The role of vascular endothelial growth factor in the development of papillary thyroid carcinoma in patients with lymphocytic thyroiditis.

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of autoimmune chronic inflammatory conditions and papillary thyroid carcinoma (PTC). We hypothesized that, as VEGF expression is increased both in PTC and in lymphocytic thyroiditis (LT), it may stimulate the development of PTC in patients with LT. To evaluate this, we examined both tumor and adjacent non-tumoral tissues of PTC patients with and without LT. METHODS: A total of 50 patients with PTC (52.50±7.41 years) and 17 patients with nodular goiter (NG) (50.47±10.38 years) were included in the study. According to the presence of LT, patients with PTC were further divided into two groups. Immunohistochemical analyses of VEGF were conducted in all patients and for PTC patients, both tumor tissue and adjacent non-tumoral tissue were evaluated. RESULTS: The scores for intensity of staining and percentage of labeled thyrocytes for VEGF were found to be significantly higher in the PTC patients than in the NG patients (p<0.001, p<0.001, respectively). The tumor tissue revealed similar scores for PTC patients with LT and without LT. However, the scores in adjacent non-tumoral tissue were higher in PTC patients with LT than in patients without LT (p=0.004, p=0.01, respectively). CONCLUSIONS: To the best of our knowledge, our results are the first to demonstrate that the expression of VEGF in adjacent non-tumoral tissue were higher in PTC patients with LT than in those without, which shows a possible role of VEGF expression in the progression of PTC in the presence of LT.

Adiponectin levels decrease independently of body mass index and diabetes type after the normalization of hyperglycemia

Background/aim: Acute hyperglycemia is generally a frequently encountered condition in the emergency department (ED), because it is seen as a complication of diabetes mellitus (DM). In this study, we aimed to detect the change in adiponectin levels during acute hyperglycemic states and after normalization of blood glucose with insulin treatment. Materials and methods: Forty-eight patients over the age of 18 years who were admitted to the ED with acute hyperglycemia were included in the study. Serum samples were taken from patients on admission and 6 h after the normalization of blood glucose with insulin treatment, and adiponectin levels were measured in both samples. Results: There were 21 female and 27 male patients with a median age of 58.7 ± 18 years. All patients' blood glucose levels were normalized with insulin treatment according to international recommendations. Serum adiponectin levels decreased significantly after the normalization of blood glucose in the whole group. Adiponectin levels decreased from 28.9 ± 16.5 to 12.1 ± 10.9 µg/mL (P < 0.0001) in the whole group. This decrease was independent of diabetes type and body mass index. Conclusion: Normalization of blood glucose in patients with hyperglycemia caused a decrease in adiponectin levels, independent of diabetes type and/or body weight in an acute emergency setting. Inhibited upregulation of adiponectin secretion and/or blunted suppressive effect of insulin due to hyperglycemia or exogenous insulin administration may have caused the decrease in adiponectin levels.

Thyroid volumes and serum VEGF levels in dyslipidemic patients: effects of statin treatment

Background/aim: Defective vascularization may be important in thyroid nodular disease. In this study, we aimed to investigate serum vascular endothelial growth factor (VEGF) levels in dyslipidemic patients with thyroid nodules, as well as the effects of statin therapy Materials and methods: The study included 37 dyslipidemic patients with thyroid nodules and 32 dyslipidemic patients without thyroid nodules. Anthropometry, serum VEGF levels, biochemical parameters, thyroid-stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) levels, and thyroid sonography were determined before and after 6 months of statin therapy. Results: Patients with and without thyroid nodules had similar metabolic parameters. Serum VEGF levels did not differ between the groups. In patients with nodules, VEGF levels remained unchanged (P = 0.931) after statin therapy. However, serum VEGF levels were lowered by statin treatment in patients without nodules (P = 0.030). Statin therapy resulted in a decrease in the dominant thyroid nodule volume. The changes in thyroid volume and dominant thyroid nodule volume were not correlated with changes in VEGF, body mass index, total cholesterol, low-density lipoprotein cholesterol, or homeostatic model assessment of insulin resistance (HOMA-IR). Conclusion: Although statin treatment decreases serum VEGF levels in dyslipidemic patients without thyroid nodules, it has no lowering effect on serum VEGF levels in patients with thyroid nodules. The decrease in thyroid nodule volume with statin treatment was associated with neither metabolic parameters nor serum VEGF levels.

