The relationship of epicardial adipose tissue thickness to clinical and biochemical features in women with polycystic ovary syndrome.

The amount of epicardial adipose tissue (EAT), a component of body visceral adiposity, has been linked to the presence and severity of cardiovascular disease through multiple mechanisms. Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and subclinical inflammation, which participate in the mechanism of atherosclerosis. We searched if the patients with PCOS have increased EAT thickness (EATT), along with its relation to the measures of adiposity and insulin sensitivity. A total of 41 subjects with PCOS and 46 age and body mass index (BMI) matched healthy controls were enrolled. EAT was measured by echocardiography above the free wall of the right ventricle. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) formula, and plasma adiponectin level was measured by ELISA. Compared to healthy controls EATT and HOMA-IR score were significantly higher (p=0.0001 for both) while plasma adiponectin concentration was significantly lower (p=0.048) in women with PCOS. EATT correlated positively with total cholesterol, triglyceride, luteinizing hormone (LH) and negatively with sex hormon binding globuline (p<0.05 for all), whereas it displayed no correlation to plasma adiponectin level (p=0.924). Triglyceride level was the significant determinant of EATT in logistic regression analysis (p=0.035). Thickness of the EAT is increased in patients with PCOS in conjunction with hyperandrogenity. Prospective studies are required to identify the relation of EAT and cardiovascular risk in patients with PCOS.

High plasma level of long Pentraxin 3 is associated with insulin resistance in women with polycystic ovary syndrome.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is characterized by insulin resistance. Chronic low-grade inflammation has been anticipated to play role in the pathogenesis of both insulin resistance and atherosclerosis. Pentraxin 3 (PTX3) is an inflammatory mediator synthesized in a variety of cells and tissues including heart, vascular endothelial cells, macrophages and adipocytes. In the present study, serum PTX3 level and its relationship with insulin resistance were investigated in patients with PCOS. MATERIALS AND METHODS: Forty patients with PCOS and 40 age- and body mass index (BMI)-matched healthy controls were enrolled in the study. PTX3 and high-sensitivity C-reactive protein (hs-CRP) levels were determined by enzyme immunoassay (EIA). Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) formula. RESULTS: Plasma levels of PTX3, hs-CRP and HOMA-IR scores were all significantly higher (p = 0.021, p = 0.002 and p = 0.0001, respectively) in women with PCOS compared with healthy controls. Blood PTX3 level correlated positively with hs-CRP, BMI, waist-to-hip ratio (WHR), HOMA-IR and negatively with high-density lipoprotein cholesterol level (p < 0.05, for all). After adjustment for age and BMI, PTX3, total testosterone levels and BMI remained as independent predictors of HOMA-IR scores (p < 0.05, for all). CONCLUSION: PTX3 level is increased in patients with PCOS in concordance with insulin resistance.

Plasma apelin and ADMA Levels in patients with essential hypertension.

Both apelin and asymetric dymethyl arginine (ADMA) regulate blood pressures. Low apelin and high ADMA levels have been reported in several cardiometabolic disorders. However, there is no data about ADMA and apelin levels in essential hypertension and any relationship between them. We investigated a group of newly diagnosed and untreated 30 young hypertensive men and 30 healthy controls. Apelin levels were significantly lower and the ADMA levels were significantly higher in the patients (p = 0.04 for both). Both ADMA and apelin were related to the systolic blood pressures (SBP) (beta = -0.393, p = 0.003; beta = 0.285, p = 0.03, respectively). Future studies are necessary in order to clearly define the role of ADMA and apelin in the pathogenesis of essential hypertension.

Relationship between hemoglobin and CD40 ligand in prediabetes.

