in a 26-week trial in pediatric patients with type 1 diabetes.

BACKGROUND: We compared the efficacy and safety of insulin glulisine with insulin lispro as part of a basal-bolus regimen in children and adolescents with type 1 diabetes. METHODS: Overall, 572 children and adolescents (4-17 years old) using insulin glargine or neutral protamine Hagedorn insulin as basal insulin were enrolled in a 26-week, multicenter, open, centrally randomized, parallel-group, noninferiority study. Subjects were randomized to receive glulisine (n = 277) or lispro (n= 295) 0-15 min premeal. RESULTS: Baseline-to-endpoint hemoglobin A1c changes were similar between the two insulins: adjusted mean change (glulisine vs. lispro), 0.10% versus 0.16%; between-treatment difference (glulisine-lispro), &minsu;0.06, 95% confidence interval (-0.24; 0.12); and prespecified noninferiority margin, 0.4%. Overall, for all age groups together, the percentage of patients achieving American Diabetes Association age-specific A1c targets at endpoint was significantly higher (P = 0.039) with glulisine (38.4%) versus lispro (32.0%). From Month 4 to endpoint, both "all" and "severe" symptomatic hypoglycemia rates were similar (3.10 vs. 2.91 and 0.06 vs. 0.07 events/patient-month, respectively). Frequency and type of adverse events, serious adverse events, or hypoglycemia reported as serious adverse events were similar between both groups. CONCLUSIONS: Glulisine was as effective as lispro in baseline-to-endpoint A1c change, and both treatments were similarly well tolerated.

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients.

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.