The association between thyroid volume, L-thyroxine therapy and hepatocyte growth factor levels among patients with euthyroid and hypothyroid goitrous and non-goitrous Hashimoto's thyroiditis versus healthy subjects.

OBJECTIVE: Hashimoto's thyroiditis (HT) is the most common etiology of hypothyroidism in regions where iodine deficiency is not a concern. To date, many clinical investigations have been conducted to elucidate its pathogenesis. Several growth factors have been shown to have a role in its development. Hepatocyte growth factor (HGF) is one of the aforementioned molecules. We aimed to demonstrate whether HGF is responsible for HT and goiter development. Also, we aimed to test the hypothesis that levo-thyroxine sodium therapy will suppress HGF levels. MATERIALS AND METHODS: Sixty-one premenopausal women who were admitted to our outpatient clinic between November 2010 and September 2011 were enrolled. Three groups were determined according to their thyroid function tests (TFTs) as euthyroid Hashimoto's, control and subclinical hypothyroid Hashimoto's groups. Basal TFTs, anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-tg), thyroid ultrasonography (USG) and HGF were studied and recorded. Subclinical hypothyroid HT patients received levo-thyroxine sodium replacement therapy, and were re-assessed for the same laboratory and radiologic features after a median 3.5 month follow-up. RESULTS: Basal HGF levels were not different between groups. In the subclinical hypothyroidism group, HGF levels (752.75 ± 144.91 pg/ml vs. 719.37 ± 128.05 pg/ml; p = 0.496) and thyroid volumes (12.51 ± 3.67 cc vs. 12.18 ± 4.26 cc; p = 0.7) before and after treatment did not change significantly. No correlations were found between HGF and other parameters. HGF levels were similar between subjects with nodular goiter and normal thyroid structure. CONCLUSIONS: HGF was not shown to be associated with HT and goiter development. In addition, levo-thyroxine sodium replacement therapy did not alter serum HGF levels significantly.

Serum Adiponectin Levels and Changes in Glucose Metabolism before and after Treatment for Thyroid Dysfunction.

OBJECTIVE: Adiponectin is an adipokine which is known to decrease in individuals associated with obesity and insulin resistance. In this study, we aimed to investigate the serum adiponectin levels and glucose metabolism in patients with thyroid dysfunction before and after treatment. METHODS: Newly diagnosed overt hypothyroid (n=20) and thyrotoxic (n=23) patients and healthy controls (n=20) with a body mass index of <30 kg/m(2) were evaluated prospectively. Patients with a known state of insulin resistance, including prediabetes and overt diabetes, and individuals with chronic diseases were excluded. Thyroid function and fasting plasma glucose (FPG), insulin, homeostatic model assessment (HOMA) insulin resistance (HOMA-IR) and HOMA-beta cell function (HOMA-beta), lipid and adiponectin levels were investigated in the basal state and after the restoration of euthyroidism. RESULTS: The basal fasting FPG levels were lower in the hypothyroid patients than the control subjects (p=0.02) and similar between the thyrotoxic patients and control subjects (p=0.127). The basal HOMA-beta levels were higher in the patients with hypothyroidism than in those with thyrotoxicosis (p=0.015). Following the restoration of euthyroidism, the FPG levels significantly increased in the hypothyroid patients (p=0.002) and decreased in the thyrotoxic (p=0.001) patients. The basal plasma adiponectin levels were 14.55±8.4 mcg/mL, 13.79±9.13 mcg/mL and 11.68±6.0 mcg/mL in the hypothyroid and thyrotoxic patients and healthy controls, respectively (p=0.503). The adiponectin levels decreased significantly in the patients with hypothyroidism (p=0.047), whereas they did not change in the patients with thyrotoxicosis (p=0.770) after achieving euthyroidism. CONCLUSION: In this study, following the restoration of euthyroidism, the FPG levels increased in the hypothyroidism patients and decreased in the thyrotoxicosis patients, despite the lack of changes in the HOMA-IR and HOMA-beta levels. Meanwhile, the hypothyroid, thyrotoxic and euthyroid subjects had similar basal adiponectin levels, and a significant decrease in the adiponectin levels was observed after treatment for hypothyroidism, despite the absence of changes after treatment for thyrotoxicosis, indicating the need for further studies with a larger sample size.