PURPOSE: Hemoglobin (Hb) regulates the endothelial function by modulating the bio-availability of NO at the tissue level. A significant direct relationship is present between the Hb levels and endothelial functions in patients with Type 2 diabetes. Testing whether this association also exists in subjects with prediabetes is important because prediabetes is associated with an increased risk of cardiovascular disease and mortality. Therefore, we investigated the association of Hb both with the classical cardiac risk factors and the markers for endothelial dysfunction and inflammation, in subjects with impaired glucose tolerance (IGT). METHODS: We enrolled 69 normotensive, and cardiovascular events free subjects with IGT (M=40, age=45.50+/-6.8 yr). Plasma insulin, hsCRP, soluble CD40L, vonWillebrand factor, p-selectin levels were measured. The parameters given according to the higher and lower median Hb values of the subjects were compared. RESULTS: Subjects with the higher Hb levels exhibited lower HDL-C (46.68+/-10.8 mg/dl vs 51.5+/-8.9 mg/dl; P=0.04) and higher systolic (122.57+/-6.2 mmHg vs 116.17+/-7.4 mmHg; p < 0.001) and diastolic (79.14+/-3.73 mmHg vs 75.58+/-6.1 mmHg; P=0.005) blood pressures and sCD40L (7.9+/-3.8 ng/ml vs 6.07+/-2.1 ng/ml; P=0.02) levels. Hb levels were correlated to the HDL cholesterol, sCD40L, systolic and diastolic blood pressures and waist circumference (r=-0.28, P=0.02; r=0.29, P=0.02; r=0.53, P < 0.001; r=0.41, P=0.001; r=0.42, P < 0.001 respectively). According to the multiple logistic regression analysis, Hb was the determinant of sCD40L levels (beta=0.437, P < 0.001). CONCLUSION: These results indicate that there may be a link with higher Hb values and cardiovascular risk factors in patients with IGT. Further investigation is warranted to understand the clinical implications of these findings in subjects with prediabetes.

Prediction of testosterone response to human chorionic gonadotrophin in idiopathic hypogonadotropic hypogonadism patients.

In clinical practice, the human chorionic gonadotrophin (hCG) stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating follice-stimulating hormone (FSH) secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. The aim of this study was to determine whether basal inhibin B levels are able to predict testosterone response to hCG in idiopathic hypogonadotropic hypogonadism (IHH) patients and to evaluate the correlation between inhibin B and gonadotropins in these patients and controls. Inhibin B (n=15) and other hormones (n=29) were measured in 29 patients with IHH and 32 controls. Inhibin B (n=8) and testosterone levels (n=25) before and after hCG stimulation were measured in 25 male patients with IHH by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. There was a significant increase in inhibin B (22.6 +/- 9.8 vs 45.07 +/- 13 pg/mL; p=.005), free testosterone (2.92 +/- 0.55 vs. 7.9 +/- 1.5 pg/mL; p=.002), and total testosterone (69.0 +/- 15.9 vs. 184.9 +/- 44.1 ng/mL; p = .013) levels 72 hours after hCG injection. Inhibin B and the hCG-induced free testosterone and total testosterone increment correlated strongly (r=0.802, P<.001; r=0.793, P<.001, respectively). We conclude that basal inhibin B predicts the testosterone response to hCG in IHH patients and therefore gives reliable information about Leydig cell reserve. Furthermore, inhibin B levels show negative correlation with luteinizing hormone (LH) in control patients and positive correlation with FSH and LH in IHH patients. LH may effect inhibin B secretion. Further studies are necessary to define the physiology of inhibin B in human males.

Trace element levels in hashimoto thyroiditis patients with subclinical hypothyroidism.

The present study was conducted to evaluate the serum copper, zinc, magnesium, and selenium levels in patients with subclinical hypothyroidism in the iodine-rich region of Ankara, Turkey. The effects of hormone replacement therapy on these elements were also studied in these patients. Basal levels of selenium and iron in patients were significantly lower than control group (67.7 +/- 10.4 vs. 83.7 +/- 17.3 microg/dl, p = 0.02; 55.7 +/- 38 vs 275.7 +/- 24, P = 0.03 microg/dl). Serum magnesium levels were significantly higher in patient group (2.16 +/- 0.31 vs 1.95 +/- 0.13 mg/dl, P < 0.0001). There was a correlation between selenium levels with hsCRP (r = -0.408, p = 0.007). HsCRP levels in patients with selenium levels <80 microg/l (n = 31) was significantly higher than hsCRP levels in patients with selenium levels >80 microg/l (n = 12; 1.99 +/- 1.0; 1.02 +/- 0.9, p = 0.014). None of these biochemical risk factors and trace elements have changed after euthyroidism in patients with SH when compared to pretreatment levels. Selenium deficiency may contribute to cardiovascular disease risk in these patients.

Dynamic changes in {beta}-cell mass and pancreatic insulin during the evolution of nutrition-dependent diabetes in psammomys obesus: impact of glycemic control.

