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Biomedical subjects

Georg Brabant

Publications and source records attributed to Georg Brabant.

At least 19 recordsLinked to original sources
PubMed2006

The Brn-3b POU family transcription factor represses plakoglobin gene expression in human breast cancer cells.

The Brn-3b transcription factor has been shown to be overexpressed in human breast cancer cells and contributes toward cell growth regulation. Using micro-arrays, more than 50 cancer-related genes regulated by Brn-3b in human breast cancer cells have been identified. For example, Brn-3b activates the cell cycle regulator CDK4 that provides a mechanism by which Brn-3b controls the growth of breast cancer cells. Here, we show that Brn-3b regulates plakoglobin (gamma-catenin), a member of the catenin family involved in cell-cell adhesion and signal transduction. Brn-3b expression inversely correlates with plakoglobin expression at both mRNA and protein levels in breast cancer cell lines and human breast biopsies. In contrast, no significant correlation was observed between Brn-3b expression and beta-catenin, or between Brn-3b expression and E-cadherin expression. Brn-3b represses the plakoglobin promoter via a Brn-3 consensus binding site contained within the region -965 to -593 relative to the transcriptional start site. Both repression of the promoter and binding of Brn-3b are lost when this site is mutated. To our knowledge, this is the first time that a Brn-3b POU family transcription factor has been shown to regulate a member of the catenin family, which provides insight into the molecular mechanisms by which Brn-3b expression may favour breast cancer progression and tumor invasion.

Binding Sites↗
PubMed2005

Wnt/beta-catenin signaling mediates antineoplastic effects of imatinib mesylate (gleevec) in anaplastic thyroid cancer.

CONTEXT: Dysregulation of Wnt signaling is a key step in neoplastic thyrocyte proliferation. However, it is unclear whether the selective tyrosine kinase (TK) inhibitor, imatinib mesylate, is linked to the Wnt/beta-catenin cascade and is able to modulate the pathway. OBJECTIVE: Conflicting data are reported on the therapeutic effects of imatinib in anaplastic thyroid carcinomas (ATCs), but the molecular mechanism of action is unclear. Here, we further delineated the antitumor effects and the potential efficacy of imatinib in dedifferentiated thyroid carcinomas. RESULTS: Tissue microarray of histologically proven ATCs (n = 12) demonstrated that six of 12 tumors expressed at least one of the imatinib-sensitive TKs. Similarily, imatinib-sensitive TKs were detected in seven of 10 thyroid cancer cell lines derived from metastatic papillary, follicular, and ATCs. Coimmunoprecipitation in ARO cells demonstrated a direct link between c-abl and beta-catenin. Imatinib (10 microM for 48 h) drastically reduced beta-catenin expression and redistributed it from the nucleus to the cell membrane. It stabilized adherens junctions by increasing beta-catenin/E-cadherin binding and reduced the invasive potential of thyroid cancer. Furthermore, imatinib (10 microM for 48 h) attenuated T cell factor/lymphoid enhancer factor activity, reduced cyclin D1 levels and dose-dependently suppressed thyrocyte proliferation by half without affecting apoptosis. CONCLUSION: Our data provide a molecular mechanism for the antitumor activity of imatinib that may help to develop it as a therapeutic option in a subset of ATC patients.

Antineoplastic Agents↗
PubMed2005

Determinants of plasma adiponectin levels in patients with anorexia nervosa examined before and after weight gain.

