Leptin and endocrine parameters in marathon runners.

Endurance training may lead to different hormonal alterations e. g., exercised induced hypothalamic ovarian/testicular dysfunction. The aim of this study was to reveal new connections between physical exercise, leptin and hormonal responses. 36 male participants of the Berlin-Marathon had their blood samples taken 2 days before the marathon. Hormones of the hypothalamic-pituitary axis and leptin were correlated with the training status and the achieved marathon time. Leptin correlated with the achieved marathon time after being adjusted for age and BMI (r=0.607, p<0.001) and was lowest in the best trained runners. Additionally, when the group was divided into quartiles of their achieved marathon time, significantly increased cortisol, fT4, cortisol/DHEAS ratio and decreased IGF-1 levels were observed in the slowest group. In the better trained group, a decrease of testosterone/DHT ratio and an increase of testosterone/cortisol ratio were observed. Our study supports the thesis of a linear relationship between physical fitness and leptin variations in the physiological range. We found an increased anabolic hormonal response in well trained marathon runners and hormonal reactions of increased stress in less trained runners. As the stress-induced neuroendocrine adaptations in our study group are associated with more higher leptin values, the pathophysiological role of decreased leptin values seems to be limited to overtrained athletes.

Effects of hyperlipidaemia on glucocorticoid metabolism: results of a randomized controlled trial in healthy young women.

OBJECTIVE: It is well established that the hypothalamic-pituitary-adrenal (HPA) axis is altered in obese individuals. Hyperlipidaemia with elevated levels of free fatty acids (FFAs) is also frequently seen in obesity and in the metabolic syndrome. We hypothesized, therefore, that hyperlipidaemia may alter the activity of the HPA axis. PATIENTS AND METHODS: The effects of hyperlipidaemia, including increased circulating FFAs, on ACTH secretion and cortisol metabolism were analysed in 13 healthy young women during the early follicular phase of two subsequent cycles. We administered a 20% lipid/heparin (LHI) or a saline/heparin infusion (SHI) using a crossover design in random order for 330 min. A detailed characterization of glucocorticoid metabolism was performed by measurement of plasma ACTH, cortisol and urinary excretion rates of adrenal glucocorticoids and the glucocorticoid metabolites. RESULTS: We observed that LHI-induced hyperlipidaemia elevated serum cortisol levels compared to SHI. No changes in plasma ACTH levels, daily urinary excretion rates of adrenal glucocorticoids, glucocorticoid precursors/metabolites and the calculated activities of the 5α-reductase, 3ß-hydroxysteroid dehydrogenase (HSD), 11-, 17-, 21-hydroxylase and 11ß-HSD 1 or 2 were found. CONCLUSION: Our randomized controlled trial suggests that the adrenal sensitivity to ACTH may be enhanced by LHI-induced hyperlipidaemia in normal-weight healthy young women. This effect might contribute to the disturbances of the HPA axis described in women with abdominal obesity and impaired lipid metabolism.

High molecular weight adiponectin correlates positively with myeloperoxidase in patients with type 2 diabetes mellitus.

Adiponectin (APN) is present in human plasma as a low molecular weight (LMW), a middle molecular weight (MMW) and a high molecular weight form (HMW). As a support to determine properties such as anti-atherogenic or atherogenic effects, recent clinical studies suppose to determine the ratio of each APN multimer to total APN but not the absolute plasma concentration of APN. In the present study, the correlation of APN and its multimers with myeloperoxidase (MPO), an enzyme with pro-inflammatory properties, was examined in patients with type 2 diabetes mellitus. MPO and APN serum levels were assessed in 49 patients with type 2 diabetes mellitus at the beginning and at the end of an anti-diabetic treatment. After treatment a significant increase in the ratio of HMW to total APN (from 0.43+/-0.16 to 0.59+/-0.14, p<0.05) was found. Before treatment, HMW-APN was correlated positively with MPO (r=0.314, p<0.05). Moreover, a positive correlation was observed between the increased HMW ratio and MPO during treatment (r=0.304, p<0.05). HMW-APN correlates positively with MPO in patients with type 2 diabetes. Therefore, HMW-APN may exert possible pro-inflammatory effects in type 2 diabetes.

