Effect of oral glucose administration on ghrelin levels in obese children

OBJECTIVE: Coexpression of GH secretagogue receptor and ghrelin in the pancreas suggests that this peptide is involved in glucose metabolism. Previous reports in adult humans have demonstrated that plasma ghrelin levels decrease after oral glucose administration. However, no data are available in children. Therefore, the aim of this study was to analyze the response of plasma ghrelin levels in obese children after oral glucose administration. SUBJECTS AND METHODS: Twenty-eight obese children ranging from Tanner I to Tanner V were studied. All subjects were given 0.75 g/kg (maximum 75 g) glucose solution after overnight fasting. Ghrelin, insulin, glucose and IGF-binding-protein-1 were determined at 0, 30, 60 and 120 min of the oral glucose tolerance test (OGTT). RESULTS: Basal plasma ghrelin levels were significantly lower than in the respective control groups. These levels decreased significantly during OGTT in obese children, reaching a nadir of 28+/-9% at 60 min in parallel with the maximum increase in glucose levels and previous to maximum insulin levels. CONCLUSION: The rapid fall in plasma ghrelin concentration in obese children after glucose load suggests a mechanism for the control of appetite after food intake.     

Oral glucose load inhibits circulating ghrelin levels to the same extent in normal and obese children

OBJECTIVE: The presence of both the GH secretagogue (GHS) receptor and ghrelin in the pancreas indicates an involvement of this hormone in glucose metabolism. Ghrelin secretion is increased by fasting and energy restriction, decreased by food intake, glucose load, insulin and somatostatin in normal adults; however, food intake is not able to inhibit circulating ghrelin levels in children, suggesting that the profile of ghrelin secretion in children is different from that in adults. Moreover, how ghrelin secretion is regulated in childhood as a function of fat mass is still unclear. DESIGN AND SUBJECTS: We studied the effect of oral glucose load (75 g solution orally) on circulating total ghrelin levels in 14 obese children (group A, four boys and 10 girls, aged 9.3 +/- 2.3 years) and 10 lean children (group B, five boys and five girls, aged 9.7 +/- 3.8 years). MEASUREMENTS: In all the sessions, blood samples were collected every 30 min from 0 up to +120 min. GH, insulin and glucose levels were assayed at each time point. RESULTS: Glucose peaks following an oral glucose tolerance test (OGTT) in groups A and B were similar; however, both basal and OGTT-stimulated insulin levels in group A were higher than in group B (P < 0.05). Basal total ghrelin levels in group A (281.3 +/- 29.5 pg/ml) were lower (P < 0.0005) than in group B (563.4 +/- 81.5 pg/ml). In both groups A and B, the OGTT inhibited total ghrelin levels (P < 0.005). In terms of absolute values, total ghrelin levels in group A were lower (P < 0.0005) than those in group B at each time point after glucose load. The percentage nadir in total ghrelin levels recorded in group A (-25% at 90 min) was similar to that recorded in group B (-31% at 120 min). Total ghrelin levels were negatively associated with BMI (r = 0.5, P < 0.005) but not with glucose or insulin levels. CONCLUSION: Ghrelin secretion is reduced in obese children. It is, however, equally sensitive in both obese and lean children to the inhibitory effect of oral glucose load.     

Comparison between beta-cell function and insulin resistance indexes in prepubertal and pubertal obese children