OBJECTIVE: To examine the determinants of adiponectin levels (i) in 23 women with anorexia nervosa (mean BMI 15.0 +/- 1.2) and 43 healthy normal weight females (mean BMI 22.3 +/- 2.3; cross-sectional design) as well as (ii) after six and twelve weeks of weight gain in subgroups of 18 and 11 anorectic patients (mean weight gain 5.8 kg; longitudinal design). Plasma adiponectin and leptin concentrations were measured and their relationships to body composition (fat mass by bioelectrical impedance analysis and anthropometrics), different hormones and metabolic parameters (insulin, ACTH, cortisol, glucose, FFA, lipid profile) were investigated. RESULTS: In anorectic patients, adiponectin levels were higher (+29 %) and leptin levels were lower (-75 %) than in control subjects. There was a high variance in adiponectin levels in patients ranging from 2.6 to 18 nM. Combining patients and controls, an inverse linear correlation was observed between adiponectin levels and fat mass (r = -0.36, p < 0.05), while a positive exponential relation was found between leptin levels and fat mass (r = 0.82, p < 0.001). In anorectic patients, there were no significant correlations between adiponectin and hormonal or metabolic parameters. Weight gain resulted in increasing leptin (+0.17 +/- 0.12 nM; p < 0.001) and a nonsignificant decrease in adiponectin concentrations (-1.12 +/- 2.51 nM). Changes in leptin levels were mainly explained by a gain in fat mass (r = 0.85, p < 0.001). In contrast, changes in adiponectin levels were closely linked to initial adiponectin levels (r = -0.84, p < 0.001) but not to changes in fat mass or BMI. CONCLUSION: Cross-sectionally serum adiponectin concentration followed a linear inverse function with fat mass when patients and controls were combined. Longitudinally gain in fat mass was not associated with changes in adiponectin levels suggesting other yet unidentified influences on adiponectin secretion in anorexia nervosa.

Adiponectin↗
PubMed2005

Hepatic leptin signaling in obesity.

Obesity, a state of apparent "leptin resistance" is well known to be associated with insulin resistance. In diet-induced obesity (DIO), hepatic insulin signaling is impaired but the link between leptin and insulin signaling pathways is only incompletely defined. The aim of the present study was to evaluate the effects of DIO on leptin and insulin cross-signaling in the liver. Leptin receptor expression was measured by in situ hybridization with pan-leptin receptor probes and by immunoblotting. Furthermore, intracellular signaling was investigated in vivo under basal conditions and at 45 and 360 min after stimulation with a bolus of human recombinant leptin (hrec-leptin; 1 mg/kg body wt) or saline. At baseline, all forms of the leptin receptor were markedly to completely down-regulated in DIO rats. Hrec-leptin bolus injection stimulated leptin-dependent signaling with a fivefold increase in JAK-2pY in lean but not in DIO rats. Basal IRpY, IRS-1pY, IRS-1p85, IRS-2pY, IRSp85, and PKBpT308 levels were reduced (P<0.01) in DIO rats as compared with lean controls. Basal GSK-3beta serine phosphorylation (S9) was higher (P<0.01) in lean animals along with lower basal PEPCK activity compared with DIO rats consistent with the insulin and leptin resistance of the latter. Only in lean animals phosphorylation of PKB (T308) and GSK-3beta (S9) was acutely stimulated by leptin at 45 min followed by inhibition at 6 h after application. AMPKalpha protein levels as well as basal and leptin-stimulated total and alpha-specific AMPK activity were comparable in both groups. These data show that in a model of dietary-induced obesity 1) leptin receptors and subsequent signaling events are down-regulated, 2) basal insulin signaling is impaired, and 3) the cross-talk between leptin and insulin signaling is differentially regulated by the nutritional status, which is sensed by AMPK in rat liver. Thus, the liver seems to play a major role in the modulation of the leptin signal and insulin resistance in obesity.

AMP-Activated Protein Kinases↗
PubMed2005

Long-term follow-up after adrenalectomy for primary aldosteronism.