Intravenous lipid and heparin infusion-induced elevation in free fatty acids and triglycerides modifies circulating androgen levels in women: a randomized, controlled trial.

BACKGROUND: The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism and associated with obesity and impaired glucose metabolism. Despite the high prevalence of PCOS and the considerable clinical impact, the precise interplay between metabolism and hyperandrogenemia is not entirely clear. OBJECTIVE: The objective of the study was to analyze the effects of iv lipid and heparin infusion on circulating androgen levels in healthy women. DESIGN: This was a randomized, controlled, crossover trial. SETTING: The study was conducted at an endocrinology center. PATIENTS: Patients included 12 healthy young women during the early follicular phase of two subsequent cycles. INTERVENTION: After an overnight fast, a 20% lipid/heparin or a saline/heparin infusion was administered in random order for 330 min. MAIN OUTCOME MEASURES: A detailed characterization of androgen metabolism was performed. RESULTS: Elevations in free fatty acids and triglycerides, induced by lipid/heparin infusion, elevates the levels of androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, 5alpha-dihydrotestosterone, estrone, and 17beta-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3beta,17beta-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 5-androstene-3beta,16alpha,17beta-triol, were reduced. CONCLUSION: The mechanism of iv lipid and heparin infusion-induced elevation of circulating androgens described here might contribute to the development of hyperandrogenism in women with PCOS and suggests that lowering of hyperlipidemia might be a potential therapeutic target in patients with PCOS to treat hyperandrogenemia.

The effect of moderate alcohol consumption on adiponectin oligomers and muscle oxidative capacity: a human intervention study.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether moderate alcohol consumption increases plasma high molecular weight (HMW) adiponectin and/or muscle oxidative capacity. MATERIALS AND METHODS: Eleven lean (BMI 18-25 kg/m(2)) and eight overweight (BMI >or=27 kg/m(2)) men consumed 100 ml whisky ( approximately 32 g alcohol) or water daily for 4 weeks in a randomised, controlled, crossover trial. After each treatment period, muscle biopsies and fasting blood samples were collected. RESULTS: Adiponectin concentrations increased (p < 0.001) by 12.5% after 4 weeks of moderate alcohol consumption. Moderate alcohol consumption tended to increase HMW adiponectin by 57% (p = 0.07) and medium molecular weight adiponectin by 12.5% (p = 0.07), but not low molecular weight (LMW) adiponectin. Skeletal muscle citrate synthase, cytochrome c oxidase and beta-3-hydroxyacyl coenzyme A dehydrogenase (beta-HAD) activity were not changed after moderate alcohol consumption, but an interaction between alcohol consumption and BMI was observed for cytochrome c oxidase (p = 0.072) and citrate synthase (p = 0.102) activity. Among lean men, moderate alcohol consumption tended to increase cytochrome c oxidase (p = 0.08) and citrate synthase activity (p = 0.12) by 23 and 26%, respectively, but not among overweight men. In particular, plasma HMW adiponectin correlated positively with activities of skeletal muscle citrate synthase (r = 0.64, p = 0.009), cytochrome c oxidase (p = 0.59, p = 0.009) and beta-HAD (r = 0.46, p = 0.056), while such correlation was not present for LMW adiponectin. Whole-body insulin sensitivity and intramyocellular triacylglycerol content were not affected by moderate alcohol consumption. CONCLUSIONS/INTERPRETATION: Moderate alcohol consumption increases adiponectin concentrations, and in particular HMW adiponectin. Concentrations of HMW adiponectin in particular were positively associated with skeletal muscle oxidative capacity.

Adiponectin oligomers in human serum during acute and chronic exercise: relation to lipid metabolism and insulin sensitivity.