Effects of L-thyroxine therapy on circulating leptin and adiponectin levels in subclinical hypothyroidism: a prospective study.

Subclinical hypothyroidism (SCH) is defined by increased thyrotropin (TSH) and normal free thyroxine (fT4) levels. Controversial data are available regarding the effects of SCH on adipose tissue. Adiponectin and leptin are two major adipokines secreted from adipose tissue. We aimed to determine the levels of adiponectin and leptin in women with SCH and potential effects of L-thyroxine therapy on those levels. Forty three women with SCH and 53 age- and BMI-matched healthy euthyroid control women were included. Adiponectin and leptin levels, total cholesterol (TC), triglycerides (TG), HDL-, and LDL cholesterol, fat mass (FM) and fat-free mass (FFM) were determined in all participants. Patients received L-thyroxine treatment for 6 months after which all measurements were repeated. Patients with SCH and controls had similar baseline values for adiponectin, leptin, lipids, FM and FFM. All patients reached euthyroid status after 6 months of replacement therapy. Treatment resulted in an increase in adiponectin (p <0.01) and a decrease in leptin levels (p <0.05). Lipid levels, FM and FFM did not show a significant change. Achievement of euthyroid status by replacement therapy increases adiponectin and decreases leptin levels in women with SCH in this prospective study independent of a change in body fat mass.

25-OH-Vitamin D and procalcitonin levels after correction of acute hyperglycemia.

BACKGROUND: Hyperglycemia is a common complication of diabetes melitis (DM) and in the absence of metabolic decompensation is a common finding in the Emergency Department (ED). We aimed to evaluate the 25 OH Vit D [25(OH)D] and procalcitonin (PCT) levels during hyperglycemia and after normalization of blood glucose. MATERIAL AND METHODS: The study included 88 patients over the age of 18 years who presented with acute hyperglycemia at the Hacettepe University Department of Emergency Medicine. Euglycemia was obtained within 6-12 hours and serum samples were taken from patients on admission and 6 hours after normalization of blood glucose. Along with plasma glucose, plasma 25(OH)D and PCT levels were measured using ELISA. RESULTS: There were 88 (45 males) patients, with a median age of 60.0±13.9 years. Serum 25(OH)D levels increased in all patients after normalization of blood glucose, and serum PCT levels decreased in the whole group. This decrease was independent of type of diabetes or presence of infection. CONCLUSIONS: We demonstrated an increase in 25(OH)D after normalization of blood glucose, and a decrease in PCT in patients with hyperglycemia. This effect was independent of the type of diabetes and presence of infection. Further studies are needed to evaluate the faster link between metabolic abnormalities, vitamin D, PCT, and inflammation.

Serum resistin and high sensitive CRP levels in patients with subclinical hypothyroidism before and after L-thyroxine therapy.