The objective of this study was to assess the long-term effects of adrenalectomy on the blood pressure and antihypertensive medication in patients with primary aldosteronism (PA). Twenty-four patients (15 female and 9 male) with a mean age of 48.3 +/- 10.8 years underwent surgery for PA in our institution between 1988 and 2001. All subjects were re-examined with a complete clinical work-up after a mean follow-up period of 86 +/- 48 months, including blood pressure readings (<140/90 mmHg defined as normal), endocrine adrenal function, and specific medication. All patients suffered from hypertension (onset 8.5 +/- 5.5 years prior to surgery). In 92% of the patients, hypokalemia was present (onset 2.0 +/- 2.6 years prior to surgery). The histopathologic examinations revealed unilateral adenomas in 23 patients and a bilateral hyperplasia in one patient. At follow-up, 33% (8) of the patients were completely cured (normal blood pressure and no antihypertensive treatment), with seven of these eight patients being under 50 years of age at the time of surgery. One patient revealed a contralateral aldosterone-secreting adrenal adenoma during the subsequent endocrine and imaging examination 44 months after the first operation. Despite normalized plasma-aldosterone concentration (PAC), plasma-renin-activity (PRA) and serum potassium levels, a long-lasting insufficiently treated hypertension due to the delayed diagnosis in patients with PA may explain the persistent blood pressure elevation, indicating the necessity of a life-long, regular control of the blood pressure and antihypertensive medication.

Adenoma↗
PubMed2005

High adiponectin in chronic liver disease and cholestasis suggests biliary route of adiponectin excretion in vivo.

BACKGROUND/AIMS: Models of fatty liver diseases and fibrosis suggest a hepatoprotective effect of adiponectin, an adipocyte-derived hormone with antidiabetic, antiobesity, antiatherogenic and anti-inflammatory effects. METHODS: We studied adiponectin serum levels in 111 chronic liver disease (CLD) patients and 226 healthy controls and the impact of cholestasis on adiponectin by bile duct ligation experiments in mice. RESULTS: Adiponectin was significantly elevated in CLD, and correlated with stage of liver cirrhosis, liver cell injury, e.g. aminotransferase activity, and inflammatory markers, but not with liver synthesis capacity, insulin sensitivity (HOMA index) or clinical complications. As patients with biliary liver diseases and cholestasis exhibited the highest adiponectin levels, we experimentally investigated a potential biliary route of adiponectin excretion. Following bile duct ligation in mice adiponectin levels rapidly increased without affecting hepatic adiponectin gene expression. Also, adiponectin was detectable in human bile. High adiponectin concentrations were associated with severe cholangitis and/or cholestasis on liver histology. CONCLUSIONS: Adiponectin is elevated in chronic liver disease and correlates with inflammation and liver damage. High adiponectin levels after bile duct ligation in mice and in human bile from cholestatic patients suggest that biliary secretion is involved in adiponectin clearance and that adiponectin could serve as a novel marker indicating cholestasis in liver cirrhosis.

Adiponectin↗
PubMed2005

Leptin and body weight regulation in patients with anorexia nervosa before and during weight recovery.

BACKGROUND: Leptin has been considered a starvation hormone, but its role in malnourished patients is unknown. OBJECTIVE: We aimed to characterize the role of leptin in metabolic adaptation in women with anorexia nervosa (AN). DESIGN: In a cross-sectional study, 57 women with AN [mean (+/-SD) body mass index (kg/m(2)) on admission: 15.2 +/- 1.5] were compared with 49 healthy, normal-weight women (mean body mass index: 22.3 +/- 2.3). Nineteen patients were reinvestigated during weight gain 43 and 84 d after baseline. We measured serum concentrations of leptin, soluble leptin receptor, insulin, ghrelin, and thyroid hormones [thyrotropin, triiodothyronine (T(3)), and thyroxine]; fat mass (FM) and fat-free mass (FFM); resting energy expenditure (REE); energy intake; and eating behavior. RESULTS: Compared with values in the control women, leptin, T(3), REE, FM, and FFM were lower in the women with AN, but the leptin secretion rate was not significantly different. Leptin correlated with FM (r = 0.83, P < 0.001), T(3) (r = 0.68, P < 0.001), respiratory quotient (r = -0.47, P < 0.001), and REE (r = 0.58, P < 0.001). The association with REE weakened after adjustment for FFM and disappeared after further adjustment for T(3). Hunger and appetite had positive, whereas satiety and restraint had negative, associations with leptin. During weight gain (9.0 +/- 3.3 kg in 84 d), serum leptin and the leptin secretion rate increased. Changes in leptin secretion were associated with energy intake and REE. The initial changes in the leptin secretion rate (ie, the difference between baseline and 43 d) were negatively associated with changes in body weight from 43 to 84 d. CONCLUSIONS: Leptin contributes to metabolic adaptation in women with AN. The leptin response is associated with weight gain.