Beneficial effects of physical exercise include improved insulin sensitivity, which may be affected by a modulated release of adiponectin, which is exclusively synthesized in white adipose tissue and mediates insulin sensitivity. Adiponectin circulates in three different oligomers, which also have a distinct biological function. We therefore aimed to investigate the distribution of adiponectin oligomers in human serum in relation to physical activity. Thirty-eight lean and healthy individuals were investigated. Seven healthy women and 8 healthy men volunteered to investigate the effect of chronic exercise, at 3 different time points with different training intensities. These individuals were all highly trained and were compared to a control group with low physical activity (n = 15). For studying acute exercise effects, 8 healthy men participated in a bicycle test. Adiponectin was determined by ELISA, oligomers were detected by non-denaturating western blot. Total adiponectin and oligomers were unchanged by acute exercise. LDL cholesterol was significantly lower in the chronic exercise group (p = 0.03). Total adiponectin levels and oligomers were not different between these two groups and were unaltered by different training intensities. However, total adiponectin and specifically HMW oligomers correlated with HDL cholesterol (r = 0.459; p = 0.009). We conclude that acute and chronic exercise does not directly affect circulating adiponectin or oligomer distribution in lean and healthy individuals. Whether such regulation is relevant in individuals with a metabolic disorder remains to be determined. However, our data suggest that adiponectin oligomers have distinct physiological functions IN VIVO, and specifically HMW adiponectin is closely correlated with HDL cholesterol.

Free fatty acids increase androgen precursors in vivo.

CONTEXT: There is considerable evidence that metabolic factors such as insulin resistance may induce hyperandrogenemia in polycystic ovary syndrome. However, other metabolic factors such as free fatty acids (FFAs) may also contribute to androgen excess. OBJECTIVE: The objective was to study effects of FFAs on adrenal production of androgen precursors in vivo. DESIGN AND PARTICIPANTS: We investigated eight healthy young men, because male individuals produce the androgen precursors dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione predominantly in the adrenal gland. A randomized controlled crossover trial was performed. INTERVENTION: After a 10-h overnight fast, 20% lipid/heparin or saline/heparin infusion was given at a rate of 1.5 ml/min. Four hours after start of lipid infusion, a euglycemic hyperinsulinemic clamp was performed. MAIN OUTCOME MEASURES: DHEA, androstenedione, 17-OH-progesterone, testosterone, estrone, LH, FSH, ACTH, and cortisol were measured. RESULTS: The adrenal androgen precursors DHEA and androstenedione showed a circadian decline during saline/heparin infusion (P < 0.05 vs. baseline, respectively), whereas no significant changes were observed during lipid/heparin infusion (P = not significant vs. baseline, respectively). Correspondingly, DHEA and androstenedione values were significantly elevated during lipid compared with saline infusion (P < 0.05, respectively), and areas under curve of both androgen precursors were significantly increased with lipid compared with saline infusion. Notably, all changes were detected before induction of insulin resistance. CONCLUSIONS: This study demonstrates that FFAs increase production of androgen precursors in vivo in men. These data tentatively suggest that hyperandrogenemia in polycystic ovary syndrome may be induced, at least in part, by elevated FFAs.

Adaptation of the hypothalamic-pituitary hormones during intensive endurance training.

OBJECTIVE: Physical activity leads to changes in the hypothalamic-pituitary hormonal system. However, acute and long-term adaptations have not yet been precisely characterized. In this study, the changes of the hormonal system as a result of marathon training and running a marathon were examined. In particular, we focused on adaptations of the hypothalamic-pituitary-adrenocortical (HPA) axis, regarding the activation or inactivation of cortisol to cortisone by the 11beta-hydroxysteroid-dehydrogenase system (11beta-HSD). DESIGN: Patient measurements: 8 healthy women and 11 healthy men volunteered for this study. Blood samples, 24-h urine and a dexamethasone suppression test were analysed for metabolic and hormonal parameters at five different dates 12 weeks around a marathon. RESULTS: Cortisol and ACTH values decreased significantly 2 days after the marathon, whereas the activity of the whole body 11beta-HSD-1 was up-regulated. An increased suppression of cortisol levels was observed in the dexamethasone suppression test after 6 weeks of reduced training levels. Ghrelin was elevated 2 days after the marathon. Only minor changes in the other hypothalamic-pituitary-hormonal axes could be observed. However, the free androgen index increased significantly after 6 weeks of reduced training. CONCLUSIONS: The HPA system appeared to become chronically activated by continuous physical training and therefore less sensitive to the dexamethasone suppression test. The acute stress of the marathon led to a central exhaustion of the HPA system with a paracrine counteraction by the activation of the 11beta-HSD system. Changes in the other hypothalamic-pituitary hormonal axes were the result of long-term differences in training levels and were not altered by the marathon.