BACKGROUND: Subclinical hypothyroidism (SH) is defined by increased thyrotropin (TSH) and normal free thyroxine (fT4) and free triiodothyronine (fT3) levels. Resistin is secreted from adipose tissue and is reported to be associated with insulin resistance and/or inflammation. High sensitive CRP (hs-CRP) is a reliable marker of inflammation. Data related to levels of resistin and hs-CRP in SH and the effect of L-thyroxine treatment on those is limited. We aimed to determine the levels of resistin and hs-CRP in women with SH, and potential effects of L-thyroxine therapy on those levels. MATERIAL AND METHODS: Thirty-six patients with SH and 27 age- and BMI-matched healthy control women were included. Waist circumference (Wc), waist-to-hip ratio (WHR), resting energy expenditure (REE), fat mass (FM) and lean mass (LM), TSH, free T4 (fT4), free T3 (fT3), total cholesterol (TC), triglycerides (TG), and HDL- and LDL-cholesterol were determined in all participants. Patients received L-thyroxine treatment for 6 months, after which all measurements were repeated. Resistin and hs-CRP levels were studied from frozen samples after the completion of the study. RESULTS: The 2 groups had similar values for Wc, WHR, FM, LM, TC, TG, HDL-C, LDL-C, resistin, and hs-CRP at the beginning. fT4 were higher, whereas TSH was lower in the control group. Resistin and hs-CRP levels did not change after treatment. hs-CRP correlated with BMI and FM before and after treatment. CONCLUSIONS: Our results suggest that achievement of euthyroid status by replacement therapy did not change resistin or hs-CRP levels in women with SH. hs-CRP correlated with parameters of obesity, which emphasizes the role of body weight in inflammation.

Impaired aortic elastic properties in patients with adult-onset hypogonadism.

BACKGROUND: Recent studies have shown a strong relationship between testosterone levels and vasomotor actions. The aim of this study is to compare the elastic properties of the aorta in male patients with hypogonadism and eugonadal healthy control subjects. METHOD: A total of 22 male with hypogonadism (mean age: 35.2 ± 9.5 years, mean disease duration: 5.3 ± 1.8 years) and 25 age-, sex- and weight-matched eugonadal healthy subjects (mean age: 34.5 ± 8.2 years) were enrolled in the study. Aortic stiffness (ß) index, aortic strain (AoS) and aortic distensibility (AoD) were calculated from the aortic diameters measured by transthoracic echocardiography and blood pressure obtained by sphygmomanometer. RESULTS: The routinely performed echocardiographic parameters were similar between patient and control groups. There were significant differences between the control and patient groups in ß index (1.75 ± 0.44 vs 2.68 ± 1.72, p < 0.001), AoS (18.52 ± 6.44 vs 12.35 ± 3.88%, p < 0.001) and AoD (7.56 ± 2.86 vs 3.96 ± 1.24, 10(-6) cm(2)/dyn, p < 0.001). There were statistically significant positive correlations between the serum total testosterone level and AoD (r = 0.539, p < 0.001) and AoS (r = 0.372, p = 0.036); moreover, there was a negative correlation between the serum total testosterone level and ß index (r = - 0.462, p = 0.001). In multivariate analysis, serum total testosterone level was significantly related with AoD, AoS and ß index (respectively, RR = 2.88, p = 0.004; RR = 3.45, p = 0.001; RR = 2.64, p = 0.01). CONCLUSION: The study results showed that aortic elasticity was impaired in patients with hypogonadism. We also have demonstrated a statistically significant correlation between aortic elastic properties and the serum total testosterone level.

Pigment epithelium-derived factor increases in type 2 diabetes after treatment with metformin.

OBJECTIVE: Pigment epithelium-derived factor (PEDF) has anti-angiogenic, immunomodulatory and anti-inflammatory properties. In addition to the significant role it plays in reducing diabetic complications, PEDF is now used in the treatment of certain cancers. It possibly plays a role in insulin resistance cases, too. However, whether metformin treatment has any significant effects on PEDF levels is not known. In this study, we investigated the regulation of PEDF in type 2 diabetes in relation to fat mass and insulin resistance before and after the use of metformin for treatment. DESIGN: Prospective cohort study. SUBJECTS: Thirty-six patients with newly diagnosed type 2 diabetes and 33 healthy individuals. MEASUREMENTS: Baseline weight, waist circumference (WC), fasting (FPG) and postprandial (PPPG) glucose, insulin, HbA1c, HOMA, PEDF and total/truncal fat mass were determined both in the diabetic and control subjects. Procedures were repeated in the diabetic group after a 6-month metformin treatment. RESULTS: Baseline FPG, PPPG, HbA1c, HOMA, weight, WC and truncal fat mass were higher in patients with diabetes whereas PEDF levels were found to be comparable with the controls. We completed the study with 31 of the 36 patients with diabetes we had selected for the study. We observed a decrease in the weight, WC, FPG, PPPG, HOMA, total and truncal fat mass of the patients while there was a significant rise in the PEDF levels (P = 0·002) after the metformin treatment. On the other hand, no significant correlation was observed between the change in PEDF levels and the clinical and laboratory findings. CONCLUSION: Our study is the first to identify a metformin-related increase in PEDF levels in diabetes. The increase observed in PEDF levels after the metformin treatment does not seem to be related to the changes in insulin resistance, fat mass or glycemic control. Hence, our results suggest that further investigation is necessary to determine the direct effects of metformin on PEDF gene and protein expression in vitro.