Several methods have been developed to assess insulin resistance (IR), insulin secretion, and sensitivity: some of them, such as the homeostasis model assessment (HOMA) for IR (HOMA IR) and for insulin secretion (HOMA beta cell) and the quantitative insulin sensitivity check index (QUICKI) are based on fasting levels of glucose (fasting G) and insulin (fasting I); others, such as the pancreatic insulin response to glucose (IRG) and the insulin sensitivity index (ISI) are derived from the glycemic and insulinemic responses to the oral glucose tolerance test (OGTT). The aim of the study was to compare these indexes in a large group of prepubertal and pubertal obese subjects and verify whether the data from fasting samples were enough for evaluating IR and insulin secretion or if OGTT was mandatory. A total of 405 obese subjects (221 boys and 184 girls) was studied. Ninty-three were prepubertal (Tanner stage I), 98 early pubertal (stage II to III) and 214 late pubertal (stage IV to V). In each subject, a 120-minute OGTT was performed, and the glycemic (mean blood glucose [MBG]) and insulinemic (mean serum insulin [MSI]) responses, expressed as AUC/120, as well as IRG and ISI were calculated. The fasting I/fasting G ratio (FIGR), HOMA IR, HOMA beta cell, and QUICKI were then measured. FIGR and HOMA IR increased in both sexes during puberty, but in girls, the increase was already evident from stage I to stage II to III, while in boys, it was evident only from stage II to III to stage IV to V. QUICKI decreased in girls at the onset of puberty and was lower than in boys in stage II to III; on the other hand, HOMA beta cell did not show any variation. IRG increased throughout puberty, although it was higher in boys than in girls in stages II to III and IV to V, while ISI decreased at the onset of puberty in boys; HOMA IR correlated with MSI and IRG, and HOMA beta cell with MSI in pubertal subjects only. In conclusion, the indexes deriving from fasting samples, such as FIGR and HOMA IR, proved to be enough for evaluating IR in prepubertal and pubertal obese subjects, as did QUICKI for insulin sensitivity, However, OGTT is still useful for assessing insulin secretion, because IRG is more sensitive in depicting the pubertal variations of IR than HOMA beta cell.     

Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients

BACKGROUND: Ghrelin exerts a wide range of metabolic functions. In contrast to the body of information accumulated on the role of ghrelin on energy balance, the possible relevance of the peptide on GH secretion in physiological and pathological conditions has so far been poorly investigated. AIM: The aim of the present study was to evaluate circulating ghrelin levels in acromegalic patients in basal conditions and in response to oral glucose tolerance test (OGTT). PATIENTS: Serum ghrelin, insulin and leptin levels were measured in 31 healthy normal weight subjects as controls, 25 patients with simple obesity and 17 non-diabetic acromegalic patients. Ghrelin and insulin response to OGTT was evaluated in six controls, four obese and six acromegalic patients. RESULTS: The acromegalic patients showed ghrelin levels lower than those observed in normal weight subjects (201+/-20 vs 329+/-32 pmol/l, P<0.05) and similar to those found in obese subjects (165+/-14 pmol/l, P=not significant). Both obese and acromegalic patients had insulin levels significantly higher than controls, while high levels of leptin were detected only in obese subjects. Serum ghrelin levels showed a significant negative correlation with insulin, leptin and body mass index (P<0.05) in normal and obese subjects. No correlation was observed in acromegalic patients, although those with severe insulin resistance showed the lowest ghrelin values (161+/-20 pmol/l). In controls and obese subjects, ghrelin levels showed a significant decrease (25-40%) during OGTT, while no effect was detectable in acromegalic patients. CONCLUSIONS: This study reports that patients with active acromegaly show low levels of circulating ghrelin that are not further reduced by OGTT, this pattern of secretion probably depending on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion.     

Ghrelin suppression in overweight children: a manifestation of insulin resistance?

Ghrelin levels increase before and decrease after meals, potentially playing a role in meal initiation and satiety in an inverse pattern to that of insulin. The role of ghrelin in childhood obesity, a state associated with hyperinsulinism and insulin resistance, is not fully understood. Therefore, the aims of the present study were to investigate the dynamics of ghrelin suppression after an oral glucose tolerance test (OGTT) in normal weight (NW) vs overweight (OW) children and the relationship of ghrelin suppression to insulin sensitivity. Thirty-seven NW (15 males and 22 females; 9.4 +/- 0.2 yr old) and 23 OW (13 males and 10 females; 9.4 +/- 0.3 yr old) prepubertal children underwent a 3-h OGTT with measurements of ghrelin, glucose, and insulin. The fasting glucose to insulin ratio and the whole body insulin sensitivity index were used to assess the relationship of insulin sensitivity to fasting ghrelin and ghrelin response to the OGTT, respectively. Fasting ghrelin levels were significantly lower in OW vs NW youth and were mainly influenced by insulin sensitivity independent of adiposity. OGTT-induced absolute suppression in ghrelin was approximately 50% less in OW vs NW children, resulting in a similar percent suppression from baseline in the two groups despite a significantly higher insulin response in OW. The suppression of ghrelin correlated positively with the whole body insulin sensitivity index (r = 0.43; P = 0.001) and negatively with the change in insulin at 30 min (r = -0.31; P = 0.02). Fasting ghrelin, the change in insulin, and the change in glucose during the OGTT were the significant independent variables contributing to the variance in absolute suppression of ghrelin (r2 = 0.42; P < 0.001). Only the change in glucose contributed significantly to the variance in the percent suppression of ghrelin (r2 = 0.14; P = 0.019). Fasting ghrelin and ghrelin suppression after OGTT are modulated by insulin sensitivity. Alterations in ghrelin suppression in OW children may be yet another manifestation of the insulin resistance of obesity. Whether this is responsible for differences in satiety in OW individuals merits additional investigation.     

