| BackgroundAs a kind of chronic disease caused by multiple reasons,obesity has become a very serious social problem globally due to the increasing of its incidence rate,especially for children and teenagers.Obesity has already been linked with insulin resistance,hypertension,dyslipidaemia,hyperglycemia and cardiovascular disease.Childhood obesity is a prominent predictors of adulthood obesity.Approximately half of the obese children remain obese as adults,and once established in adulthood,obesity can rarely be resolved through voluntary physical exercises.Thus,early intervention is an attractive strategy to avoid the complications of adult obesity.Life style modification and caloric restriction are the preferred treatment options for childhood obesity treatment,but the limitation of these methods are their low success rate.Also sustained weight reduction,and pharmacological treatment has not been widely studied.The major physiologic and bioactive components of Growth hormone(GH)which is generated by anterior pituitary is a 22 kDa single-chain of 191 amino acids.The main function of GH is to regulate linear growth,energy expenditure,body composition,hepatic lipid metabolism,and on vascular function.As an important mediator of GH secretion,Insulin-like growth factor 1(IGF-1)is primarily synthesized from the liver.It also plays a key role in normal growth and development.The functions of IGF-1 are to regulate growth,to improve glucose sensitivity,and to stimulate protein synthesis as well as inhibit protein breakdown.Apart from the most commonly reported obesity-related co-morbidities,obesity is also associated with the abnormalities in the GH-IGF-1 axis.But unlike the unequivocal effects of significantly lower GH observed in patients with obesity,there are some controversies about the relationship between obesity and IGF-1.Reduced IGF-1,normal or high IGF-1 in obese subjects have been reported previously.In addition,there are still some controversies with regard to the relationship among IGF-1,the components of metabolic syndrome and cardiovascular risk factors.Furthermore,very few of previous studies focused on the samples of children and adolescents,especially those of obese group.For both children and adults,obesity is associated with impaired spontaneous GH secretion and decreased GH response to stimulation test.This GH deficiency(GHD)associated with obesity is relative and is reversible with weight loss,so this change of GH is relative and functional.During the last decades,several studies started to focus on the research question around the association between functional hyposomatotropism and cardiometabolic risk markers in obesity.However,few of previous literature have investigated whether recombinant human growth hormone(rhGH)could improve complications of childhood obesity in obese with relative GHD children.Therefore,relevant studies should be carried out to further confirm the effects of rhGH as a treatment in obesity with relative GHD children.In this present study,we investigated the association between IGF-1 and low high-density lipoprotein cholesterol(HDL-C),Non-alcoholic fatty liver disease(NAFLD)and other components of metabolic syndrome in obese children and adolescents.We also assessed the effects of rhGH on body weight,cardiovascular risk factors and safety in obese with relative GHD patients.Our overreaching goal is to provide clinical evidences for the effects of rhGH on treating obesity with relative GHD children.Part I The change of insulin-like growth factor 1 and the association with low high-density lipoprotein cholesterol in obese children and adolescentsObjectives As the central feature of the metabolic syndrome,obesity it is always associated with several short-term and long-term metabolic and cardiovascular complications.Low HDL-C,which is identified as an independent risk factor for developing cardiovascular disease is also linked with obesity.As an important mediator of GH secretion,lower IGF-1 level is also closely linked with obesity,insulin resistance,metabolic syndrome and cardiovascular disease.At present,some studies have already reported the positive correlation between IGF-1 and HDL-C.However,this relationship didn't focus on the samples of children and adolescents,especially those of obese group.Therefore,due to the particularity of such samples,in this present study,our purpose is to investigate the relationship among IGF-1 and HDL-C,metabolic syndrome in obese children and