A new link between skeleton, obesity and insulin resistance: relationships between osteocalcin, leptin and insulin resistance in obese children before and after weight loss.

BACKGROUND: The skeleton is regarded recently as an endocrine organ that affects energy metabolism. However, there are very limited data available concerning the relationships between the osteoblast-derived hormone osteocalcin, weight status, adiponectin and leptin in obese humans, especially in children. METHODS: We analyzed osteocalcin, adiponectin, leptin and insulin resistance (IR) index homeostasis model assessment (HOMA) in 60 obese and 19 age- and gender-matched normal weight children. Furthermore, these parameters were determined in 60 obese children after participating in an outpatient 1-year lifestyle intervention based on exercise, behavior and nutrition therapy. RESULTS: Sixty obese children had significantly lower osteocalcin levels (26.8+/-0.8 ng ml(-1)) than 19 normal weight controls (32.2+/-2.3 ng ml(-1)). Boys (29.9+/-1.1 ng ml(-1)) showed significantly (P=0.046) higher osteocalcin levels compared with girls (26.4+/-1.2 ng ml(-1)). In stepwise multiple linear regression analysis adjusted for age, gender and pubertal stage, osteocalcin was significantly negatively related to leptin and HOMA, but not to adiponectin. Changes of osteocalcin in the course of 1 year correlated significantly negatively with changes of IR index HOMA (r=-0.25), standard deviation score-body mass index (SDS-BMI) (r=-0.33) and leptin (r=-0.50). Substantial weight loss in 29 obese children led to a significant increase in osteocalcin and a significant decrease in leptin and HOMA. In 31 obese children without substantial weight loss, osteocalcin levels did not change significantly in the course of 1 year. CONCLUSION: Osteocalcin levels were lower in obese children and were related to IR and leptin both in cross-sectional and longitudinal analyses. Therefore, osteocalcin might be a new promising link between obesity and IR.

Effect of moderate intake of sweeteners on metabolic health in the rat.

The rise in prevalence of obesity, diabetes, metabolic syndrome, and fatty liver disease has been linked to increased consumption of fructose-containing foods or beverages. Our aim was to compare the effects of moderate consumption of fructose-containing and non-caloric sweetened beverages on feeding behavior, metabolic and serum lipid profiles, and hepatic histology and serum liver enzymes, in rats. Behavioral tests determined preferred (12.5-15%) concentrations of solutions of agave, fructose, high fructose corn syrup (HFCS), a combination of HFCS and Hoodia (a putative appetite suppressant), or the non-caloric sweetener Stevia (n=5/gp). HFCS intake was highest, in preference and self-administration tests. Groups (n=10/gp) were then assigned to one of the sweetened beverages or water as the sole source of liquid at night (3 nights/wk, 10wks). Although within the normal range, serum cholesterol was higher in the fructose and HFCS groups, and serum triglycerides were higher in the Agave, HFCS, and HFCS/Hoodia groups (vs. water-controls, p<0.05). Liver histology was normal in all groups with no evidence of steatosis, inflammation, or fibrosis; however serum alanine aminotransferase was higher in the fructose and HFCS groups (vs. water-controls, p<0.05). Serum inflammatory marker levels were comparable among Stevia, agave, fructose, HFCS, and water-consuming groups, however levels of IL-6 were significantly lower in association with the ingestion of Hoodia. There were no differences in terminal body weights, or glucose tolerance assessed by 120-min IVGTTs performed at the end of the 10-week regimen. We conclude that even moderate consumption of fructose-containing liquids may lead to the onset of unfavorable changes in the plasma lipid profile and one marker of liver health, independent of significant effects of sweetener consumption on body weight.

TCF7L2 polymorphism rs7903146 and predisposition for type 2 diabetes mellitus in obese children.

Polymorphism RS7903146 in transcription factor 7-like2 gene ( TCF7L2) is associated with type 2-diabetes mellitus (T2DM) in adults. Concerned with predisposition for diabetes mellitus in obese children, we tested if risk genotypes TC and TT of rs7903146 are more common in obese children with increased homeostasis model assessment insulin resistance index (HOMA-IR) compared to obese controls with normal HOMA-IR. As exploratory analysis, we also calculated beta-cell function for these risk genotypes and measured glucagon-like peptide 1 (GLP-1) in a subgroup. The cohort was 401 obese children (BMI > 2SDS; 211 female; 59% presenting increased HOMA-IR) from two German outpatient obesity referral centers. Genotype distributions in patients presenting increased HOMA-IR (TT: 10.18%, CT: 35.65%, CC: 54.17%) and in patients with normal HOMA-IR (TT: 8.66%, CT: 42.67%, CC: 48.67%) provided no significant effect of these two risk genotypes (p > 0.2). Correction for possible confounder's gender, age, pubertal stage, and BMI revealed no association with glucose metabolism parameters including GLP-1. However, exploratory HOMA-B% index was comparatively higher in TT-homozygotes (p=0.021) as compared to CC-homozygotes. We conclude that even though TT and CT genotypes were not higher in patients presenting elevated HOMA-IR, the higher HOMA-B% index in TT-homozygotes indicates TCF7L2 to be a susceptibility gene for the development of impaired glucose tolerance in obese children as demonstrated in several adult cohort studies.

