The prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents is on the rise, and the increase in prevalence of this disorder parallels the modern epidemic of childhood obesity ...worldwide. T2DM affects primarily post-pubertal adolescents from ethnic/racial minorities and those from socioeconomically disadvantaged backgrounds. Youth with T2DM often have additional cardiovascular risk factors at diagnosis. T2DM in youth is more progressive in comparison to adult onset T2DM and shows lower rates of response to pharmacotherapy and more rapid development of diabetes-related complications. Lifestyle modifications and metformin are recommended as the first-line treatment for youth with T2DM in the absence of significant hyperglycemia. Assessment of pancreatic autoimmunity is recommended in all youth who appear to have T2DM. Pharmacotherapeutic options for youth with T2DM are limited at this time. Liraglutide, a GLP-1 agonist, was recently approved for T2DM in adolescents 10 years of age and older. Several clinical trials are currently underway with youth with T2DM with medications that are approved for T2DM in adults. Bariatric surgery is associated with excellent rates of remission of T2DM in adolescents with severe obesity and should be considered in selected adolescents.
Context:
Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies ...(thyroid-stimulating antibodies TSAbs) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction.
Objective:
The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH).
Design:
Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling.
Main Outcome Measures:
cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed.
Results:
Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production.
Conclusions:
Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.
ABSTRACT
Biotherapeutics are known for their potential to induce drug specific immune responses, which are commonly evaluated by the detection of anti-drug antibodies (ADAs). For some ...biotherapeutics, pre-existing ADAs against drug have been observed in drug-naïve matrix. The presence of pre-existing drug specific antibodies may significantly complicate assessment of the screening ADA assay cutpoint value, which is usually established based on the statistical analysis of signal distribution from the drug-naïve individuals. A Gaussian mixture model-based approach is presented herein to address high prevalence of pre-existing ADAs to a modified monoclonal antibody-based biotherapeutic (m-mAb). A high prevalence of pre-existing anti-m-mAb antibodies was observed in drug-naïve individual cynomolgus monkey serum samples with signal ranging from 100 to 7000 relative light units (RLU, as determined in an electrochemiluminescence readout-based assay). Application of the industry standard statistical algorithm resulted in a relatively high floating screening assay cutpoint factor (CPF) of 9.80, which potentially would have reported a high percent of false negative samples. An alternative, Gaussian mixture model-based approach was applied to identify the least reactive individual samples in the tested population, which resulted in a floating screening assay CPF of 2.35. The low CPF value significantly reduced the risk of reporting false negative results. The proposed Gaussian mixture model-based approach described herein provides an alternate method for the calculation of biologically relevant screening assay CPF when high prevalence of pre-existing drug specific antibodies is observed.
Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital tissues associated with elevated serum levels of TSH receptor (TSHR) autoantibodies. Because previous studies have ...demonstrated evidence of adipogenesis within the GO orbit, we sought to determine whether M22, a human monoclonal antibody directed against TSHR, enhances adipogenesis in orbital fibroblasts from patients with GO and, if so, to identify signaling mechanisms involved. GO orbital fibroblast cultures (n=10) were treated for 10 days with bovine TSH (1 or 10.0 U/l) or M22 (1 or 10 ng/ml) in serum-free adipocyte differentiation medium. Some cultures also received a phosphoinositide 3-kinase (PI3K) inhibitor or an inhibitor of cAMP production. In other experiments, confluent cultures (n=8) were treated for between 1 and 30 min with TSH (0.1-10.0 U/l) or M22 (0.1-100 ng/ml) with measurement of cAMP production or levels of phosphorylated AKT (pAKT). We found levels of adiponectin, leptin, and TSHR mRNA to be increased in GO cultures treated for 10 days with either M22 (2.6 mean fold ± 0.7; P=0.03) or TSH (13.2 ± 5.8-fold, P=0.048). In other studies, M22 and TSH stimulated cAMP production and pAKT levels in GO cells. Inhibition of PI3K activity during 10 days in culture decreased the levels of M22-stimulated mRNA encoding adiponectin (67 ± 12%; P=0.021), as well as adiponectin and CCAAT/enhancer-binding protein α protein levels. In conclusion, M22 is a pro-adipogenic factor in GO orbital preadipocytes. This antibody appears to act via the PI3K signaling cascade, suggesting that inhibition of PI3K signaling may represent a potential novel therapeutic approach in GO.