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.     

Growth hormone suppression after an oral glucose load in children

BACKGROUND: GH nonsuppression after oral glucose is diagnostic for GH excess, but normative data are lacking in children. Adult data cannot be extrapolated to children given the pubertal increase in GH concentration. In addition, because GH levels are higher in pubertal girls than boys, nadir GH may differ across gender. OBJECTIVE: Our objective was to determine whether nadir GH during an oral glucose tolerance test (OGTT) is gender and pubertal stage specific. We hypothesized that nadir GH would be higher in girls, and at the pubertal stage known to correspond with peak height velocity (Tanner 2-3 in girls and Tanner 3-4 in boys) and maximal GH concentrations. SUBJECTS/ METHODS: A 2-h OGTT using 2.35 g/kg oral glucose (maximum 100 g) was performed in 64 girls and 43 boys, 9-17 yr (10th-90th percentiles for body mass index). Girls were grouped as group 1 (Tanner 1), group 2 (Tanner 2-3), and group 3 (Tanner 4-5), and boys as group 1 (Tanner 1-2), group 2 (Tanner 3-4), and group 3 (Tanner 5). RESULTS: Nadir GH was higher in girls than boys, and in group 2 girls and boys than the other two groups. The upper limit for nadir GH was highest in group 2 girls (1.57 ng/ml), and lower for the other two groups of girls (0.64 ng/ml), and for boys (0.50 ng/ml). All but one girl, and all boys suppressed to less than 1.0 ng/ml. There were 16 girls and five boys who had a nadir GH of more than 0.3 ng/ml. CONCLUSION: GH suppression after oral glucose is gender and pubertal stage specific.     

Insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic children with a family history of type 2 diabetes

OBJECTIVE: To examine cross-sectional differences in insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic boys and girls with a family history of type 2 diabetes. STUDY DESIGN AND PARTICIPANTS: This cross-sectional, observational study included 214 8-13-y-old Hispanic children with a BMI percentile > or = 85th percentile and family history of type 2 diabetes. METHODS AND ANALYSES: Participants underwent a physical examination, body composition measures, oral glucose tolerance test (OGTT), and frequently-sampled intravenous glucose tolerance test. Unadjusted and adjusted general linear models (GLM) tested whether insulin/glucose dynamics differed by Tanner stage and gender. RESULTS: Unadjusted group comparisons showed that fasting insulin increased whereas insulin sensitivity (SI) and the disposition index (DI) (a measure of pancreatic beta-cell function) decreased across Tanner stage groups (all P < 0.05). No differences in the acute insulin response to glucose (AIRg), fasting glucose or 2-h glucose were found. After adjusting for covariates, there was no independent effect of Tanner stage on SI (P = 0.9) or AIRg (P = 0.2), but DI was slightly lower in later Tanner stages suggesting decreased beta-cell function in the more mature groups (P = 0.10). CONCLUSIONS: Overweight Hispanic children with a family history of type 2 diabetes may represent a unique population given that pubertal insulin resistance was not evident once analyses controlled for body composition. Longitudinal analyses are required to determine whether the slightly diminished beta-cell function in later Tanner stages plays a role in the development of type 2 diabetes.     

Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis

To test the hypothesis that the relative insulin resistance of puberty is associated with changes in IGF-I levels, we compared IGF-I, IGF binding protein-3 (IGFBP-3), and IGFBP-1 levels to insulin resistance [M(lbm), milligrams glucose used per kilogram of lean body mass (LBM) per minute] measured during euglycemic, hyperinsulinemic clamp studies in 342 children and adolescents. IGF-I levels rose and fell during the Tanner stages of puberty in a pattern that closely followed the rise and fall of insulin resistance. IGF-I levels were significantly related to M(lbm) in boys (P = 0.0006) and girls (P = 0.02). IGF-I was significantly related to fasting insulin levels only in girls (P = 0.006; boys, P = 0.26), and this relation was significantly influenced in girls by body fat (P = 0.007), with the strongest association between IGF-I and fasting insulin seen in thin girls. IGFBP-1 correlated negatively with insulin resistance in both boys (P = 0.0004) and girls (P = 0.04), whereas IGFBP-3 correlated positively with insulin resistance in boys (P = 0.0004) but not girls (P = 0.85). These data suggest that the GH/IGF-I axis is an important contributor to the insulin resistance of puberty.     