adolescents.Subjects and Methods1.Subjects:This study was conducted at the Department of Pediatric Endocrinology of Shandong Provincial Hospital Affiliated to Shandong University between July 2011 and November 2015.A total of 120 obese children were included in our final analysis.Low HDL-C was defined as HDL-C levels<1.03mmol/L.Obese children were further divided into two groups according to HDL-C level.120 children and adolescents which were selected from a population of non-obese healthy children and adolescents are identified as control group.The obesity group and control group were matched on age,pubertal status and gender.2.Methods:Clinical examination and laboratory examinations were assessed for all participants.Height,weight,systolic blood pressure(SBP),diastolic blood pressure(DBP),pubertal stages,IGF-1,total cholesterol(TC),HDL-C,low density lipoprotein-cholesterol(LDL-C),triglycerides(TG),fasting blood glucose(FBG),fasting insulin,alanine aminotransferase(ALT)and uric acid(UA)were performed in all participants.These parameters were compared between obesity group and control group,also between obese subjects with low HDL-C group and obese subjects with HDL-C ?1.03mmol/L.We finally applied logistic regression analysis to verify the association among IGF-1 SDS,HDL-C,and other components of metabolic syndrome.Results1.Obese subjects had significantly lower IGF-1 SDS and higher Height standard deviation score(Ht SDS)than those in the control group.2.Among 120 obese children and adolescents,22(18.3%)subjects had an HDL-C level lower than 1.03mmol/L.IGF-1SDS was significantly lower(P= 0.001)in obese subjects with low HDL-C.According to the results of bivariate correlation analysis,IGF-1 SDS was significantly correlated with HDL-C in study population(r=0.19,P=0.003).3.According to the results of multivariate logistic regression analysis,IGF-1 SDS is significantly associated with low HDL-C(OR 0.518,95%CI 0.292-0.916;P=0.024),after being adjusted for age,gender,pubertal status,Body mass index standard deviation scores(BMI SDS),SBP,DBP,Homeostasis model assessment of insulin resistance(HOMR-IR),TC3 LDL-C,TG,ALT and UA.In addition,Based on logistic regression analysis with adjustment for age,gender and pubertal status,the increased IGF-1 SDS was associated with a decreased probability of metabolic syndrome(OR 0.555,95%CI 0.385-0.801;P=0.002)and hypertriglyceridemia(OR 0.582,95%CI 0.395-0.856;P=0.006),but no significant correlation with hypertension.Conclusions1.Apart from the most commonly reported obesity-related co-morbidities,obese children had lower IGF-1 SDS compared with samples in control group.2.The level of IGF-1 SDS was positively associated with the level of HDL-C in Chinese nondiabetic obese children and adolescents,independent of insulin resistance,as well as other traditional cardiovascular disease risk markers.Partr ? Insulin-like growth factor 1 and metabolic parameters are associated with non-alcoholic fatty liver disease in obese children and adolescentsObjectivesNAFLD has gradually become one of the major public health problems for children and adolescents,due to the rising obesity levels of such population.The definition of NAFLD covers a wide spectrum of liver diseases,ranging from simple steatosis to nonalcoholic steatohepatitis(NASH)that can evolve into cirrhosis and hepatic carcinoma.As the hepatic manifestation of metabolic syndrome,NAFLD has always been considered to be associated with several metabolic and cardiovascular disorders.IGF-1 production is mainly produced in liver.The first part of our study has demonstrated that IGF-1 is associated with the components of metabolic syndrome in obese children.The aim of this part was to investigate the relationships between IGF-1,metabolic parameters and NAFLD.Subjects and Methods1.Subjects:This study was conducted at the Department of Pediatric Endocrinology of Shandong Provincial Hospital Affiliated to Shandong University between July 2013 and September 2015.A total of 168 obese children were included in our final analysis.The diagnosis of NAFLD was estimated with an ultrasound scan.Obese children were divided into two groups according to NAFLD level:90 in the NAFLD group and 78 in the non-NAFLD control group.Anthropometric measurements,laboratory examinations and liver ultrasonography were assessed for all participants.2.Methods:Height,weight,SBP,DBP,pubertal stages,IGF-1,ALT,Aspartate aminotransferase(AST),Gamma-glutamyl-transferase(GGT),TC,HDL-C,LDL-C,TG,FBG,Fasting