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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: 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. WHAT THIS STUDY ADDS: Children with increased risk for cardiometabolic diseases show significant differences in insulin levels even before the onset of puberty compared with those without risks. The pattern of appearance of dyslipidaemia also varies in children with risk factors even in the pre-pubertal group from those without risk. Children with metabolic syndrome display considerably pronounced changes in their metabolic parameters before the onset of puberty, which become more pronounced as puberty passes. BACKGROUND: Insulin resistance (IR) has a key role in the metabolic changes in obese children. In commencing puberty, the insulin levels elevate. It is not clear, however, how insulin levels develop if the metabolic syndrome appears. OBJECTIVES: Metabolic changes were assessed in obese children before, during and after puberty to analyse the relationship between IR and puberty in subjects with and without metabolic syndrome. METHODS: Three hundred thirty-four obese children (5-19 years) attended the study. The criteria of the International Diabetes Federation were used to assess the presence of cardiometabolic risks (CMRs). Subjects with increased CMR were compared with those without risk (nCMR). Pubertal staging, lipid levels, plasma glucose and insulin levels during oral glucose tolerance test were determined in each participant. IR was expressed by homeostasis model assessment (HOMA-IR) and the ratio of glucose and insulin areas under the curve (AUC-IR). RESULTS: Significantly higher AUC-IR were found in pre-pubertal CMR children compared with nCMR subjects (11.84 ± 1.03 vs. 8.00 ± 0.69; P < 0.01), but no difference was discovered during and after puberty. HOMA-IR differs between CMR and nCMR only in post-puberty (6.03 ± 1.26 vs. 2.54 ± 0.23; P < 0.01). CMR children have dyslipidaemia before the onset of puberty. CONCLUSIONS: CMR is associated with increased postprandial IR in pre-pubertal and increased fasting IR in post-pubertal obese children. Dyslipidaemia appeared already in pre-puberty in CMR children.

[Latent autoimmune diabetes in adults(LADA): part of the clinical spectrum of type-1 diabetes mellitus of autoimmune origin]. / A lassan kialakuló felnóttkori autoimmun diabetes (LADA): az autoimmun eredetú 1-es típusú cukorbetegség klinikai spektrumának része.

According to the most recent classification of diabetes mellitus the latent autoimmune diabetes in adults belongs to the group of type 1 autoimmune diabetes mellitus, as a slowly progressive form. It is not clear whether LADA is a distinct clinical entity or it is a part of the clinical spectrum of type 1 diabetes mellitus. The authors compare the antropologic (body mass index, waist to hip ratio), immunologic (occurrence of islet cell cytoplasmic autoantibodies and autoantibodies against glutamic acid decarboxylase and tyrosin phosphatase), genetic (HLA DR and DQ alleles known to be associated to type 1 diabetes mellitus) characteristics and occurrence of the features of the metabolic syndrome in the groups of type 1 and type 2 diabetes and LADA. 81 type 1 and 190 type 2 diabetics and 38 LADA patients were involved into the study. Freshly diagnosed type 1 diabetics served for controls of the autoantibody study: 48 patients manifested < or = 16 years of age and 89 type 1 diabetics manifested above 16 years of age. The three main diabetic groups differed in age: the average age in the type 1, type 2 and LADA groups were 37, 63 and 58 years respectively. There was no difference among the three groups in gender. The duration of the disease differed significantly between the type 2 and LADA groups (4.0 and 8.0 years respectively). In spite of the shorter duration of the disease in the LADA group, compared to the type 2 diabetics the frequency of insulin dependency was significantly higher in the LADA (81.6%) than in the type 2 group (46.7%). The BMI and WHR were comparable between the type 1 and LADA patients (average values were 23 and 0.83 in type 1 patients and 23.25 and 0.89 in LADA). The type 2 group differed significantly from type 1 and LADA (average values were 29.1 and 0.5). The concentration of glycated hemoglobin was comparable in the three groups. But there was a significant difference in HbA1c concentration between the freshly diagnosed subgroups of type 1 and LADA patients: 10.85% and 8% respectively. The fasting C-peptid levels were significantly higher in the sera of type 2 diabetics (0.75 pmol/l) compared to type 1 (0.2 pmol/l) and LADA patients (0.29 pmol/l). There was a significant difference in C-peptid concentrations between the type 1 and LADA groups, too. The insulin deficiency in LADA seemed to be not as severe as in type 1 diabetes. The serum total cholesterol and triglyceride levels were significantly higher and the HDL cholesterol concentration significantly lower in type 2 diabetics comparing to type 1 and LADA patients and there was no significant difference in this respect between the type 1 and LADA groups. The frequency of occurrence of hypertension differed no significantly between type 2 and LADA, but that of in type 1 diabetes was significantly lower than both type 2 and LADA. The occurrence of multiple autoantibodies (ICA + GADA + anti-IA2) was much more frequent in type 1 diabetes compared to LADA. In the sera of LADA patients the occurrence of ICA and GADA alone or ICA + GADA was characteristic (31.5% - 21.1% - 15.8% respectively). There was no difference between type 1 diabetes and LADA in the occurrence of the alleles of the MHC kown to be associated with type 1 diabetes. The occurrence of the haplotypes HLA DQ2/DR3 and/or DQ8/DR4 was observed in two thirds of type 1 diabetic and LADA patients. Chronic diabetic complications were observed in all of the groups and there was only a secondary connection of the complications with the type of the diabetes. Based on the results the authors suggest that LADA is a part of the clinical spectrum of type 1 diabetes of autoimmune origin.

