On the occurrence of the diabetes-associated antigen GAD 65 in human sera.

BACKGROUND: Glutamic acid decarboxylase (GAD 65) is involved as an antigen in diabetes mellitus type 1 and is generally considered to be located intracellularly in pancreas ß-cells. In this study we demonstrate its appearance in 64 human sera samples representing a cross-section of a blood bank. METHOD: The proof of GAD 65 in sera was done using an enzyme-linked immunosorbent assay (ELISA) setup where it was detected by interaction with corresponding antibodies labeled with an enzyme. The enzyme catalyzes a substrate reaction, resulting in a change of color, that is used for the quantitative evaluation of the antigen-antibody interaction. RESULT: The measurements showed that GAD 65 exists in various amounts in the sera of blood donors, with an average concentration of 58.00 ng/ml. The correlation analysis of samples stored at -80° C and at room temperature demonstrates the stability of GAD 65 at room temperature. The correlation coefficient between the GAD 65 concentrations of samples stored at room temperature and of the same samples after 1 week shows that the molecule remains stable. CONCLUSION: Our results encourage us to propose antigen GAD 65, due to its frequency in human sera in different concentrations and its stability, as a biomarker for the early diagnosis of type 1 diabetes and related inflammations.

Acylated ghrelin increases after controlled short-time exercise in school-aged children.

Ghrelin is a peptide hormone, which plays an important role in appetite regulation. The effects of exercise on ghrelin plasma concentrations are still not clear, especially in children and adolescents. The aim of this study was to investigate the response of acylated and total ghrelin concentrations to controlled exercise in school-aged children. Thirty-six healthy school-aged children (mean age 12.61 years, SD ± 0.39) underwent a controlled bicycle exercise test. Before and immediately after exercise, blood samples were taken in order to measure plasma ghrelin concentrations. The control group consisted of 24 healthy school-aged children. After controlled short-time exercise, total ghrelin concentrations showed no significant difference, whereas acylated ghrelin concentrations increased significantly (P<0.001) in the study population compared with the control group. Moreover, we found a correlation between the proportional increase of acylated ghrelin and the duration of exercise (P<0.01), and between the proportional increase of acylated ghrelin and maximal performance (P<0.01). Increased levels of acylated ghrelin after exercise could be a physiological response to ensure a sufficient caloric intake after energy consumption in children and adolescents.

Ghrelin does not regulate the GH response to insulin-induced hypoglycaemia in children but could be involved in the regulation of cortisol secretion.

OBJECTIVE: Ghrelin activates the growth hormone secretagogue receptor GHS-R. It strongly stimulates GH secretion and has a role in energy homeostasis. The relationship between plasma ghrelin and cortisol levels during insulin-induced hypoglycaemia in prepubertal and pubertal children has not yet been investigated. The aim of the present study was to establish whether insulin-induced hypoglycaemia stimulates ghrelin secretion and whether changes in ghrelin concentrations are related to changes in GH and cortisol in children. DESIGN AND PATIENTS: We studied a group of 20 children and adolescents (five girls, 15 boys, mean age 10.8 +/- 3.7 years) undergoing insulin tolerance tests (ITTs) for clinical investigation of GH deficiency. MEASUREMENTS: Stimulation tests were performed to investigate the relationship between ghrelin, GH, cortisol and glucose levels according to age and pubertal stage by determining the ghrelin profiles during insulin-induced hypoglycaemia (at 0, 60 and 120 min). RESULTS: Ghrelin was significantly and inversely related to body weight, height, body mass index (BMI) and age of children (P < 0.05). Significant changes in ghrelin levels (P = 0.00013) were found after the insulin bolus, with a decline at 60 min and an increase to baseline values at 120 min. Changes in cortisol levels were negatively correlated with changes in ghrelin at 60 min (r = -0.59, P = 0.004) and at 120 min (r = -0.605, P = 0.003). CONCLUSIONS: This study shows that ghrelin might not regulate the GH response to insulin-induced hypoglycaemia in prepubertal and pubertal children. A role for ghrelin in the regulation of cortisol secretion can be hypothesized concerning the negative correlation between changes in ghrelin and cortisol. Furthermore, the results imply that ghrelin secretion is age dependent and is a function of growth.

Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis.