Ghrelin and peptide YY in youth: are there race-related differences?

OBJECTIVE: Obesity prevalence is higher in African-American (AA) vs. American white (AW) youth. Ghrelin is a "hunger" peptide that is high preprandially and decreases postprandially, and peptide YY (PYY) is a "satiety" hormone increasing after meals. Impaired regulation of ghrelin/PYY may be conducive to obesity. We hypothesized that racial differences in childhood obesity could partly be explained by differences in ghrelin/PYY dynamics. RESEARCH DESIGN AND METHODS: We investigated: 1) ghrelin suppression/PYY elevation in response to an oral glucose tolerance test (OGTT) in AA vs. AW, and 2) the relationship of ghrelin and PYY dynamics to insulin sensitivity. Thirty-three AA and 54 AW prepubertal children underwent an OGTT measuring ghrelin, PYY, glucose, and insulin. Fasting glucose to insulin ratio (G(F)/I(F)) was used to assess the relationship of insulin sensitivity to fasting and post-OGTT ghrelin and PYY levels. RESULTS: OGTT-induced suppression in ghrelin (Delta ghrelin) was lower in AA youth. Delta ghrelin correlated with G(F)/I(F) (r = 0.47, P < 0.001) and Delta insulin at 30 min (r = -0.47, P < 0.001). In multiple regression analysis, race (P = 0.013) and G(F)/I(F) (P = 0.004) contributed independently to the variance in Delta ghrelin (R(2) = 0.28, P < 0.001). Fasting and post-OGTT PYY levels were lower in AAs and were not related to insulin sensitivity. CONCLUSION: The lower suppression of ghrelin in AA, but not the lower PYY levels, correlates with insulinemia and insulin resistance. Less ghrelin suppression and PYY elevation after a meal in black youth could be a potential mechanism of race-related differences in hunger/satiety predisposing to risk of obesity.     

Effects of ghrelin on the insulin and glycemic responses to glucose,arginine, or free fatty acids load in humans

Ghrelin possesses central and peripheral endocrine actions including influence on the endocrine pancreatic function. To clarify this latter ghrelin action, in seven normal young subjects [age (mean +/- SEM), 28.3 +/- 3.1 yr; body mass index, 21.9 +/- 0.9 kg/m(2)), we studied insulin and glucose levels after acute ghrelin administration (1.0 microg/kg i.v.) alone or combined with glucose [oral glucose tolerance test (OGTT), 100 g orally], arginine (ARG, 0.5 g/kg i.v.) or free fatty acid (FFA, Intralipid 10%, 250 ml). Ghrelin inhibited (P < 0.05) insulin and increased (P < 0.05) glucose levels. OGTT increased (P < 0.01) glucose and insulin levels. FFA increased (P < 0.05) glucose but did not modify insulin levels. ARG increased (P < 0.05) both insulin and glucose levels. Ghrelin did not modify both glucose and insulin responses to OGTT as well as the FFA-induced increase in glucose levels; however, ghrelin administration was followed by transient insulin decrease also during FFA. Ghrelin blunted (P < 0.05) the insulin response to ARG and enhanced (P < 0.05) the ARG-induced increase in glucose levels. In all, ghrelin induces transient decrease of spontaneous insulin secretion and selectively blunts the insulin response to ARG but not to oral glucose load. On the other hand, ghrelin raises basal glucose levels and enhances the hyperglycemic effect of ARG but not that of OGTT. These findings support the hypothesis that ghrelin exerts modulatory action of insulin secretion and glucose metabolism in humans.     

