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Background:In adults without thyroid disease, increasing levels of thyroid-stimulating hormone (TSH) within the range of that considered normal have been shown to be associated with increases in total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, and with decreases in high-density lipoprotein cholesterol. Serum TSH has also been found to be positively associated with fasting and postload insulin concentrations and negatively associated with insulin sensitivity in euthyroid adults. We hypothesized that such relationships also exist in euthyroid children and adolescents.Methods:This was a retrospective record review of pediatric outpatients (ages 2–18 years) having measurements of TSH or free thyroxine (T4) and a concurrent lipid panel, fasting glucose, or fasting insulin. Pearson correlation coefficient was used to estimate the correlation between TSH or free T4 and logarithmic transformed lipid, plasma glucose, or insulin levels. Lipid levels, fasting plasma glucose, insulin, and homeostasis model assessment (HOMA) were also compared between subjects with TSH levels in the high normal range (2.5–5 mIU/L) and those with TSH in the low normal range (0.3–2.4 mIU/L).Results:TSH levels were positively correlated with triglyceride levels (r= 0.10, p= 0.001). Conversely, free T4 levels were inversely correlated with triglyceride levels (r= −0.10, p= 0.011). TSH levels were also positively correlated with fasting insulin (r= 0.26, p= 0.002) and with HOMA (r= 0.27, p= 0.001). These associations remained significant after adjustment for age, gender, and body mass index z-score. Children who had TSH levels between 2.5 and 5.0 mIU/L had higher triglycerides (p= 0.003), insulin levels (p= 0.040), and HOMA (p= 0.021) than those having TSH values between 0.3 and 2.4 mIU/L.Conclusions:In euthyroid children without a history of hypo- or hyperthyroidism, increasing levels of TSH and decreasing levels of free T4 are associated with higher triglyceride levels and elevated markers of insulin resistance. Whether these findings carry implications regarding optimal TSH levels in children at increased risk for cardiovascular disease awaits further study. [ABSTRACT FROM AUTHOR]

Background:Patients with Graves'' ophthalmopathy (GO) have circulating autoantibodies directed against the thyrotropin receptor (TSHR) and elevated levels of the proinflammatory cytokine interleukin-6 (IL-6) in both serum and orbital tissues. We hypothesized that these autoantibodies might increase IL-6 expression and secretion in preadipocyte fibroblasts and adipocytes from patients with GO, and thus directly impact the clinical activity of the disease.Methods:IL-6mRNA levels were measured in cultures of GO orbital preadipocytes (n= 3) treated during adipocyte differentiation with a monoclonal stimulatory TSHR antibody (M22; 10 ng/mL), IL-6 (1 ng/mL), or TSH (10 U/L). Additionally, levels of IL-6 protein secretion were assessed after adipocyte differentiation in orbital cultures exposed to TSH or M22 for 24 or 48 hours (n= 8). IL-6mRNA levels were also measured in orbital adipose tissue specimens from well-characterized GO patients (n= 9) and normal individuals (n= 9).Results:Treatment of GO orbital preadipocyte cultures with IL-6, TSH, or M22 during adipocyte differentiation resulted in increased IL-6mRNA levels (3.1-fold, 2.9-fold, and 2.7-fold, respectively; p< 0.05). Treatment of orbital cultures with M22 or TSH after adipocyte differentiation enhanced the release of IL-6 protein into the medium at both 24 and 48 hours for TSH (mean 1.9- and 2.3-fold; p= 0.002 and 0.015, respectively) and at 48 hours for M22 (mean 2.0-fold; p= 0.005). In addition, we found mean IL-6mRNA levels to be significantly increased in GO orbital adipose tissue specimens (10-fold; p< 0.01), primarily attributable to high levels in three of the four patients with clinical activity scores ≥5.Conclusions:Both TSH and M22 increase IL-6expression in orbital preadipocyte fibroblasts and IL-6 secretion by mature adipocytes. These results suggest that circulating TSHR autoantibodies in GO might play a direct role in the clinical activity of the disease. [ABSTRACT FROM AUTHOR]

Background:Thy-1 is a surface protein that defines functionally distinct subpopulations of fibroblasts, with those lacking the antigen being capable of adipogenesis. Because increased fat cell development is a hallmark of the orbit in Graves'' ophthalmopathy (GO), we wished to compare baseline Thy-1 expression in orbital fibroblasts from GO patients and normal individuals, and determine whether levels of the protein might be impacted by adipogenesis following peroxisome proliferator activator-γ ligation.Methods:Orbital adipose/connective tissue specimens were obtained from euthyroid patients undergoing orbital decompression surgery for severe GO (n= 9) and from normal individuals (n= 9). Thy-1 mRNA and protein levels were assessed in tissue specimens and in orbital fibroblast cultures at baseline using RT-PCR, quantitative immunofluorescent staining, and flow cytometry using a specific Thy-1 mouse anti-human CD90/Thy-1 monoclonal antibody. In addition, some orbital fibroblast cultures were treated with rosiglitazone (1 μL/mL; 2 nM) or control for 10 days in culture.Results:We found that Thy-1 mRNA and protein expression was higher in uncultured GO connective/adipose tissue specimens (3.8-fold; 0.835 ± 0.116 relative expression) compared with normal (0.22 ± 0.062; p= 0.002) and in cultured orbital fibroblasts from GO patients (3.3-fold; 9.28 ± 1.82 relative expression) compared with normal cultures (2.80 ± 0.42; p= 0.013). Adipocyte differentiation had no effect on Thy-1 expression. Flow cytometry and immunofluorescent staining showed increased numbers of Thy-1–positive cells in the GO (mean 77.9 + 4.09%; range 66.5–84.8%) compared with the normal fibroblast cultures (66.8 + 1.6%; range 63.3–71.0% positive; p= 0.046), as well as higher levels of expression on the positive cells.Conclusions:Increased Thy-1 expression in GO orbital tissues and cultures is likely a consequence of the orbital disease process, reflecting both the presence of increased numbers of Thy-1–positive cells and higher expression on those cells. Adipogenesis itself does not appear to impact Thy-1 expression. Increased expression of this protein in GO could represent an adaptive response to cell injury, in effect limiting disease progression within the orbital adipose/connective tissues. [ABSTRACT FROM AUTHOR]