Recent studies ascribe a major role to pancreatic beta-cell loss in type 2 diabetes. We investigated the dynamics of beta-cell mass during diabetes evolution in Psammomys obesus, a model for nutrition-dependent type 2 diabetes, focusing on the very early and the advanced stages of the disease. P. obesus fed a high-calorie diet for 26 days developed severe hyperglycemia, beta-cell degranulation, and markedly reduced pancreatic insulin content. Reducing calories for 7 days induced normoglycemia in 90% of the animals, restoring beta-cell granulation and insulin content. To dissociate effects of diet from blood glucose reduction, diabetic animals received phlorizin for 2 days, which normalized glycemia and increased the pancreatic insulin reserve to 50% of control, despite a calorie-rich diet. During diabetes progression, beta-cell mass decreased initially but recovered spontaneously to control levels, despite persistent hyperglycemia. Strikingly, however, beta-cell mass did not correlate with degree of hyperglycemia or pancreatic insulin content. We conclude that reduced insulin reserve is the main cause of diabetes progression, whereas irreversible beta-cell mass reduction is a late event in P. obesus. The rapid recovery of the pancreas by phlorizin-induced normoglycemia implies a causal relationship between hyperglycemia and islet dysfunction. Similar mechanisms could be operative during the evolution of type 2 diabetes in humans.

Insulin does not mediate glucose stimulation of proinsulin biosynthesis.

It has recently been suggested that insulin augments its own production by a physiologically important feed-forward autocrine loop. We studied the kinetics of glucose-regulated proinsulin gene expression and proinsulin biosynthesis in normal rat islets with emphasis on the potential role of insulin as a mediator of the glucose effect. There was a time-dependent increase in steady-state proinsulin mRNA in islets cultured at 16.7 mmol/l compared with 3.3 mmol/l glucose; no early (1-3 h) increase in proinsulin gene expression was observed. In contrast, there was a threefold increase in proinsulin biosynthesis within 1 h of glucose stimulation that was not affected by inhibition of glucose-stimulated proinsulin gene transcription with actinomycin D. In addition, inhibition of glucose-stimulated insulin secretion with diazoxide had no effect on glucose-stimulated proinsulin mRNA or biosynthesis. Furthermore, addition of different concentrations of insulin to islets cultured in low glucose failed to affect proinsulin biosynthesis. Taken together, our data suggest that the early glucose-dependent increase in proinsulin biosynthesis is mainly regulated at the translational level, rather than by changes in proinsulin gene expression. Moreover, we could not demonstrate any effect of insulin on islet proinsulin mRNA level or rate of proinsulin biosynthesis. Thus, if insulin has any effect on the proinsulin biosynthetic apparatus, it is a minor one. We conclude that the secreted insulin is not an important mediator of insulin production in response to glucose.

Glucose-regulated proinsulin gene expression is required for adequate insulin production during chronic glucose exposure.

Psammomys obesus, an animal model of type 2 diabetes, shows rapid and marked depletion of pancreatic insulin content as hyperglycemia develops when fed a high-calorie diet. P. obesus islets do not increase proinsulin gene expression when exposed to high glucose, which may be related to absence of the conserved form of the transcription factor insulin promoter factor 1/pancreatic-duodenal homeobox 1. The present study assesses the importance of regulation of proinsulin gene expression by glucose for insulin production. Islets of diabetes-prone P. obesus and diabetes-resistant Wistar rats, cultured at various glucose concentrations for up to 24 h, were analyzed for proinsulin mRNA by quantitative RT-PCR, proinsulin biosynthesis by leucine incorporation into proinsulin, and insulin content and secretion by RIA. No increase in proinsulin mRNA was observed in P. obesus islets during 24-h exposure to increasing concentrations of glucose. In contrast, rat islets exposed to high glucose responded with a 2- to 3-fold stimulation of proinsulin mRNA. The failure of P. obesus islets to increase proinsulin mRNA was accompanied by a reduced proinsulin biosynthetic response: after 24 h, maximal proinsulin biosynthesis was blunted, associated with depletion of islet insulin content. Inhibition of glucose-stimulated proinsulin gene transcription in rat islets by actinomycin D did not affect the early proinsulin biosynthetic response, which, however, was reduced to the level of P. obesus islets after 24 h in culture. We conclude that stimulation of proinsulin gene transcription by glucose is necessary for maintaining proinsulin biosynthesis and hence conserving pancreatic insulin stores, under conditions of sustained secretory drive, but not for short-term regulation of proinsulin biosynthesis Our findings support the hypothesis that inadequate regulation of proinsulin gene expression by glucose contributes to the failure of P. obesus to cope with the increased demand for insulin associated with caloric excess, leading to depletion of insulin stores and diabetes.