Shorter remission period in young versus older children with diabetes mellitus type 1.

BACKGROUND: The initial period of diabetes type 1 is of great importance, since early metabolic adjustment has profound impact on long term control. The majority of pediatric centers in Germany participate in a national quality initiative, providing longitudinal data for central analysis. PATIENTS: 104543 anonymous data sets were obtained from 6123 pediatric patients under 18 years who were treated in 157 pediatric centers and monitored for 36 months at the same center starting from diagnosis. RESULTS: Partial remission (insulin <0.5 U/kg/d and HbA1c < or = 7.0%) was present in 1992 children (32.5%) within the first 3 months after diagnosis. Remission phase lasted in average for 0.74 +/- 0.77 years and was significantly shorter in children below 10 years of age at onset of diabetes compared to the older patients. The remission period was significantly longer in boys, particularly in children under 10 years (p=0.0039). Multiple regression analysis showed a longer remission phase in children with pubertal diabetes onset. The children entering remission were younger, more often boys and had a lower initial HbA1c level. CONCLUSION: These data from a large multicenter group of children with diabetes type 1 emphasize the influence of gender, pubertal stage and age at manifestation on the amount of insulin required, and therefore the clinical remission, during the first three years of the disease.

Pancreatic polypeptide in obese children before and after weight loss.

OBJECTIVE: Little is known concerning pancreatic polypeptide (PP) in weight loss and in childhood obesity. METHODS: Fasting PP, leptin and insulin concentrations were determined in 38 obese children and compared with 35 lean children of the same age, gender and pubertal stage. Furthermore, changes of PP concentrations over a 1-year period were analyzed in the obese children participating in a weight loss intervention program. RESULTS: Obese children had significantly (P<0.01) lower PP, and higher leptin and insulin levels compared to lean children. In multiple linear regression analysis, PP was significantly negatively correlated to body mass index (P<0.01), but not to leptin, insulin, age, gender and pubertal stage. Changes of PP did not significantly correlate to changes of insulin (r=0.07, P=0.343) and leptin (r=-0.02, P=0.459). The substantial weight loss in 17 children led to a significant (P<0.05) increase in PP and decrease in insulin and leptin. In the 21 children without substantial weight loss, there were no significant changes in PP, insulin and leptin. CONCLUSIONS: PP concentrations are decreased in obese children and independent of age, gender, pubertal stage, leptin and insulin. The decrease of PP in obese children normalized after weight loss. Therefore, low PP concentrations reflect the overweight status, rather than cause it.

Resistin concentrations before and after weight loss in obese children.

OBJECTIVE: The influences of gender, puberty, and obesity on resistin levels and the longitudinal relationships between insulin resistance, weight loss, and resistin have not yet been studied in childhood. METHODS: Age, pubertal stage, gender, weight status (standard deviation score-body mass index (SDS-BMI)), resistin levels, and insulin resistance index calculated by homeostasis model assessment (HOMA) were evaluated in 63 obese children and compared to 36 lean children of same age, gender, and pubertal stage. Furthermore, we analyzed the changes of weight status (SDS-BMI, percentage body fat based on skinfold measurements), waist-to-hip ratio, resistin, and HOMA over a 1-year period in 38 obese children. RESULTS: The resistin levels did not significantly (P = 0.079) differ between obese (median resistin 8.7 ng/ml) and lean children (median resistin 9.7 ng/ml). Resistin concentrations were independent of age and pubertal stage, but girls demonstrated significantly higher resistin levels than boys (P = 0.021). There were no significant correlations between changes of resistin and changes of SDS-BMI (r = 0.14, P = 0.198), changes of percentage body fat (r = -0.01, P = 0.466), changes of waist-to-hip ratio (r = 0.17, P = 0.141), and changes of insulin resistance index (r = 0.01, P = 0.472) over the 1-year period. The weight loss of > or = 0.5 SDS-BMI in 16 children was associated with a significant decrease in HOMA (P = 0.030), while there was no significant change in resistin levels (P = 0.878). CONCLUSIONS: Girls demonstrated higher resistin concentrations than boys. Our data do not support a relationship between resistin, insulin resistance index, and weight status in childhood.

Different effects of agonistic vs. antagonistic gnrh-analogues (triptorelin vs. cetrorelix) on bone modeling and remodeling in peripubertal female rats.