insulin,Glycosylated haemoglobin(HbA1C),UA and liver ultrasonography were performed for all obese children.These parameters were compared between with and without NAFLD in obese children.Univariate and multivariate logistic regression analyses were then applied to investigate the relationship between IGF-1,Body mass index(BMI),HOMA-IR,UA and NAFLD.The receiver operating characteristic curve was constructed to predict the presence of NAFLD.Results1.Lower IGF-1 SDS levels and HDL-C were more significant for the subjects with NAFLD(P=0.001,P=0.018)compared with those in control group,and samples in treated group also had higher levels of BMI,HOMA-IR,UA,SBP,DBP,insulin,HbA1C,TG and liver enzymes(ALT?AST?GGT)(p<0.05).2.Univariate and multi-variable risk factor analyses for NAFLD:(1)univariate analysis showed that IGF-1 SDS,BMI,HOMA-IR,UA,SBP,DBP,HbA1C and HDL-C were all closely associated with NAFLD,and could be selected as the variables of final equation.(2)results from the multivariable analysis showed that the following were associated with NAFLD:IGF-1 SDS(OR 0.727,95%CI 0.559-0.946,p=0.017);BMI(OR 1.14,95%CI 1.043-1.247,p=0.004),HOMA-IR(OR 1.136,95%CI 1.017-1.269,p=0.024)and uric acid(OR 1.005,95%CI 1.001-1.009,p=0.02).Therefore,BMI,HOMA-IR and uric acid were found to be independent risk factors for NAFLD,and IGF-1 SDS was a protective factor for NAFLD.3.The receiver operating characteristic curve was developed to predict the presence of NAFLD and the area under the curve(AUC)indicated the clinical usefulness of these markers and their diagnostic power.The value of the AUC was 0.649(95%CI 0.571-0.721,p<0.001),when the cut-off value for the IGF-1 SDS was?-1.6 and the sensitivity and the specificity were 37.78%and 87.18%,respectively.The AUC,for a BMI of>27.04 kg/m2 was 0.758(95%CI 0.686-0.821,p<0.001),the sensitivity was 83.33%and the specificity was 60.26%.The AUC for HOMA-IR>5.58 was 0.702(95%CI 0.626-0.770,p<0.001)and the sensitivity and specificity were 63.33%and 73.08%,respectively.The AUC for uric acid>345?mol/L was 0.694(95%CI 0.618-0.762,p<0.001),the sensitivity was 76.67%and the specificity was 57.69%.Furthermore,we performed an analysis for the receiver operating characteristic curve of multiple variables,including IGF-1 SDS,BMI,HOMA-IR and uric acid.The combined analysis of the AUC was 0.812(95%CI 0.745-0.868,p<0.001)and the combined detection of all four markers improved sensitivity to 78.89%and specificity to 74.36%.These variables predicted 81.2%of the cases with NAFLD in obese children.Conclusions 1.We found that IGF-1 SDS,BMI,HOMA-IR and uric acid were independently associated with NAFLD in Chinese obese children and adolescents based on our results.BMI,HOMA-IR,uric acid and low IGF-1 SDS were found to be independent risk factors for NAFLD.2.The combined analysis of IGF-1 SDS.BMI,HOMA-IR and uric acid can detect NAFLD accurately with a good area under the curve(0.812),with high sensitivity(78.89%)and high specificity(74.36%)in this cohort.So we suggested that IGF-1,BMI,HOMA-IR and uric acid may be useful to identify the risk of NAFLD.Thus,our findings have important and useful implications for the clinical management of NAFLD.Part ? Effects of recombinant human growth hormoneadministration in obese with relative GHD childrenObjectivesIn obesity,low GH secretion have been recognized.The altered somatotroph of obesity can be reversed with weight loss,so this change of GH is relative and functional.During the last decades,several studies indicated that the relative GHD was associated with cardiovascular complications in obesity.GH treatment of obese adults,who exhibit similar GH axis abnormalities as obese children,reduces abdominal obesity and improves insulin sensitivity,as well as blood lipid profiles.However,studies targeting to the effect of rhGH on children's obesity are very scant,thus its usefulness for children is still unobserved.To this end,by requesting the obese with relative GHD participants to receive a 6 months of rhGH treatment,the purpose of this study was to examine the effect of GH treatment on obesity-related co-morbidities,and to assessed the safety in obese with relative GHD children.The results of this study can provide clinical evidences for whether rhGH can be treated as a potential treatment for obese with relative GHD children.Subjects and Methods1.Subjects:This study was conducted at the Department of Pediatric Endocrinology of Shandong Provincial Hospital Affiliated