The accuracy of home glucose meters in hypoglycemia.

BACKGROUND: Home glucose meters (HGMs) may not be accurate enough to sense hypoglycemia. We evaluated the accuracy and the capillary and venous comparability of five different HGMs (Optium Xceed [Abbott Diabetes Care, Alameda, CA, USA], Contour TS [Bayer Diabetes Care, Basel, Switzerland], Accu-Chek Go [Roche Ltd., Basel, Switzerland], OneTouch Select [Lifescan, Milpitas, CA, USA], and EZ Smart [Tyson Bioresearch Inc., Chu-Nan, Taiwan]) in an adult population. METHODS: The insulin hypoglycemia test was performed to 59 subjects (56 males; 23.6 +/- 3.2 years old). Glucose was measured from forearm venous blood and finger capillary samples both before and after regular insulin (0.1 U/kg) was injected. Venous samples were analyzed in the reference laboratory by the hexokinase method. In vitro tests for method comparison and precision analyses were also performed by spiking the glucose-depleted venous blood. RESULTS: All HGMs failed to sense hypoglycemia to some extend. EZ Smart was significantly inferior in critical error Zone D, and OneTouch Select was significantly inferior in the clinically unimportant error Zone B. Accu-Chek Go, Optium Xceed, and Contour TS had similar performances and were significantly better than the other two HGMs according to error grid analysis or International Organization for Standardization criteria. The in vitro tests were consistent with the above clinical data. The capillary and venous consistencies of Accu-Chek Go and OneTouch Select were better than the other HGMs. CONCLUSIONS: The present results show that not all the HGMs are accurate enough in low blood glucose levels. The patients and the caregivers should be aware of these restrictions of the HGMs and give more credit to the symptoms of hypoglycemia than the values obtained by the HGMs. Finally, these results indicate that there is a need for the revision of the accuracy standards of HGMs in low blood glucose levels.

The relationship between hemoglobin levels and endothelial functions in diabetes mellitus.

BACKGROUND AND OBJECTIVES: Hemoglobin (Hb) is the main carrier and buffer of nitric oxide. Evidence has been produced that Hb concentration is inversely related with endothelial function in human diseases. Testing whether this association exists also in diabetic patients stage 1 to 2 chronic kidney disease (CKD) is important because anemia in these patients starts at an earlier stage than in other renal diseases. The relationship was investigated between Hb and flow-mediated dilation (FMD) levels of the patients with diabetic nephropathy in a cross-sectional design. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Eighty-nine diabetics with mild to moderate proteinuria and normal to mildly reduced GFR who were normotensive, nondyslipidemic, and cardiovascular-events free were enrolled. None of the patients was taking metformin or renin-angiotensin system blockers. RESULTS: FMD was inversely related with Hb levels. Furthermore, there was an inverse link between proteinuria and FMD. However, further analysis of this association showed that the FMD-proteinuria link was confined to patients with proteinuria exceeding 150 mg/d, while no such association existed in patients with proteinuria <150 mg/d. Adjustment of the Hb-FMD relationship for pertinent Framingham risk factors, proteinuria, homeostasis model assessment (HOMA) index, and GFR levels had a modest influence on this association, which remained significant. CONCLUSIONS: Endothelial function is inversely associated with Hb levels in diabetic patients with stage 1 to 2 CKD, and proteinuria is an effect modifier of this association. Overall, the observations of this study generate the hypothesis that proteinuria exposes a situation wherein Hb may limit the endothelium-mediated vasoregulation in diabetes.

Adipose tissue 11-beta-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-Phosphate Dehydrogenase gene expressions are increased in patients with type 2 diabetes mellitus.

AIMS: We have determined 11-beta-Hydroxysteroid Dehydrogenase Type 1 (HSD11B1) and Hexose-6-Phosphate Dehydrogenase (H6PD) mRNA expression levels in adipose tissues from patients with type 2 diabetes mellitus. METHODS: Six non-diabetic and seven diabetic male patients who undergo elective abdominal surgery were included in the study and visceral and subcutaneous adipose tissue samples were obtained. Fresh preadipocyte cultures were administered to low and high glucose medium (11M and 25M) in vitro for 24h and mRNA extractions were performed. HSD11B1 and H6PD gene mRNA expression levels were determined by real-time PCR and compared. Glyceraldehyde-3-phosphate Dehydrogenase (G3PD) mRNA level is used as housekeeping gene expression. RESULTS: HSD11B1 mRNA levels were significantly higher in patient with T2DM than controls in both visceral and subcutaneous adipose tissues (3.35+/-0.7 vs. 0.37+/-0.1; P=0.01 and 2.07+/-0.8 vs. 0.11+/-0.05; P=0.01, respectively). H6PD mRNA levels were also significantly higher in patient with T2DM than controls in both visceral and subcutaneous adipose tissues (3.95+/-1.2 vs. 1.95+/-0.8; P=0.050 and 2.23+/-1.1 vs. 0.46+/-0.1; P=0.043, respectively). CONCLUSIONS: Failure to down-regulate HSD11B1 activity in patients with type 2 diabetes may contribute to the pathogenesis of T2DM. Subcutaneous and visceral adipose tissues similarly exhibit the same variation in patients with type 2 diabetes mellitus.

HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) accompanied by renal tubular acidosis and endocrine abnormalities.

Type 1 (distal) and type 2 (proximal) renal tubular acidosis (RTA) are uncommon disorders, particularly in adults. HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) is an autosomal dominant condition, defined by the triad hypoparathyroidism, renal dysplasia and hearing loss. Here, we describe a 19-year-old man with HDR syndrome accompanied by renal tubular acidosis and endocrinopathic changes.

Increased serum chitotriosidase activity following restoration of euthyroidism in patients with subclinical hypothyroidism.

OBJECTIVE: Whether to treat subclinical hypothyroidism (SH) remains controversial. Serum chitotriosidase activity, a marker of activated macrophages, predicts new cardiovascular events. Chitotriosidase activity (ChT) is a new cardiovascular risk marker and is independent of C-reactive protein. The purpose of this study was to determine ChT levels in SH and to examine the effect of levothyroxine replacement on ChT. SUBJECTS AND METHODS: A cohort of 60 patients with subclinical hypothyroidism and 62 healthy controls were enrolled in this study. Serum total and LDL cholesterol, total homocysteine (t-Hyc), highly sensitive C-reactive protein (hsCRP) levels and serum ChT in patients with subclinical hypothyroidism at baseline and after achieving euthyroid state by levothyroxine were assessed. RESULTS: Pretreatment levels of TSH (10.06+/-5.09 vs. 2.08+/-0.95 mIU/L, p<0.05), and free T4 (0.94+/-0.21 vs. 1.35+/-0.26 ng/dl, p<0.05) were significantly higher than controls while total cholesterol, LDL cholesterol, t-Hyc, ChT and hsCRP levels were not different. ChT levels significantly increased after replacement therapy (137.2+/-14.18 vs. 156.88+/-13.10 nmol/mL/h, p<0.05). T-Hyc and hsCRP levels were not significantly different after treatment with levothyroxine therapy even in this subgroup of patients. None of the other biochemical risk factors improved after euthyroidism in patients with SH with average dose of 85+/-30 mug/day when compared to pretreatment levels. CONCLUSION: We conclude that clinical management of subclinical hypothyroidism does not decrease the serum hsCRP or t-Hyc levels but does increase the serum ChT levels. The clinical significance of this increment should be studied in further studies.

Asymptomatic kindred of patients with coronary events have increased peripheral T-cell activities.

T cells are involved in the pathogenesis of atherosclerosis. We aimed to search for any association between the peripheral T-cell activities and atherogenic risk factors in healthy subjects. Fifty male volunteers (age 22.0 +/- 2.4 years) were enrolled. No subject had any chronic disease or was under any drug treatment. Lymphocytes were isolated from heparinized venous blood and the proliferative responses to phytohemagglutinin (PHA) were measured from the amount of radioactive thymidine uptake by the lymphocyte DNA. T-cell activity responses of patients with a family history of coronary events were compared with others. The activity responses of smokers were compared with nonsmokers. Subjects with a positive family history of coronary events had higher PHA stimulated T-cell response and delta cpm (P < 0.05 for each). Total and low-density lipoprotein cholesterol levels of the subjects with a positive family history of cardiovascular events were positively correlated with the PHA-activated T-cell responses (P = 0.022, r = 0.604 and P = 0.015, r = 0.635, respectively). There was no significant difference between the T-cell activity responses of smokers and nonsmokers. No correlation was found between the biochemical parameters and T-cell activities in these groups. Peripheral T-cell activity responses to PHA are higher in the asymptomatic relatives of patients with coronary events. This may be a clue for the familial tendency of atherosclerotic diseases. Further follow-up studies are necessary to investigate the relationship.