BACKGROUND: Subclinical inflammation has been implicated in the initiation and/or progression of atherosclerosis. Diabetes mellitus and obesity are risk factors for atherosclerosis, and asymptomatic low grade inflammation occurs prior to overt vascular lesions in these patients. In contrast to adults, little information exists concerning low grade inflammation in young type 1 diabetes and juvenile obesity. AIM: To investigate low grade inflammation and immune activation in juvenile diabetes mellitus and obesity. METHODS: hs-CRP, soluble interleukin-2 receptor (sIL-2R), C-peptide, insulin, cortisol, vitamin B12, folic acid, leptin, and homocysteine were determined in 148 patients with juvenile type 1 diabetes, 86 obese children and 142 normal weighted age-matched healthy controls. Intima-media thickness (IMT) and lumen diameter of both common carotid arteries (CCA) was measured by ultrasonography in 52 healthy pediatric controls, 10 diabetics, and 34 obese juveniles. RESULTS: Serum hs-CRP was significantly elevated in patients with type 1 diabetes (p < 0.0001), and obese children (p < 0.0001) as compared to the control group. The obese juveniles (p < 0.0001) and the diabetics (p < 0.0001) showed significantly increased values for IMT of CAAs. Levels of homocysteine, sIL-2R, insulin, cortisol, vitamin B12, and folic acid did not differ from the controls. The elevation of hs-CRP was more pronounced in obesity as compared to type 1 diabetes (p < 0.0001), and the hs-CRP values correlated significantly with body mass index standard deviation score (BMI-SDS) values. Furthermore, the IMT and the luminal diameter of CCAs showed significant correlations with BMI-SDS values. CONCLUSION: A low grade inflammation as determined by serum hs-CRP is significantly increased in children with type 1 diabetes, and even more pronounced in apparently healthy juveniles with obesity. The increased IMT of CCAs strongly argues for an association between this low grade inflammation and early atherosclerotic vessel injury.

[Disorders of the thyroid gland in neonates and youth: latent hypothyroidism and hyperthyroidism]. / Funktionsstörungen der Schilddrüse im Kindes- und Jugendalter: latente Hypothyreose und Hyperthyreose.

Etiology and clinical manifestation of subclinical hypothyroidism is different in neonates and in young. In the neonatal period babies present with jaundice and/or constipation due to thyroid hypoplasia, thyroid ectopia or transient hypothyroidism. The main reason for subclinical hypothyroidism in the youth is Hashimoto thyroiditis. Indication for thyroxin therapy in subclinical hypothyroidism is discussed controversial in the literature. For best growing and maturation in childhood thyroxin therapy should be given. Subclinical hyperthyroidism is rare in childhood. The main reasons are Graves' disease or Hashimoto thyroiditis (initial period). The therapy of subclinical hyperthyroidism is the same as in overt hyperthyroidism.

[Congenital hypopituitarism and giant cell hepatitis in a three month old girl]. / Konnataler Panhypopituitarismus und Riesenzellhepatitis bei einem 3 Monate alten Säugling.

CASE REPORT: A three month old girl, with recurrent hypoglycemia and neonatal cholestasis, is reported. A metabolic disease could be excluded. The liver biopsy revealed giant cell hepatitis and intrahepatic bile duct hypoplasia. ACTH, Cortisol and hGH measured during hypoglycemia were low. Magnetic tomography (MR) of the brain showed an "empty sella". After beginning a replacement therapy with hydrocortisone, growth hormone and thyroxine there was no further episode of hypoglycemia. Transaminases and bilirubin levels normalized. The girl is in good condition, growth and development are normal. DISCUSSION: Hypoglycemia is often the first sign in childrens with neonatal hypopituitarism. The association of liver disease and hypopituitarism has been documented in a few reports. The pathophysiological mechanism leading to the liver dysfunction is not well understood. The prognosis of neonatal hypopituitarism as well as the concomitant liver disease is good under sufficient replacement therapy.

Changes in serum interleukin-6 concentrations in obese children and adolescents during a weight reduction program.