Adolescent↗
PubMed2005

Hepatic steatosis in Dunnigan-type familial partial lipodystrophy.

OBJECTIVES: Characterization of familial clusters of subjects with metabolic derangements predisposing to hepatic steatosis and nonalcoholic steatohepatitis could facilitate genomic studies to identify risk factors for their development. Dunnigan-type familial partial lipodystrophy (FPLD) is an autosomal dominantly inherited disorder caused by mutations in the LMNA gene. Affected subjects have loss of subcutaneous fat from the extremities and symptoms similar to those characterizing the metabolic syndrome, including insulin resistance and dyslipidemia. The goal of this study was to determine the prevalence of steatosis in subjects with FPLD. METHODS: We examined 18 subjects from six families with FPLD for mutations in LMNA and analyzed plasma lipid and serum glucose concentrations. Liver ultrasound and serum aminotransferase activities were used as indicators of steatosis or steatohepatitis. In two subjects, histological examination of hepatic tissue was performed. RESULTS: All subjects had FPLD-causing mutations in LMNA. Plasma lipids were measured in 17 subjects, 16 of whom had hyperlipidemia and 14 presented with either documented insulin resistance or diabetes mellitus. Hepatic steatosis was present in 15 subjects who had ultrasound examinations and 9 of these had elevated serum aminotransferase activities. Liver biopsy confirmed steatosis in 2 subjects. CONCLUSIONS: Hepatic steatosis is part of the clinical phenotype of FPLD. This familial disorder may provide a human metabolic model system to facilitate genomic and environmental studies to determine risk factors for hepatic steatosis and nonalcoholic steatohepatitis.

Adipose Tissue↗
PubMed2005

Machine learning approaches for phenotype-genotype mapping: predicting heterozygous mutations in the CYP21B gene from steroid profiles.

OBJECTIVE: Non-linear relations between multiple biochemical parameters are the basis for the diagnosis of many diseases. Traditional linear analytical methods are not reliable predictors. Novel nonlinear techniques are increasingly used to improve the diagnostic accuracy of automated data interpretation. This has been exemplified in particular for the classification and diagnostic prediction of cancers based on expression profiling data. Our objective was to predict the genotype from complex biochemical data by comparing the performance of experienced clinicians to traditional linear analysis, and to novel non-linear analytical methods. DESIGN AND METHODS: As a model, we used a well-defined set of interconnected data consisting of unstimulated serum levels of steroid intermediates assessed in 54 subjects heterozygous for a mutation of the 21-hydroxylase gene (CYP21B) and in 43 healthy controls. RESULTS: The genetic alteration was predicted from the pattern of steroid levels with an accuracy of 39% by clinicians and of 64% by linear analysis. In contrast, non-linear analysis, such as self-organizing artificial neural networks, support vector machines, and nearest neighbour classifiers, allowed for higher accuracy up to 83%. CONCLUSIONS: The successful application of these non-linear adaptive methods to capture specific biochemical problems may have generalized implications for biochemical testing in many areas. Nonlinear analytical techniques such as neural networks, support vector machines, and nearest neighbour classifiers may serve as an important adjunct to the decision process of a human investigator not 'trained' in a specific complex clinical or laboratory setting and may aid them to classify the problem more directly.