Objective To study the relationships between serum vitamin D levels and plasma glucose or lipid levels in children and adolescents. Study design We conducted a retrospective record review of ...pediatric outpatients (age, 2-18 years) with simultaneous measurement of 25-hydroxyvitamin D (25OH D) and fasting plasma glucose (n = 302) or 25(OH) D and a lipid panel (n = 177). Pearson correlation coefficient was used to estimate the correlation between 25(OH) D and logarithmic transformed plasma glucose or lipid levels. Plasma glucose and lipid levels were compared in subjects with 25(OH) D concentrations greater or less than 30 ng/mL. Results 25(OH) D levels were inversely correlated with fasting plasma glucose levels (r = –0.20, P < .001). Lower 25(OH) D levels were also associated with lower serum high-density lipoprotein cholesterol (HDL) concentrations (r = 0.41; P ≤ .001). The relationship between 25(OH) D levels and fasting glucose and HDL levels did not vary significantly with sex, age, body mass index z-score, or season. Children who were vitamin D insufficient (25OH D ≤30 ng/mL) had higher fasting plasma glucose ( P = .002) and lower HDL levels ( P < .001) than children who were vitamin D sufficient (25OH D >30 ng/mL). Conclusions Low 25(OH) D levels in children and adolescents are associated with higher plasma glucose and lower HDL concentrations.
The study aim was to test hypotheses informed by self-determination theory (SDT) regarding associations of adolescent motivators for weight loss and family feeding practices on understanding ...adolescent weight management and dietary behaviors. Adolescents (n = 71) with obesity were recruited from a large medical center in the Midwest USA and completed questionnaire assessments via an online survey. Results supported hypotheses that endorsement of health motivators for weight loss, conceptualized as autonomous (intrinsic) motivation, and positive family support would be associated with healthier weight management practices and dietary behaviors. Nuanced findings related to social- and self-esteem-related motivators for weight loss indicated a need for further understanding of these weight-loss motivators in the context of SDT. The current study findings highlight the importance of addressing motivational factors and family influences in research and practice related to promoting healthy dietary habits and weight management strategies among adolescents with obesity.
Childhood obesity has emerged as an important public health problem in the United States and other countries in the world. Currently 1 in 3 children in the United States is afflicted with overweight ...or obesity. The increasing prevalence of childhood obesity is associated with emergence of comorbidities previously considered to be "adult" diseases including type 2 diabetes mellitus, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and dyslipidemia. The most common cause of obesity in children is a positive energy balance due to caloric intake in excess of caloric expenditure combined with a genetic predisposition for weight gain. Most obese children do not have an underlying endocrine or single genetic cause for their weight gain. Evaluation of children with obesity is aimed at determining the cause of weight gain and assessing for comorbidities resulting from excess weight. Family-based lifestyle interventions, including dietary modifications and increased physical activity, are the cornerstone of weight management in children. A staged approach to pediatric weight management is recommended with consideration of the age of the child, severity of obesity, and presence of obesity-related comorbidities in determining the initial stage of treatment. Lifestyle interventions have shown only modest effect on weight loss, particularly in children with severe obesity. There is limited information on the efficacy and safety of medications for weight loss in children. Bariatric surgery has been found to be effective in decreasing excess weight and improving comorbidities in adolescents with severe obesity. However, there are limited data on the long-term efficacy and safety of bariatric surgery in adolescents. For this comprehensive review, the literature was scanned from 1994 to 2016 using PubMed using the following search terms: childhood obesity, pediatric obesity, childhood overweight, bariatric surgery, and adolescents.
PDF