In vivo activity of 11beta-hydroxysteroid dehydrogenase type 1 and free fatty acid-induced insulin resistance.

INTRODUCTION: Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA-induced hepatic insulin resistance is mediated by increased activity of hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), accompanied by elevated hepatic cortisol levels. METHODS: Following a 10-h overnight fast, six healthy male volunteers were investigated. A euglycaemic hyperinsulinaemic clamp was performed during lipid or saline infusion. To assess hepatic 11beta-HSD1 activity, plasma cortisol levels were measured after oral administration of cortisone acetate during lipid or saline infusion. In addition, 11beta-HSD activities were determined in vivo by calculating the urinary ratios of GC metabolites. RESULTS: Lipid infusion increased FFAs (5.41 +/- 1.00 vs. 0.48 +/- 0.20 mmol/l; P < 0.005) and significantly increased insulin resistance [glucose infusion rate (GIR) 6.02 +/- 2.60 vs. 4.08 +/- 2.15 mg/kg/min; P < 0.005]. After lipid and saline infusions no changes in 11beta-HSD1 activity were found, neither by changes in cortisone acetate to cortisol conversion nor by differences in urinary free cortisol (UFF) or cortisone (UFE), 5beta-tetrahydrocortisol (THF), 5alpha-THF, cortisone (THE), UFF/UFE and (5alpha-THF + THF)/THE ratios. CONCLUSIONS: We found no change in hepatic and whole-body 11beta-HSD1 activity during acute FFA-induced insulin resistance. Further studies are necessary to clarify whether 11beta-HSD1 in muscle and adipose tissue is influenced by FFAs and whether 11beta-HSD1 is involved in other conditions of insulin resistance.

[Significance of biomarkers for metabolic syndrome during weight reduction]. / Bedeutung von Biomarkern des metabolischen Syndroms bei Gewichtsreduktion.

INTRODUCTION: Obesity is a risk factor for type 2 diabetes, hypertension, dyslipidemia and cardiovascular disease. We aimed to analyse the changes of parameters of the metabolic syndrome and to investigate which markers are useful in the prediction of a successful weight loss. Preliminary data of an ongoing study are presented. METHODS: 18 obese individuals (15 female, 3 male, mean age 50.9 years, mean BMI 36.1) finished a 12 month weight loss program. This weight loss program was based on a hypocaloric diet (50 % carbohydrates, 30 % fat, 20 % protein) and at least 60 min physical activity per week. At baseline, 6 months and 12 months physical examination, indirect calorimetry, bioimpedance analysis were performed and blood was taken for routine laboratory. An oral glucose tolerance test and an euglycemic hyperinsulinemic clamp (n = 13) were carried out at baseline and after 6 months. RESULTS: There was a decrease of the BMI (+/- SEM) from 36.1 +/- 1.3 to 33.4 +/- 1.2 after 6 months and 32.8 +/- 1.3 after 12 months. Waist circumference (-8.8 cm), fasting blood glucose (98.0 to 91.2 and 92.5 mg/dl) and HDL cholesterol (47.2 to 64.6 mg/dl after 12 months) improved significantly. Other parameters of the metabolic syndrome (blood pressure, lipids, insulin resistance) and adiponectin improved slightly, but changes failed to be significant. In a linear regression analysis age, insulin resistance (M-value) and adiponectin at baseline were significant and independent predictors of a successful weight loss. CONCLUSION: In conclusion, most parameters of the metabolic syndrome improved after successful weight reduction, although changes of most parameters were modest and did not reach statistical significance.