Adult↗
PubMed2005

Applicability of recently established reference values for serum insulin-like growth factor 1: A comparison of two assays--an (automated) chemiluminescence immunoassay and an enzyme-linked immunosorbent assay.

Analysis and interpretation of insulin-like growth factor 1 in serum (IGF-1) is a principal diagnostic and follow-up tool in growth hormone-related disorders and is becoming of interest for many other disorders. Only for the automated chemiluminescence immunoassay Nichols Advantage have age- and sex-specific reference values based on a large population and valid for different laboratories been established. The aim of the present study was to compare two different assays (the automated chemiluminescence immunoassay and the enzyme-linked immunosorbent assay DSL-10-2800) in order to prove applicability of recently published reference values. The study included 95 serum samples from 88 patients, adults as well as children, with different or no endocrine disorders, and acromegalic as well as growth hormone-deficient patients. IGF-1 measurements were performed with both methods. The results have shown a very high correlation between the IGF-1 values obtained with the two assays (r=0.971, p<0.0001). In conclusion, the reference values established for the chemiluminescence assay are applicable also for the enzyme-linked immunosorbent assay.

Adolescent↗
PubMed2004

Heritability of free and receptor-bound leptin in normal twins.

Free and receptor-bound leptin may be regulated by different mechanisms. Genes that influence the concentration of these fractions may have an important functional bearing. We determined circulating leptin receptor concentrations, bound as well as free leptin concentrations, and body composition in 24 monozygotic (MZ) and in 22 dizygotic (DZ) twin pairs. Bound leptin and leptin receptor concentrations were inversely correlated with body fat content. Free leptin concentrations were directly correlated with body fat content. The correlations in age- and sex-adjusted free leptin, bound leptin, and leptin receptor concentrations were higher between MZ twins than between DZ twins. Adjusted heritability (h2) estimates were 0.28 for free leptin, 0.73 for bound leptin, and 0.55 for leptin receptor. The genetic correlation with body fat was -0.58 for the leptin receptor, -0.20 for bound leptin, and 0.93 for free leptin. Our data are consistent with a strong genetic influence on leptin receptor and bound leptin and a weaker genetic influence on free leptin concentrations. The same genes that lower bound leptin and leptin receptor concentrations may increase fat mass or vice versa.

Adult↗
PubMed2004

Serum pattern of circulating free leptin, bound leptin, and soluble leptin receptor in the physiological menstrual cycle.

OBJECTIVE: To investigate the serum pattern of free leptin, bound leptin, and soluble leptin receptor throughout the physiological menstrual cycle. DESIGN: Prospective observational study. SETTING: Tertiary care center for gynecological endocrinology and reproductive medicine and a university research laboratory. PATIENT(S): Thirty regularly cycling volunteers (age, 29 +/- 4.2 years). INTERVENTION(S): Blood sampling was performed at different phases (early and mid follicular phase, preovulatory phase, and early and late luteal phase) of three consecutive menstrual cycles; each phase of the menstrual cycle was investigated twice. MAIN OUTCOME MEASURE(S): Free leptin, bound leptin, soluble leptin receptor, LH, E(2), P, vaginal ultrasound. RESULT(S): A peak of serum free leptin levels was found in the late luteal phase followed by a significant drop in the early follicular phase and again by a continuous increase up to the next luteal peak. There were no significant alterations in serum bound leptin and soluble leptin receptor levels. CONCLUSION(S): The present study shows that there are significant circacyclic fluctuations of free leptin levels with the highest concentrations in the late luteal phase and the lowest levels in the early follicular phase, which suggests that circulating free leptin is up-regulated by the C(21)-steroid (P). Circulating bound leptin and soluble leptin receptor are not altered by the cyclic hormone status. The significant rise of the leptin bioequivalent, free leptin, in the late luteal phase might be of importance for the luteal-follicular and the luteal-preimplantatory functional shift.