[Detection of antibodies against pancreatic islet cells in clinical practice]. / Hasnyálmirigy-szigetsejt elleni antitestek vizsgálata a klinikai gyakorlatban.

Development of diabetes mellitus caused by pancreatic beta-cell destruction of autoimmune origin is the result of a long lasting process. The most easily examinable feature of this stage is the occurrence of the islet cell antibodies. The sera which are positive for islet cell cytoplasmic antibodies (ICA), examined by indirect immunofluorescence, contain a mixture of antibodies. The glutamic acid decarbocylase (GAD), the tyrosin phosphatase (IA2), the insulin, and the GM2-1 glycolipid can be the targets of these antibodies. One can routinely examine the ICA, the GADA, the IA2 antibodies. The detection of antibodies against insulin (IAA) and GM-2-1 glycolipid is not invented in the routine laboratory work. The aim of the authors was the evaluation of clinical significance of occurrence of islet cell antibodies: one hundred and eighteen nondiabetic children an adult human being without known diabetic first degree relatives and 366 type 1 diabetic children and adult patients served as controls. The authors evaluated the predictive value of the different islet cell antibodies to the development of type 1 diabetes mellitus in 596 nondiabetic children with type 1 diabetic first degree relatives. The authors looked for markers of beta-cell destruction among sera of 320 diabetics manifested after 30 years of age with at least half a year of non-insulin-dependency and in the sera of 68 females suffered from gestational diabetes after 0-14 years of the index pregnancy. Finally the authors report 7 cases in which the examination of islet cell antibodies helped the diagnosis and classification of diabetes mellitus. Indirect immunofluorescence method was used for the detection of ICA, radioimmunoassay for that of GADA and IA2 antibodies. There was no positive reaction for ICA and GADA in the nondiabetic population without diabetic first degree relatives. Among the freshly diagnosed type 1 diabetic children 39% were positive for only ICA, 44% for only GADA and 80% for any antibodies. Among the freshly manifested type 1 diabetic adults ICA positivity only was observed in 21%, GADA positivity only in 7.1% and 93% for any antibodies. From the 595 nondiabetic children with type 1 diabetic first degree relatives 23 were positive for ICA, from whom 5 became diabetic during a two years observation period. These diabetic children had multiplex autoantibodies besides ICA. One child from this group, who was negative for ICA became diabetic, too. Among type 2 diabetic patients 13% were positive for ICA alone, 17% were positive for GADA alone and 27% were positive for any antibodies. The insulin dependency manifested in a short time was associated with antibody positivity. Among the gestational diabetics 10 were found positive for ICA. From them, 7 were type 1 diabetics, and 3 were type 2 diabetics at the time of the detection of antibodies. The authors suggest the need of determination of islet cell antibodies in the group of nondiabetic first degree relatives of type 1 diabetic patients (ICA, GADA, IA2 and IAA), in the group of non-insulin-dependent diabetics (ICA and GADA) as a screening for later insulin dependency, and in gestational diabetes after delivery (ICA) as screening for type 1 diabetes mellitus.

Pathological and experimental investigations in a case of gigantism.