Little is known about the effects of antagonistic GnRH analogues vs. agonists on bone strength, specifically in context of treating precocious puberty. Peripubertal female rats were treated from postnatal day 25 - 36 with either the GnRH agonist triptorelin (TRIP) or the antagonist cetrorelix (CET). Using peripherial quantitative computerized tomography (pQCT) we investigated effects on bone parameters. Onset of puberty was retarded by both analogues as measured by prevention of vaginal opening at 36 d of age and reduced uterine weights. In the tibia, cortical content, cortical area related to body weight, and periosteal circumference related to weight were significantly reduced in CET-treated rats - indicating reduced bone modeling and reduced bone strength (cortical circumference related to body weight: CET 0.066 +/- 0.001 vs. TRIP 0.068 +/- 0.001 vs. controls 0.071 +/- 0.001 mm/g, mean +/- SEM, p < 0.05 CET vs. controls; cortical area related to body weight: CET 3.87 +/- 0.46 vs. TRIP 6.80 +/- 0.63 vs. controls 8.07 +/- 1.13, x 10 (-3) mm (2)/g, p < 0.001 CET vs. controls; cortical content: CET 0.316 +/- 0.038 vs. TRIP 0.546 +/- 0.051 vs. controls 0.624 +/- 0.089 mg/mm, p < 0.01 CET vs. controls). In conclusion, although both CET and TRIP inhibit puberty in rats, cortical thinning was only seen in CET-treated rats. This indicates that GnRH antagonist treatment might cause reduced bone strength which is partly comparable to postmenopausal bone loss. When using new GnRH antagonists for treating precocious puberty in humans, parameters for bone strength and mineralization should be monitored.

Antagonistic and agonistic GnRH analogue treatment of precocious puberty: tracking gonadotropin concentrations in urine.

BACKGROUND: The pharmacodynamics of gonadotropin-releasing hormone (GnRH) agonists includes an initial 'flare-up' of the pituitary-gonadal axis, followed by reduced luteinizing hormone (LH) secretion. The question is if combining a short-acting antagonist with a long-acting agonist can diminish gonadotropin flare-up. METHODS: To achieve quick downregulation in patients with recently diagnosed central precocious puberty (CPP, 7 patients) or short stature with short predicted final height (3 patients), we combined the GnRH antagonist cetrorelix (3 subcutaneous injections every 72 h) at the beginning of GnRH agonist treatment (leuprorelin or triptorelin) in 6 patients and compared the effect to 4 patients treated solely with GnRH agonist. To monitor effects, we measured LH and FSH concentrations in urine collected from initial morning urination during the first month of treatment. RESULTS: In both treatment groups, gonadotropin flare-up could be detected in urine levels increased due to the flare-up phenomenon which was of short duration (<5 days) in the majority (5 of 6) of combined-treated patients and in the minority (1 of 4) of patients treated by agonist alone. During the first 10 days of treatment, mean LH concentration measured in urine was significantly lower in 4 CPP patients treated by the combined therapy compared to 3 CPP patients treated by the agonist only (mean LH combined therapy: 10.4 +/- 2.8 vs. 20.1 +/- 11.0 mU/ml in the agonist-only group, mean +/- SEM, p < 0.05). Significant correlations between stimulated serum LH in GnRH test prior to treatment and maximum urine LH after initiating GnRH analogue treatment (r = 0.547, p = 0.043), as well as basal serum LH and basal urine LH (r = 0.685, p = 0.014) were found. CONCLUSION: Combined GnRH agonist and antagonist treatment led to rapid gonadotropin suppression. Also, urine measurements of LH and FSH seemed suitable for monitoring gonadotropin-inhibiting or -stimulating properties of GnRH analogues in individual patients. However, a controlled trial of a larger patient cohort is required to decide which treatment is the most effective.

Ghrelin levels before and after reduction of overweight due to a low-fat high-carbohydrate diet in obese children and adolescents.

BACKGROUND: There are conflicting results for ghrelin changes in reduction of overweight. Increasing ghrelin levels in weight reduction are considered to be responsible for compensatory mechanisms that make the reduction of overweight unlikely to be sustained. METHODS: We have analyzed fasting serum ghrelin levels, weighed dietary record and, as biochemical markers of clinically relevant reduction of overweight, leptin, adiponectin and insulin levels and insulin resistance measured by homeostasis model assessment (HOMA) at baseline and after a 1-y outpatient weight reduction program based on a high-carbohydrate and low-fat diet in 37 obese children (median age 10 y). We divided these children into two subgroups according to their degree of weight loss (substantial reduction of overweight: decrease in SDS-BMI > or = 0.5). Furthermore, we analyzed ghrelin levels in 16 normal-weight children. RESULTS: Obese children demonstrated significant (P<0.001) lower ghrelin levels compared to normal-weight children. Daily caloric intake (P = 0.004) and percentage fat content decreased significantly (P<0.001), while percentage carbohydrate content increased significantly (P = 0.003) between baseline and 1-y follow-up in the obese children. The substantial reduction of overweight in 16 children (median SDS-BMI = -0.7) was associated with significant changes in insulin resistance (median decrease of HOMA 27%; P = 0.013), insulin (median decrease 25%, P = 0.036), adiponectin (median increase 15%; P = 0.003), and leptin levels (median decrease 19%; P = 0.023), while there were no significant changes in ghrelin levels (median increase 4%; P = 0.326). In the 21 children without substantial reduction of overweight (median SDS-BMI = -0.3), there were no significant changes in insulin resistance and in insulin, adiponectin, leptin and ghrelin levels. CONCLUSIONS: We conclude that in obese children, low-fat high-carbohydrate diet-induced weight loss does not change ghrelin secretion, but significantly decreases leptin levels, increases adiponectin levels and improves insulin resistance determined by significantly decreased insulin resistance indices as well as lowered serum insulin levels.