Adult↗
PubMed2004

Cognitive changes in short-term hypothyroidism assessed with event-related brain potentials.

Hypothyroidism is a common clinical problem during (131)Iodine-therapy of thyroid cancer. In the present investigation, possible cognitive dysfunction during hypothyroid state was assessed by means of neuropsychological tests and the recording of event-related brain potentials (ERPs). Fifteen patients undergoing therapy for thyroid cancer were examined twice: (1) substituted with thyroid hormones, (2) during hypothyroid state immediately prior to treatment. Standard neuropsychological tests were applied during both sessions and subjects showed a mild-to-moderate impairment in their hypothyroid state. In addition, ERPs were recorded from 19 scalp sites while subjects performed two visual search tasks. The serial task required the effortful one-by-one scanning of several items within a visual array, while the parallel task allowed processing of all stimulus items in parallel and automatically. ERPs showed a marked amplitude decrement and delay of the P3 component known to index the speed of stimulus evaluation and the amount of available processing resources. This effect was present only for the serial search task, while no changes were seen in the parallel search task. These data show that hypothyroidism during (131)Iodine-therapy is associated with clinically relevant cognitive dysfunctions, especially with effortful attention demanding tasks.

Acute Disease↗
PubMed2004

Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome.

OBJECTIVE: The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. PATIENTS AND MEASUREMENTS: Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. RESULTS: Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. CONCLUSIONS: PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity.

Adiponectin↗
PubMed2004

Plasma ghrelin in obesity before and after weight loss after laparoscopical adjustable gastric banding.

Weight reduction after gastric bypass surgery has been attributed to a decrease of the orexigenic peptide ghrelin, which may be regulated by insulin and leptin. This study examined effects of long-term weight loss after laparoscopical adjustable gastric banding on plasma ghrelin and leptin concentrations and their relationship with insulin action. Severely obese patients (15 women, three men, 36 +/- 12 yr) underwent clinical examinations every 3 months and modified oral glucose tolerance tests to assess parameters of insulin sensitivity and secretion every 6 months. After surgery, body mass index fell from 45.3 +/- 5.3 to 37.2 +/- 5.3 and 33.6 +/- 5.5 kg/m(2) at 6 and 12 months, respectively (P < 0.0001). This was associated with lower (P < 0.0001) plasma glucose, insulin, insulin resistance, waist circumference, and blood pressure. Plasma leptin decreased from 27.6 +/- 9.5 to 17.7 +/- 9.8 (P = 0.0005) and 12.7 +/- 5.1 ng/ml (P < 0.0001). Plasma ghrelin was comparable before and at 6 months (234 +/- 53; 232 +/- 53 pmol/liter) but increased at 12 months (261 +/- 72 pmol/liter; P = 0.05 vs. 6 months). At 6 and 12 months, ghrelin levels correlated negatively with fasting plasma insulin levels and hepatic insulin extraction but not with body mass or insulin action. In conclusion, prolonged weight loss results in a rise of fasting ghrelin concentrations that correlates with fasting insulin concentrations but not improvement of insulin sensitivity.

Adult↗
PubMed2004

The polycystic ovary syndrome per se is not associated with increased chronic inflammation.