A pituitary adenoma was transsphenoidally removed from a 4.5-year-old girl suffering from gigantism. Prior to the operation both the growth hormone (GH) and the prolactin (PRL) levels in the serum were elevated. By light microscopy the tumor appeared to be an acidophilic adenoma. Two distinct cell types, the densely granulated and the sparsely granulated cells, could be distinguished by electron microscopy. Double immunolabeling revealed the presence of GH alone in some densely granulated cells and PRL alone in some sparsely granulated cells, as well as GH and PRL co-localized in both of the morphologically distinguished cell types. Both cell types were identified in the monolayer and the suspension cultures by electron microscopy. GH and PRL concentrations in the culture media were measured by radioimmunoassay. The basal secretion of growth hormone was almost uniform during the 3-week cell culture period. GH and PRL release was significantly inhibited by bromocriptine. Our studies revealed a bimorphous and bihormonal mixed adenoma in childhood.

Insulin metabolism in hypothalamic obesity.

Serum C-peptide and Immunoreactive Insulin (IRI) level was measured during per os glucose tolerance test as well as fasting specific insulin binding percentage and capacity of erythrocytes in hypothalamic obesity and in obese children due to hypercalorization, and was compared with ideal-weight controls. Integral values of curves (sigma) and sigma C-peptide/sigma IRI ratios were calculated. In 4 cases fasting C-peptide content was substantially increased as compared to the other groups. The data suggest that hyperinsulinism in diencephalic obesity is primary. The ratio of the two peptides was normal or increased: insulin binding % of erythrocytes corresponded to that of the control group, which explains in these cases normal or favourable glucose metabolism. It is thought that in obese children high fasting C-peptide levels with an adequate clinical picture can indicate the functional examination of the hypothalamic-pituitary system. Sigma C-peptide/sigma IRI ratio differing from normal indirectly shows the changes of receptor function.

[Insulin metabolism in obese children tested by oral and intravenous glucose loading]. / Elhízott gyermekek inzulin anyagcseréjének vizsgálata per os és i.v. glukóz-terhelés során.

Authors performed 0.5 g/kg intravenous and 1.75 g/kg p.os glucose tolerance tests in 25 alimentary obese children. C-peptide and Immunoreactive Insulin determinations were performed in every case. The average ratio of the two peptide during i.v. loads was calculated, too. Results were compared with the data of 6 children with ideal body weight respectively, whose results were obtained in similar circumstances. They find that i.v. glucose load produces different degrees in detected by C-peptide insulin secretion in normal as well as in obese children and the secretion rate is practically permanent till the end of the test in both groups. The low C-peptide/insulin ratio during i.v. glucose tolerance test in obese children indicates insulin resistance and explains decreased glucose tolerance. The "early-phase insulin release" detected in insulin curves of i.v. glucose load is resulted not only by the insulin reservoir capacity of beta-cells, but also by the insulin excretion capacity of the liver and the receptor activity of target cells. There is no connection between maximum glucose level responses to i.v. load and maximum C-peptide and insulin responses, whereas increases in maximum C-peptide response are parallel with those of in weight. C-peptide responses, being different in degree and experienced during the two types of tolerance test, support the "incretin" phenomenon. This mechanism may be important in the development of beta-cell hyperfunction which has been proved in obesity.

Experience with neonatal screening for congenital hypothyroidism in Hungary.

The experience obtained in one of two Hungarian screening centers for congenital hypothyroidism (CH) is reported which is based on the examinations of dried blood samples tested with the aid of TSH-RIA developed in this laboratory. During the past six years (1982-88) and CH was diagnosed in 54 cases out of a total of 306,265 newborns (prevalence: 1:5470). The recall rate because of increased TSH values was 0.28-0.29% within the last two years. The triple of this had to repeat for technical reasons (imperfect samples, borderline results). Within the last year the treatment of diagnosed infants with L-thyroxine was started at the average age of 13 days. The history of three missed cases is briefly reported. Four out of 54 patients (7.4%) died in infancy. Since the pituitary sensitivity for TSH suppression by replacement doses of L-thyroxine appeared to be decreased in several cases, the control of free thyroxine levels is preferred to avoid the clinical hypo- or hyperthyroidism. The shortening of the present three days TSH RIA method, the extension of systematic examination of TSH binding antibodies and psychological studies are in progress.