to Shandong University between July 2012 and September 2016.A total of 23 obese with relative GHD children were included in our final analysis.Control group includes 20 children and adolescents recruited from non-obese healthy children and adolescents.The obesity group and control group were matched on age,pubertal status,Ht SDS and gender.2.Methods:Height,weight,pubertal stages,GH stimulating tests,free triiodothyronine(FT3),free thyroxine(FT4),thyroid-stimulating hormone(TSH),adrenal corticotropic hormone(ACTH),cortisol(COR),IGF-1,TC,HDL-C,LDL-C,TG,ALT,AST,FBG,Fasting insulin,hypothalamic-pituitary(Magnetic resonance imaging MRI)and bone age(BA)were performed in all children.Obese with relative GHD children all received rhGH replacement therapy.Anthropometric measurements,laboratory examinations(thyroid function,IGF-1,liver function,FBG,lipid profile,HbA1C,hemogram,urinalysis,and urinary calcium)were reassessed after 3 month and 6 month of therapy.Parameters were compared between children with relative GHD,and those in control group.For obese with relative GHD children,differences in parameters between before and after therapy were compared.Results1.Clinical and laboratory characteristics of obese with relative GHD children:Significantly higher BMI SDS were observed in the subjects with relative GHD children(p=0.001)than in the control group.GH secretion was evaluated using arginine test and levodopa test in two groups.Obesity subjects had lower peak GH based on the arginine-levodopa stimulation test(P<0.001),and they also had lower IGF-1 and IGF-1 SDS compared with the control group(P=0.012,P=0.004).Subjects in the obese with relative GHD group had higher ALT,AST,higher levels of serum insulin,HOMA-IR,TC,LDL-C and TG compared with normal-weight controls.It also had lower HDL-C compared with the control group(P=0.037).There were no significant differences in fasting glucose.2.Clinical and endocrine metabolic changes before and after rhGH treatment:(1)In obese with relative GHD children,after 3 and 6 months of treatment,BMI SDS decreased significantly during GH treatment compared with those before therapy(P=0.002,P=0.001).(2)However,after 3 month and 6 months of therapy,IGF-1 and IGF-1 SDS increased(all P<0.05).(3)After 3 month of rhGH therapy,AST decreased non-significantly compared with those before therapy.At 6 months,AST decreased compared with those before therapy(P=0.005).Additionally,After 3 month and 6 months of rhGH therapy,ALT decreased compared with those before therapy(P=0.027,P=0.003).(4)After 3 month and 6 months of therapy,TC,TG,LDL-C values decreased compared with those before therapy(all P<0.05).After 3 month of therapy,HDL-C level increased compared with those before therapy(P=0.042).However,there was a rising trend for GH to HDL-C after 6 month of therapy(P=0.056).(5)No significant effects of GH treatment on on FBG were observed after 3 month of therapy,but FBG level increased after 6 month of therapy compared with subjects before therapy(P=0.022).For HbA1C,we did not measure it at base period.After 6 month of therapy,no significant effects of GH treatment on HbA1C compared were observed with 3 month of rhGH therapy(P=0.641).There were no significant differences in serum insulin and HOMA-IR before and after 3 month and 6 months of rhGH therapy.3.Adverse events:There were no serious adverse events during the experiment.rhGH was well tolerated and no subject required a dose reduction.There were 4 cases of hypothyroidism during rhGH treatment,but their thyroid function returned to normal after levothyroxine treatment.2 children were found to have arthralgias,and no other adverse reactions have been observed.Conclusions1.Significantly lower peak GH,IGF-1,IGF-1 SDS levels were observed in the relative GHD group than in the control group,and they also had higher levels of BMI SDS,higher ALT,AST,higher levels of serum insulin,HOMA-IR,TC,LDL-C and TG compared with normal-weight controls.But lower HDL-C was observed comparing with the control group.2.rhGH treatment for 6 monthsr of obese with relative GHD children reduces BMI SDS,stabilize IGF-1 levels,exerted beneficial effects on blood lipid profiles and live enzyme.3.rhGH treatment for 6 monthsr of obese with relative GHD children with no significant effects on increased insulin resistance and minimal or no effect on glucose homeostasis.No other serious adverse reactions occurred during the experment. |
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