Serum vaspin levels in hypothyroid patients.

OBJECTIVE: To elucidate the link between TSH and obesity, the relationship between TSH and adipocytokines were previously studied. Animal studies demonstrated a possible relationship between vaspin levels and thyroid functions. In this study, we aimed to investigate vaspin levels in hypothyroid states and its relationship with insulin resistance parameters in humans. DESIGN: Prospective observational study. METHODS: We enrolled 27 overt hypothyroid, 33 subclinical hypothyroid and 41 euthyroid patients. We measured the body mass index (BMI), fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), lipid profile, TSH, free triiodothyronine, free thyroxine and vaspin levels. The change in vaspin levels in 12 overt hypothyroid patients after establishment of euthyroidism was analysed. RESULTS: All groups were age-matched. Overt hypothyroid group had higher BMI values (P<0.05) than other groups. No significant difference was observed in insulin levels and HOMA-IR among the groups (P>0.05). Adjusted vaspin levels for BMI and age were similar among the groups. Mean vaspin levels in overt, subclinical and euthyroid patients were 1.20 ± 1.17, 1.48 ± 0.93 and 0.95 ± 0.75  ng/ml respectively (P>0.05). There was no significant association between vaspin levels and BMI, fasting glucose, insulin and HOMA-IR (P>0.05). Establishing euthyroidism in hypothyroid patients did not result in a significant change in vaspin levels (before and after treatment, 1.35 ± 1.06 and 1.25 ± 0.68  ng/ml, respectively; P>0.05). CONCLUSION: We herein present novel data indicating vaspin levels are neither altered in overt and subclinical hypothyroidism nor have a relationship with features of insulin resistance in hypothyroid patients.

Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells.

Statins show antiproliferative activity in various cancer cells. The aim of this study was to evaluate the effects of rosuvastatin treatment on papillary thyroid carcinoma. The papillary thyroid carcinoma (B-CPAP) and normal (Nthy-ori 3-1) thyroid cell lines were treated with rosuvastatin at 12.5, 18.5, 25, 50, 100, and 200 µM concentrations. After 48 and 72 h of rosuvastatin treatment, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Ki-67 immunolabeling, FACS analysis, electron microscopy, caspase-3, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) analysis were performed. Decreased cell viability and G1 phase arrest were detected in papillary thyroid cell line treated with rosuvastatin. Positive immunoreactivity of Ki-67 and dose-dependent increase in S phase on Nthy-ori 3-1 cells were also detected. B-CPAP cells showed intense vacuolisation and autophagosomes with low concentrations and 48 h incubations, while Nthy-ori 3-1 cells showed these changes at higher concentrations. A decrease in the percentage of cells showing autophagy was determined with increasing concentrations of rosuvastatin in B-CPAP cells. Rosuvastatin treatment also caused a dose- and time-dependent increase in caspase-3 activity and apoptotic index by TUNEL assay in B-CPAP cells compared with the Nthy-ori 3-1 cells. Apoptotic cells with nuclear condensation and fragmentation were observed in B-CPAP cell line. Rosuvastatin induced autophagic changes in B-CPAP papillary thyroid cancer cells in lower doses and caused a shift from autophagy to apoptosis. Rosuvastatin may be an alternative treatment for refractory papillary thyroid cancer. Further in vivo studies are necessary to clarify the effects of rosuvastatin in papillary thyroid carcinoma and the clinical implications of rosuvastatin treatment.

Macroprolactinaemia in diabetic patients.