Insulin resistance has no impact on ghrelin suppression in pregnancy

Ghrelin is reduced in various states of insulin resistance. The aim of this study was to examine the relationship between ghrelin and glucose metabolism during pregnancy - a natural insulin-resistant state - in women with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM) and potential changes 3 months after delivery. A total of 54 women, 37 pregnant and with various degrees of insulin resistance and 24 postpartum (PP, seven of them also studied during pregnancy) were studied. Ghrelin plasma concentrations at fasting and 60' following glucose loading (75 g-2 h-oral glucose tolerance test), area under the curve of plasma glucose (G-AUC(OGTT)) and insulin sensitivity [homeostatic model assessment (HOMA) and oral glucose sensitivity index (OGIS) indices, respectively] were determined. Both baseline and 60' ghrelin concentrations were to a comparable degree ( approximately by 65%) suppressed in NGT, IGT and GDM as compared to the PP group (the latter being indistinguishable from NGT regarding glucose tolerance and insulin sensitivity). In all women studied both during and after pregnancy, ghrelin levels rose from pregnancy to PP (mean increase 313.8%; P < 0.03). There was no correlation between baseline ghrelin and insulin sensitivity as estimated from both baseline (HOMA) and dynamic (OGTT:OGIS) glucose and insulin data. Ghrelin is substantially decreased during pregnancy, but glucose-induced ghrelin suppression is preserved at a lower level. There is apparently no relation to the degree of insulin resistance.     

Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.     

Suppression of acylated ghrelin during oral glucose tolerance test is correlated with whole-body insulin sensitivity in children with Prader-Willi syndrome

CONTEXT: Decreased fasting ghrelin levels and decreased ghrelin suppression in overweight children have been reported to be associated with insulin resistance. However, Prader-Willi syndrome (PWS) is associated with increased total ghrelin levels and relative hypoinsulinemia. OBJECTIVE: The objective of the study was to analyze changes in acylated ghrelin (AG) and des-acylated ghrelin (DAG) levels after glucose loading and characterize correlations between insulin sensitivity and ghrelin suppression. DESIGN: Plasma glucose, insulin, AG, and DAG levels were measured in PWS children (n = 11) and normal obese controls (n = 10) during oral glucose tolerance testing. SETTING: All subjects were admitted to the Samsung Medical Center. INTERVENTIONS: Oral glucose tolerance testing was performed in all subjects after an overnight fast. MAIN OUTCOME MEASURES: Plasma levels of the hormones AG, DAG, and insulin, and those of glucose at 0, 30, 60, 90, and 120 min after glucose challenge were measured, and whole-body insulin sensitivity index (WBISI) values were calculated. RESULTS: AG levels fell markedly more from fasting levels in PWS children than normal healthy obese controls at 30, 60, and 90 min after glucose challenge, but no significant differences in DAG levels were observed at any time between PWS patients and controls. Fasting AG and DAG levels were found to correlate with WBISI in PWS, and absolute suppressions (Delta from baseline) in AG at 30 min after glucose challenge (nadir) were also correlated with WBISI in PWS (r = 0.64, P = 0.035). CONCLUSIONS: Our results suggest that AG is sensitively suppressed by insulin and that this suppression correlated with insulin sensitivity in PWS children.     

Regulation of ghrelin is related to estimated insulin sensitivity in obese children

OBJECTIVE: To investigate whether ghrelin concentrations and their changes during weight loss in obese children are associated with parameters of glucose and insulin metabolism. DESIGN: Total plasma ghrelin, insulin and glucose were measured during oral glucose tolerance testing before and after diet-induced weight loss over 6 weeks. SETTING: In-patient rehabilitation program in a pediatric hospital. PARTICIPANTS: Twenty-three obese children (age 10-16 years) and 11 normal weight controls (age 10-15 years). OUTCOME MEASURES: Changes in ghrelin concentrations during weight loss and correlation analysis of changes in ghrelin and changes in parameters of glucose and insulin metabolism. After data collection, subgroup analysis of obese patients with high, medium and low estimated insulin sensitivity whole-body insulin sensitivity index (WBISI) was performed. RESULTS: Weight loss increased the area under the curve (AUC) of ghrelin by 26% (P<0.001). The increase in ghrelin AUC correlated significantly with improved estimated insulin sensitivity (WBISI) (r=0.69, P<0.001). The independent predicting effect of WBISI was confirmed in multivariate analysis. In children with low WBISI, ghrelin reached the level of control values after weight loss. In children with high WBISI, ghrelin increased markedly above control levels. CONCLUSIONS: Changes in ghrelin are independently associated with changes in glucose and insulin metabolism. The increase in plasma ghrelin above control levels was limited to obese children with high WBISI.     

Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance

OBJECTIVE: It was hypothesized that resistin links obesity with diabetes, but this has not been studied in children and adolescents to date. PATIENTS: We determined serum resistin levels of 135 obese (body mass index, 32.0 +/- 6.2 kg/m2; age, 12.6 +/- 3.4 yr) and 201 lean children (body mass index, 18.7 +/- 2.4 kg/m2; age, 12.5 +/- 2.5 yr) by a newly developed and extensively evaluated in-house immunoassay. These results were controlled for their association with markers of puberty, obesity, and insulin sensitivity. RESULTS: The analytical evaluation of our assay revealed different resistin isoforms with major peaks of higher than 660 and 55 kDa in the size exclusion chromatography. Using this assay system we found no difference in the resistin levels of obese compared with lean subjects (P = 0.48). However, resistin was significantly higher in girls than in boys (6.74 +/- 2.42 vs. 5.79 +/- 2.45; P < 0.001). Interestingly, in both obese and lean children, resistin correlated with age (P < 0.01), Tanner stage, and testosterone and estradiol levels (P < 0.05). In contrast, no significant correlation was found with parameters of insulin resistance such as homeostasis model assessment, insulin sensitivity index, or insulin, proinsulin, and glucose concentrations in obese subjects. CONCLUSIONS: Resistin appears to be not the main link between obesity and insulin resistance in children and adolescents but because of its association with Tanner stage, it may be related to the maturation of children during pubertal development. Additionally, we have demonstrated the presence of different molecular isoforms of resistin in human blood, and this may raise problems in comparing data from diverse assay systems.     

Circulating ghrelin levels in patients with polycystic ovary syndrome

The syndrome of polycystic ovaries (PCOS) is associated with adiposity and metabolic changes predisposing to insulin resistance and diabetes mellitus. Because the recently discovered GH secretagogue, ghrelin, is intimately involved in the control of appetite and weight regulation, we studied ghrelin levels in a group of 26 otherwise healthy women with PCOS. They were compared with 61 healthy female control subjects and 5 gastrectomized women. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and continuous infusion of glucose with model assessment (CIGMA) in all patients. In PCOS women, serum ghrelin levels were significantly lower than in healthy lean or obese controls (P < 0.001). In insulin-sensitive PCOS women, ghrelin concentrations compared well with the healthy controls, whereas in insulin-resistant PCOS ghrelin levels were significantly lower and indistinguishable from the low levels found in the gastrectomized women. There was a close correlation of ghrelin to insulin sensitivity (HOMA, r(2) = 0.330, P < 0.002; CIGMA, r(2) = 0.568, P < 0.0001). Treatment of 10 insulin-resistant PCOS women with metformin significantly increased circulating fasting ghrelin concentrations (P < 0.02). Ghrelin levels did not correlate to any of the parameters of hyperandrogenemia, to the LH/FSH ratio, to body mass index, or to fasting insulin and glucose concentrations. In summary, ghrelin levels are decreased in PCOS women and are highly correlated to the degree of insulin resistance. This suggests that ghrelin could be linked to insulin resistance in PCOS women. However, whether low ghrelin in PCOS is a cause or the consequence of insulin resistance awaits further investigations.     

Insulin resistance and the persistence of obesity from childhood into adulthood.

Insulin resistance and obesity are associated in children as they are in adults. However, although insulin resistance seems to oppose further weight gain in adults, opposite results have been found in children. To investigate the relationship between childhood obesity, insulin resistance, and long-term weight gain, we selected 215 obese Caucasian children (120 males and 95 females) aged 10.5 (+/-2.4) yr, with a relative body mass index (BMI) of 153.8% (+/-27.7%) and normal glucose tolerance. Insulin resistance was assessed at baseline by using the homeostasis model assessment. Fourteen (+/-5) years later, 103 subjects returned for a follow-up examination of height and weight. At follow-up, 37 subjects (36%) were obese (BMI > or = 30), 33 (32%) were overweight (25 < or = BMI < 30), and 33 (32%) were of normal weight (20 < or = BMI < 25). In a multiple regression, relative BMI and insulin resistance at childhood were independent predictors of adulthood BMI (r(2) = 0.44; P < 0.01) in girls. A multivariate logistic regression analysis showed that high relative BMI [odds ratio, 1.06; 95% confidence interval, 1.00-1.13; P = 0.04] and low insulin resistance index at baseline (odds ratio, 0.58; 95% confidence interval, 0.34-0.99; P = 0.04) predicted obesity in adulthood for girls, no matter their age, Tanner stage, and their parents' BMI. In boys, insulin resistance was not a significant predictor of adult obesity. In conclusion, obesity tracks into adulthood for many obese Caucasian children. In obese girls, insulin resistance during childhood appears to oppose the risk of obesity in adulthood.     

Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans

OBJECTIVE: Circulating ghrelin levels are increased by fasting and decreased by feeding, glucose load, insulin and somatostatin. Whether hyperglycaemia and insulin directly inhibit ghrelin secretion still remains matter of debate. The aim of the present study was therefore to investigate further the regulatory effects of glucose and insulin on ghrelin secretion. DESIGN AND SUBJECTS: We studied the effects of glucose [oral glucose tolerance test (OGTT) 100 g orally], insulin-induced hypoglycaemia [ITT, 0.1 IU/kg insulin intravenously (i.v.)], glucagon (1 mg i.v.), arginine (0.5 mg/kg i.v.) and saline on ghrelin, GH, insulin, glucose and glucagon levels in six normal subjects. MEASUREMENTS: In all the sessions, blood samples were collected every 15 min from 0 up to + 120 min. Ghrelin, GH, insulin, glucagon and glucose levels were assayed at each time point. RESULTS: OGTT increased (P < 0.01) glucose and insulin while decreasing (P < 0.01) GH and ghrelin levels. ITT increased (P < 0.01) GH but decreased (P < 0.01) ghrelin levels. Glucagon increased (P < 0.01) glucose and insulin without modifying GH and ghrelin. Arginine increased (P < 0.01) GH, insulin, glucagon and glucose (P < 0.05) but did not affect ghrelin secretion. CONCLUSIONS: Ghrelin secretion in humans is inhibited by OGTT-induced hyperglycaemia and ITT but not by glucagon and arginine, two substances able to increase insulin and glucose levels. These findings question the assumption that glucose and insulin directly regulate ghrelin secretion. On the other hand, ghrelin secretion is not associated with the GH response to ITT or arginine, indicating that the somatotroph response to these stimuli is unlikely to be mediated by ghrelin.     

Increased 24h mean insulin-like growth factor binding protein-3 proteolytic activity in pubertal type 1 diabetic boys

Hyperglycaemia and increased variability of blood glucose in pubertal children with type 1 diabetes may be related to increased growth hormone (GH) secretion and insulin resistance. The role of changes in insulin-like growth factor-I (IGF-I) bioavailability for the glycaemic control in these patients has not been completely elucidated. In particular, the possible role of increased IGF binding protein-3 (IGFBP-3) proteolysis reported in other insulin resistant states awaits further characterization. The aims of this study were to assess if hyperglycaemia in children with type 1 diabetes was associated with changes in free dissociable IGF-I (fdIGF-I) and IGF binding protein-3 protease activity (IGFBP-3-PA) and if increased insulin resistance during puberty was associated with changes in IGFBP-3-PA in healthy and diabetic children. In diabetic boys in the period of maximal linear growth (Tanner stage 3, n = 5), the mean level and the variability of IGFBP-3-PA, determined every second hour throughout 24 h, were significantly higher both compared to postpubertal diabetic boys (n = 6; P = 0.003 and P = 0.001, respectively), and to age matched healthy boys (n = 4; P = 0.006 and P < 0.001 respectively). This activation of IGFBP-3-PA was most prominent during the day time.The mean 24 h blood glucose level (determined hourly) was the only parameter studied that significantly predicted the changes in mean 24 h IGFBP-3-PA in the diabetes group. The mean 24 h concentrations of fdIGF-I were decreased in the diabetic boys compared to the healthy controls but statistical significance was only achieved in Tanner Stage 5 (p = 0.03). We speculate that the elevated levels of IGFBP-3-PA in Tanner 3 diabetic boys are related to deteriorated glucose homeostasis and that it may be a compensatory mechanism to attenuate the decrease in fdIGF-I in order to partly restore insulin sensitivity and glycemic control.