OBJECTIVE: To investigate the effect of short term energy restriction combined with physical activity on serum concentrations of Interleukin-6 (IL-6) in obese children and adolescents. DESIGN: Longitudinal intervention study of 3.8-5 MJ daily with exercise. SUBJECTS: Forty-nine white obese children and adolescents (31 girls, age 11.9+/-1.8 y; 18 boys, age 11.6+/-1.7 y). MEASUREMENTS: Indexes of obesity, IL-6, leptin, estradiol, systolic and diastolic blood pressure, heart rate at baseline and after 3 weeks. RESULTS: All determined parameters decreased significantly during the 3 week program (IL-6: 3.9+/-4.7 vs 2.0+/-2.2 pg/ml; P<0.05). Body mass index (BMI) fat mass, percentage fat mass (indexes of obesity), and leptin were not related to IL-6 before the program. In contrast, IL-6 concentrations correlated significantly with indexes of obesity and leptin after weight loss. IL-6 concentrations did not correlate with estradiol, systolic and diastolic blood pressure, and heart rate. Changes in IL-6 concentrations correlated significantly with changes in BMI (r=0.25, P<0.05). CONCLUSION: An improved body composition induced by restriction of energy intake and increase in physical activity is associated with more favorable serum concentrations of IL-6 in obese children and adolescents.

The effects of changes in body mass and subcutaneous fat on the improvement in metabolic risk factors in obese children after short-term weight loss.

The pattern of subcutaneous fat (SAT) is related to metabolic risk factors in obese children. Because weight loss improves the risk-factor profile, we sought to determine whether changes in SAT or SAT-pattern contribute to the improvement in the risk-factor profile after 3 weeks of a low-calorie diet and physical activities. In 22 obese boys (mean age, 11.9 years) and 40 obese girls (mean age, 12 years), fat mass (by means of impedance) and fat distribution (waist and hip circumference) were assessed. The thickness of 15 different subcutaneous adipose tissue layers (SAT-layers) was measured using a Lipometer (Moeller Messtechnik, Graz, Austria). SAT and SAT-pattern (arm-SAT, trunk-SAT, leg-SAT) were calculated. Blood samples were taken for the determination of insulin, glucose, triglycerides, and cholesterol. After 3 weeks, fat mass, waist and hip circumference, SAT, arm-SAT, trunk-SAT (all P <.0001), and leg-SAT (P <.01) were reduced. Besides glucose, metabolic parameters were lowered (all P <.001) but changes in metabolic parameter were interrelated in boys and girls. Age- and sex-adjusted regression revealed that changes in body mass contributed to the variability in changes of insulin (adjusted R(2) =.15, P =.0015). For the change in triglycerides, changes in cholesterol together with subtle alterations in glucose and changes in leg-SAT were found to be the main determinants (adjusted R(2) =.587, P <.0001). The results indicate that the change in the atherogenic and metabolic risk factor profile is largely independent from the concomitant loss in SAT. The reduction in body mass explained only a small part of the variability in changes of insulin, but leg-SAT might participate in the lowering of triglycerides, especially in boys. The contribution of SAT-pattern to the risk factor profile is an issue that needs further investigation.

Determinants of homocysteine during weight reduction in obese children and adolescents.

Plasma homocysteine levels have been shown to be associated with indexes of obesity and insulin resistance in obese children and adolescents. We, therefore, investigated the contribution of changes in body composition, markers of insulin resistance, folate, and vitamin B(12) to changes in homocysteine during a weight reduction program in obese children and adolescents. Thirty-seven obese white girls (mean SD; age, 12 +/- 1.8 years, body mass index [BMI], 26.9 +/- 5.25) and 19 obese white boys (age, 11.9 +/- 1.7 years; BMI, 26.2 +/- 5.2) were investigated for body composition, fasting total plasma homocysteine (tHcy), insulin, C-peptide, folate, and vitamin B(12) before and after a 3-week weight reduction program including physical activities. During weight reduction BMI, fat mass (FM), percentage fat mass, insulin, and C-peptide decreased significantly, whereas homocysteine and vitamin B(12) showed a significant increase. Folate and lean body mass (LBM) remained unchanged. tHcy concentration before weight reduction was a function of age, folate, and C-peptide, whereas tHcy concentration after weight reduction was a function of folate and baseline LBM. Changes in tHcy during weight reduction correlated significantly with baseline LBM and were related inversely to changes in LBM during weight reduction. Children who increased LBM showed lower increases in tHcy compared with children who lost LBM. In multiple linear regression analysis, only baseline LBM contributed independently and significantly to changes in tHcy. Our study suggests that LBM has a significant impact on tHcy metabolism during weight reduction.