OBJECTIVE: The syndrome of polycystic ovaries (PCOS) is a known risk factor for type 2 diabetes. It is not known, however, whether the increase in diabetes risk is related to endocrine abnormalities associated with PCOS such as hyperandrogenemia, or whether it is a consequence of the anthropometric or metabolic alterations frequently observed in PCOS women. DESIGN: Since markers of inflammation are supposed to predict type 2 diabetes, interleukin-6 (IL-6) and C-reactive protein (CRP) in combination with parameters of obesity, insulin resistance and hyperandrogenism were determined in 57 PCOS women and in 20 age-matched healthy controls. In addition, the C-174G IL-6 promoter polymorphism was analyzed as a determinant in influencing IL-6, obesity, and androgen levels in women. RESULTS: Neither CRP nor IL-6 were significantly elevated in lean or obese PCOS women compared with age-matched lean or obese controls. In PCOS patients, variables of body composition (body mass index (BMI), waist to hip ratio, dual-energy X-ray-absorptiometry fat mass) and of insulin resistance were correlated with IL-6 or CRP, while parameters of hyperandogenism were not. Multivariate linear regression analysis revealed that obesity is the dominant force, thus explaining 18% and 24% of the IL-6 or CRP levels, respectively, in PCOS women. No association of IL-6 or BMI to a certain genotype at C-174G could be demonstrated in 50 PCOS patients. The heterozygous GC genotype, however, was associated with lower androstendione levels. Metformin treatment of 9 obese, insulin-resistant PCOS patients over a period of 6 months caused a significant decrease in body weight, body fat mass and total testosterone, but showed no significant decline in IL-6 or CRP concentrations. CONCLUSIONS: In PCOS women, plasma levels of IL-6 and CRP were not increased when compared with age- and BMI-matched controls. BMI was, however, the parameter most strongly related to IL-6 and CRP in PCOS; thus PCOS-related endocrine abnormalities do not appear to activate inflammatory parameters thereby enhancing the risk of diabetes. In PCOS, the type 2 diabetes risk may, therefore, be confined to those with obesity and/or metabolic alterations rather than affecting all women suffering from the syndrome.

Adult↗
PubMed2003

Palmitate-induced Ca2+-signaling in pancreatic beta-cells.

Free fatty acids (FFA) have been proposed to participate in the regulation of insulin release from pancreatic beta-cells (beta-cells). As a rise in cytosolic free Ca2+ ([Ca(2+)]i) is a key event for the stimulation of insulin secretion, the effects of saturated FFA on [Ca2+]i were investigated. Palmitate was used as a reference compound and [Ca2+]i was measured in single fura-2 loaded HIT-T15 and in primary mouse beta-cells. Stimulation of single beta-cells with palmitate (100 microM) caused either repetitive Ca2+ transients or a plateau-like rise in [Ca2+]i. In HIT-T15 and in mouse beta-cells, the number of palmitate-responsive cells, and the amplitude of the palmitate-induced Ca2+-signals were dependent on the extracellular glucose concentration. In Ca2+-free medium palmitate (100 microM) caused only 1 or 2 Ca2+ transients indicating mobilization of Ca2+ from internal stores. Withdrawal of external Ca2+, the addition of voltage-sensitive Ca2+ channel (VSCC) blockers, as well as the K(ATP)-channel opener diazoxide (100 microM) reversibly blocked the palmitate-induced cytosolic Ca2+ responses. This demonstrates that Ca2+ influx through VSCC of the L-type coupled to membrane depolarization through closure of K(ATP)-channels are crucial for a sustained Ca2+-signal in response to palmitate. Methyl palmoxirate (100 microM) and 2-bromopalmitate (100 microM), which both inhibit transport of acyl-CoA into the mitochondria, reversibly blocked the palmitate-induced Ca2+-signals in HIT-T15 as well as in primary mouse beta-cells. By contrast, cerulenin (100 microM), an inhibitor of protein acylation, had no effect on the palmitate-induced changes in [Ca2+]i, which suggests that mitochondrial palmitate metabolism is required for eliciting the Ca2+-signals. Simultaneous measurement of [Ca2+]i and the mitochondrial membrane potential (DeltaPsi) revealed palmitate-induced depolarization of DeltaPsi which demonstrates that palmitate does not enhance mitochondrial ATP production. Therefore mitochondrial signals other than ATP appear to be generated from palmitate metabolism that underly the palmitate-induced Ca2+-signals in pancreatic beta-cells.

Adenosine Triphosphate↗