OBJECTIVE: Prolactin levels have been shown to be reduced in poorly controlled diabetes mellitus; however, diabetic patients with high prolactin levels may be seen in clinical practice. The aim of this study was to evaluate diabetic patients with hyperprolactinemia, and to determine the role of macroprolactinaemia in these patients. MATERIALS AND METHODS: The study included 174 patients (153 women and 21 men) with hyperprolactinemia, retrospectively reviewed over a 2 years period. Data on presenting symptoms, the presence of diabetes mellitus, prolactin levels, macroprolactin levels, pituitary magnetic resonance imaging were collected in all patients. In addition; HbA1c, fasting blood glucose levels and postprandial glucose levels were collected in diabetic patients. RESULTS: Of the 174 patients, 27 were diagnosed with diabetes mellitus (15.5%). Eighteen of the diabetic patients with hyperprolactinaemia had macroprolactinaemia (66.6%). The prevalence of macroprolactinaemia in diabetic patients is higher than the non-diabetic population (66.6% vs. 39.5%, p=0.009). In diabetic patients with macroprolactinaemia, HbA1c levels were higher than the diabetic patients without macroprolactinaemia. CONCLUSION: The prevalence of macroprolactinaemia in diabetic patients was higher than the non-diabetic population. It seems necessary to determine macroprolactin levels in diabetic patients with hyperprolactinaemia; and in this case, further diagnostic evaluation is not warranted.

Role of adipocytokines in predicting the development of diabetes and its late complications.

Diabetes is an important health problem since the incidence of diabetes is continuously increasing. Early diagnosis is important as type 2 diabetes begins long before we diagnose it, leading to a complicated course of the disease. In order to prevent delay in the diagnosis of type 2 diabetes, novel predictors and pathways for type 2 diabetes are mounting. Diabetic complications are common cause of morbidity and mortality among subjects with diabetes. In the pathogenesis of diabetic complications some factors other than chronic hyperglycemia may be involved. Adipocytokines play important roles in the pathogenesis of diabetes mellitus, insulin resistance, and associated metabolic conditions such as hypertension and dyslipidemia. The investigations on the role of adipocytokines in developing diabetes and its complications have been made. In this review, we discussed the implications of adipocytokines in predicting diabetes and diabetic complications, with particular attention on the roles of adiponectin, leptin, visfatin, and vaspin.

Serum vaspin levels in type 2 diabetic women in relation to microvascular complications.

OBJECTIVE: Vaspin is a novel adipokine that has insulin sensitizing effects. The association between serum vaspin levels and diabetic complications is unknown. In this study, we aimed to evaluate serum vaspin levels as related to glycemic status and the presence of complications in a group of type 2 diabetic women. MATERIALS AND METHODS: We evaluated 37 type 2 diabetic female patients and 37 control female subjects who were matched for age and body-mass index. Anthropometric measurements, insulin, hemoglobin A1c (HbA1c), C-reactive protein, and serum vaspin levels were measured in each participant. Furthermore, the patients were evaluated for diabetic neuropathy, nephropathy, and retinopathy. RESULTS: In diabetic patients, serum vaspin levels correlated positively with HbA1c and correlated negatively with insulin levels and homeostasis model assessment. The patients with HbA1c levels 7% (0.11+/-0.06 ng/ml versus 0.20+/-0.09 ng/ml, P<0.05). In patients with neuropathy, retinopathy, and nephropathy, serum vaspin levels were lower than in patients without neuropathy (0.10+/-0.07 ng/ml versus 0.17+/-0.09 ng/ml, P=0.041), retinopathy (0.11+/-0.06 ng/ml versus 0.18+/-0.09 ng/ml, P=0.019), and nephropathy, (0.11+/-0.05 ng/ml versus 0.18+/-0.09 ng/ml, P=0.02). Diabetic patients receiving metformin therapy had lower vaspin levels than patients not receiving metformin. CONCLUSION: Diabetic women with good glycemic control have lower levels of vaspin than those with poor glycemic control. However, presence of microvascular complications is also associated with low vaspin levels. In order to use serum vaspin levels as a marker, evaluating patients for complications and medications interfering with serum vaspin levels seems appropriate.