Effects of weight loss on leptin, sex hormones, and measures of adiposity in obese children.

Adipose tissue influences steroid conversion by paracrine and autocrine mechanisms. Leptin is secreted by adipocytes and influenced by sex hormones and adiposity. Short-term weight loss in the treatment of childhood obesity reduces leptin and adipose tissue. We therefore asked, Do alterations in sex hormones occur owing to weight loss? and can these alterations be explained by changes in fat mass or sc fat and are alterations in sex hormones directly related to the fall in leptin? Twenty obese boys and 40 obese girls were studied before and after 3 wk of low-calorie diet and physical activity. The weight loss program significantly lowered fat mass, abdominal fat distribution, sc fat (all p < 0.0001), leptin, insulin, and estradiol (all p < 0.0001) but not testosterone. Changes in leptin were related to changes in body mass and to changes in fat mass in boys. In girls, changes in leptin were related to changes in sc fatness and also to changes in insulin. In boys, the reduction in sc fat was positively correlated to changes in testosterone (r = 0.54; p < 0.01) and inversely related to the fall in estradiol (r = -0.41; p < 0.05). In girls, changes in testosterone (r = 0.33; p < 0.05) and in estradiol (r = 0.40; p < 0.01) were related to changes in insulin. Stepwise regression showed that initial leptin was the best determinant for the fall in leptin (adjusted R2 = 0.87; p < 0.0001). The results show that alterations in sex hormones are related to changes in certain fat depots in boys whereas in girls changes in insulin might participate in changes in sex hormones. A greater fall in leptin owing to short-term weight loss is not associated with greater alterations in sex hormones and initial leptin is the best determinant to explain the variability in changes in leptin. The possibility of sex differences in changes in sex hormones secondary to the reduction in fatness warrants further study.

Subcutaneous adipose tissue layers as a stable correlate of leptin in response to short term energy restriction in obese girls.

AIMS: We studied the relationship of subcutaneous adipose tissue layers (SAT-layers) measured at 15 specified body sites with leptin before and after a weight loss program for three weeks. SUBJECTS AND METHODS: In 70 obese girls, SAT-layers were measured by means of the optical device, lipometer. Fat mass (FM) was estimated by means of bioelectrical impedance. RESULTS: At the beginning of the study, all estimates of adiposity, insulin, and SAT-layers from the upper body (from 1-neck to 6-lateral chest) were correlated to leptin at a P-value of<0.0001. Percentage FM together with SAT-layer 4-upper back and insulin explained 75% of the variation in leptin (P<0.0001). After three weeks, estimates of adiposity and leptin were reduced (all P<0.0001). Most SAT-layers were reduced, but SAT-layers 8-lower abdomen and 9-lower back were significantly increased. Changes in leptin were best explained by initial leptin, but percentage change (Delta) in insulin, Delta SAT-layer 1-neck, and Delta SAT-layer 3-biceps contributed to the Delta leptin (adj. r(2)=0.47, P<0.0001). In the weight-reduced state, circulating leptin was best explained by three SAT-layers and insulin (adj. r(2)=0.67, P<0.0001). DISCUSSION: The results suggest that Delta changes in leptin are attributable to changes in the endocrine state and subcutaneous fat, and SAT-layers may serve as a stable correlate of leptin in the weight-reduced state.

Interrelationship between estimates of adiposity and body fat distribution with metabolic and hemostatic parameters in obese children.

Adiposity in childhood is often associated with metabolic abnormalities and accompanied by a dysregulation of the coagulation and fibrinolytic systems. We studied the interrelationship of metabolic and hemostatic parameters and explored their relationship with measures of adiposity and fat distribution in obese children. In 34 obese boys (mean age, 11.7 years) and 57 obese girls (12.1 years), blood samples were determined for insulin, glucose, triglycerides, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator-antigen (tPA-Ag). Body composition was assessed by means of impedance. Waist (Wc) and hip circumference were measured. The thickness of subcutaneous adipose tissue-layers (SAT-layers) was measured at 15 different body sites (from 1-neck to 15-calf) by means of the optical device, Lipometer. Overall subcutaneous fatness (SAT) was calculated and SAT-distribution was estimated by means of factor analysis. Significant correlations were found between different measures of adiposity and Wc with metabolic parameters. Fibrinogen was mainly associated with upper body subcutaneous fatness (factor 1) in boys. In girls, hemostatic parameters were associated with nearly all measures of adiposity and also with factor 1 and SAT. Regression analysis showed that factor 1 together with PAI-1 (both P <.0001) contribute to fibrinogen (adjusted [adj], R(2) =.30). PAI-1 together with trigylcerides (both P <.0001) and age (P <.04) were main determinants for tPA-Ag (adj, R(2) =.41). tPA-Ag (P <.0001) together with glucose (P <.001, negative slope), fibrinogen (P <.001, negative slope), and percentage fat mass (%FM) (P <.01) contributed to PAI-1 (adj, R(2) =.54). These results favor the concept of an interrelationship between metabolic and hemostatic parameters resulting from increased adiposity, perhaps influenced by pubertal development of children. Although upper body subcutaneous fatness was found to be a main correlate of metabolic and hemostatic parameters, it remains to be investigated whether this type of subcutaneous fat distribution is involved in the expression of metabolic and hemostatic risk factors and participates in the dysregulation of the hemostatic system in the state of childhood obesity.

Effects of short-term energy restriction and physical training on haemostatic risk factors for coronary heart disease in obese children and adolescents.

OBJECTIVE: To study the changes of haemostatic risk factors for coronary heart disease during a weight reduction programme in obese children and adolescents. DESIGN: A short-term longitudinal study. SUBJECTS: Thirty-seven obese white girls (age, 12+/-1.8 y; body mass index (BMI), 26.9+/-5.25) and 19 obese white boys (age, 11.9+/-1.7 y; BMI, 26.2+/-5.2). MEASUREMENTS: Fibrinogen, factor VII coagulant activity, von Willebrand factor antigen, and soluble P-selectin were determined before and after a 3 week programme including energy restriction and physical activities. RESULTS: All determined haemostatic risk factors decreased significantly during the programme. Changes in risk factors were correlated to changes in body composition. Children and adolescents with the highest initial concentrations showed the greatest decreases. CONCLUSION: Energy restriction combined with physical activity improves the haemostatic risk profile in obese children and adolescents.

The influence of weight loss on fibrinolytic and metabolic parameters in obese children and adolescents.

We studied i) whether short-term weight loss alters plasminogen activator inhibitor-1 antigen (PAI-1-Ag) and tissue-type plasminogen activator antigen (tPA-Ag) in obese children, and ii) whether changes in body composition and/or abdominal adiposity are responsible for changes in PAI-1 and tPA-Ag. 20 obese boys (mean age 11.9 yr) and 40 obese girls (mean age 12 yr) were studied before and after three weeks of low-caloric diet and physical activity. Body composition was assessed by means of bioelectrical impedance, and the waist-to-hip ratio (WHR) was measured. Blood samples were determined for insulin, glucose, triglycerides, PAI-1-Ag, tPA-Ag, and the fasting insulin resistance index (FIRI) was calculated. Boys had a greater WHR, higher levels of glucose, and a slightly greater FIRI than girls. Estimates of adiposity, insulin, and triglycerides were correlated with PAI-1 and tPA-Ag. WHR was significantly correlated with fibrinolytic parameters only in girls. Insulin and tPA-Ag contributed to PAI-1 (adj. R2 = 0.36, p <0.0001), whereas percentage fat mass and triglycerides contributed to tPA-Ag (adj. R2 = 0.469, p <0.0001). The weight loss program significantly reduced adiposity, abdominal adiposity, and lowered fibrinolytic and metabolic parameters. Initial levels of PAI-1 and changes in body mass contributed to the fall in PAI-1 (adj. R2 = 0.18, p = 0.0016) and initial levels of tPA-Ag contributed significantly to changes in tPA-Ag (adj. R2 = 0.57, p <0.0001). The results suggest that changes in fibrinolytic parameters are associated with the loss in body mass but can occur independently of a concomitant reduction in fatness. Although initial PAI-1 and tPA-Ag predict the changes of these fibrinolytic parameters, the results do not exclude the possibility that the improvement in metabolic state and changes in unmeasured parameters related to physical activity and low-caloric diet could have influenced our findings.

Insulin is an independent correlate of plasma homocysteine levels in obese children and adolescents.

OBJECTIVE: The aim of the study was to investigate whether anthropometric and metabolic risk factors for coronary heart disease (CHD) contribute to the variation in homocysteine levels in obese children and adolescents. RESEARCH DESIGN AND METHODS: A total of 84 children and adolescents were assessed for fasting total homocysteine, methylenetetrahydrofolate reductase polymorphism (C677T mutation), folate and vitamin B12 status, and anthropometric and metabolic risk factors for CHD. RESULTS: No significant sex differences were found for all available anthropometric and metabolic characteristics except for homocysteine, which was significantly higher in boys than in girls (7.1 vs. 6.3 micromol/l; P<0.05). After adjustment for age and sex, homocysteine correlated significantly with BMI, fat mass, percentage of fat mass, and insulin and showed an inverse correlation with folate levels. Homocysteine did not correlate with vitamin B12; total cholesterol; LDL, HDL, and VLDL; triglycerides; and glucose. BMI and fat mass correlated significantly with insulin and showed a significant inverse correlation with folate. We found no association between homocysteine and the C677T mutation. In multiple regression analyses, insulin was found to be the main correlate of homocysteine. CONCLUSIONS: Our study demonstrates for the first time that insulin is a main correlate of homocysteine in obese children and adolescents and suggests that fat mass-associated hyper-insulinism may contribute to impairment of homocysteine metabolism in childhood obesity

No relationship between leptin and cortisol in obese children and adolescents.

Recent findings have shown that leptin downregulates the steroid producing system in the adrenal. We studied the interactions of leptin, insulin and cortisol in obese children and adolescents at different stages of maturation. In 44 boys (age 11+/-3.1 yr, body mass index [BMI] 29+/-5.3 [mean +/- SD]) and 35 girls (age 11.4+/-2.6 yr, BMI 29+/-4.3), blood levels of leptin, insulin, cortisol, and glucose were determined. Fat mass (FM) was calculated by bioelectrical impedance. No significant differences were found between boys and girls with respect to humoral and anthropometric characteristics. When children were divided according to maturation stage (prepubertal, pubertal, and late/postpubertal) insulin was higher in the more mature groups (p<0.01) and leptin was higher in the pubertal group (p=0.03). In the prepubertal and pubertal groups, the expected positive relationship between adiposity and leptin was found although the magnitude of this association decreased with maturity. In none of the groups studied was cortisol significantly correlated to leptin. Insulin (p=0.03) and glucose (p=0.01) were positively associated with cortisol in the prepubertal group after adjustment for adiposity. However, in the pubertal group an inverse correlation was found between insulin and cortisol (p=0.03), and between insulin and glucose after control for adiposity. In the late/ postpubertal group, no significant correlations were found between estimates of adiposity and humoral parameters even after adjustment for gender. Stepwise multiple regression failed to detect a significant influence of cortisol to explain the variation in leptin, and vice versa. BMI contributed to the variation in leptin (adj. R2 =0.275, p<0.0001), and glucose added 5% to the variation in cortisol (p=0.03). The results do not confirm the inverse association between leptin and cortisol found in adults. Although BMI reflects levels of leptin, it is likely that several other factors in conjunction with fatness modulate the relationship with leptin. Whether leptin per se exerts an influence on the hypothalamic-adrenal-adipo axis remains to be investigated in longitudinal studies.

Insulin and insulin resistance index are not independent determinants for the variation in leptin in obese children and adolescents.

Recent findings have questioned the independent influence of insulin on leptin. We studied whether insulin contributes to leptin in obese children, independent of confounding parameters, such as total adiposity, fasting insulin resistance index, and fat free mass. In 100 obese boys and 103 obese girls, blood levels of leptin, insulin, glucose, and triglycerides were determined. The fasting insulin resistance index (FIRI) was calculated, and body composition was assessed by means of impedance. Leptin and glucose were higher in girls, and all estimates of adiposity were significantly associated with leptin. However, when adjusted for adiposity, the relationship between insulin and leptin, and also between FIRI and leptin, remained significant in boys and girls (p<0.05). Although several regression models were tested, neither insulin nor FIRI were found to contribute significantly and independently to leptin. BMI together with triglycerides and FFM were the main determinants for the variation in leptin in boys (adj. R2=0.46, p<0.0001). In girls, BMI explained a great magnitude of the variation in leptin (adj. R2=0.60, p<0.0001). These findings indicate that in the state of childhood and adolescent obesity, total adiposity but not insulin or insulin resistance index is the main determinant for leptin. In contrast to obese girls, the fat free mass and triglycerides contribute significantly to the variation in leptin in obese boys. The biological significance for these findings should be elucidated in longitudinal studies.

Relationship between plasminogen activator inhibitor-1 antigen, leptin, and fat mass in obese children and adolescents.

Hyperleptinemia may be associated with cardiovascular risk and is linked with parameters of fibrinolytic processes in adults. We studied whether body fatness, leptin, and insulin interact with plasminogen activator inhibitor-1 antigen (PAI-1-Ag) and tissue-type plasminogen activator antigen (tPA-Ag) in obese children and adolescents. Twenty-three boys (mean +/- SD: age, 10.7 +/- 3.3 years; body mass index [BMI], 28.7 +/- 5.4 Kg/m2) and 19 girls (age, 11.9 +/- 2.7 years; BMI, 29.4 +/- 4.8 Kg/m2) were investigated. Body fat mass (FM) in the children was calculated by bioelectrical impedance analysis, and blood samples were obtained for leptin, insulin, C-peptide, PAI-1-Ag, and tPA-Ag. The children were divided into 3 subgroups according to maturation. Maturity was associated with greater adiposity and higher levels of leptin and C-peptide, but insulin and PAI-1-Ag were not different between prepubertal, pubertal, and late/postpubertal children. PAI-1-Ag was associated with leptin and insulin, but not after adjustment for fatness. PAI-1-Ag was independently associated with tPA-Ag (r = .36, P < .02). Multiple regression analysis showed that tPA-Ag failed to reach the level of significance (P = .07), but FM contributed to the variation in PAI-1-Ag (adjusted R2 = .29). The BMI was the main determinant for the variation in leptin (adjusted R2 = .386) and in insulin (adjusted R2 = .60, all P < .001). Neither gender, maturation, chronological age, or leptin contributed significantly to the variation in either PAI-1-Ag or tPA-Ag. Our data suggest that adiposity and other variables contribute to higher levels of PAI-1-Ag. Leptin seems not to be independently linked with fibrinolytic parameters, but an unfavorable metabolic and fibrinolytic risk profile might emanate from the obese pubertal stage.

Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors.

OBJECTIVE: To estimate the impact of type 1 diabetes during pregnancy on transgenerational genetically caused and/or fuel-mediated amplification of types 1 and 2 diabetes and to estimate the impact of elevated amniotic fluid insulin levels. RESEARCH DESIGN AND METHODS: A total of 75 white offspring of type 1 diabetic mothers and 49 control subjects of similar age and pubertal stage were examined at 5-15 years of age. All offspring had an oral glucose tolerance test. Glucose, insulin, and C-peptide were measured at 0, 30, 60, and 120 min after loading. Lipids and autoimmune antibodies were measured in fasting plasma. RESULTS: Of the 75 offspring, 4 (5.3%) had overt diabetes, and 16 of 71 (22.5%) had autoimmune antibodies. Offspring of diabetic mothers had significantly higher BMI; symmetry indexes; cholesterol, glucose, insulin, and C-peptide levels; and insulin resistance than control subjects. With the exception of cholesterol, these values were significantly elevated in offspring who had elevated amniotic fluid insulin levels (>8 microU/ml, >48 pmol/l) during pregnancy compared with normoinsulinemic offspring and control subjects. CONCLUSIONS: Offspring of type 1 diabetic mothers have an increased risk for diabetes later in life. The relative risk for type 1 and type 2 diabetes is 71.6 and 3.2, respectively. Type 2 diabetes-associated risk factors, such as high BMI; elevated glucose, insulin, and C-peptide levels; and insulin resistance, are related to the fetal metabolic experience in utero, as reflected by amniotic fluid insulin concentration.