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As part of an institutional investigation by University of Bremen, the work carried out by Kathrin Maedler's laboratory has been reviewed.

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, p0.001) 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.

Summary 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, 3β-hydroxysteroid dehydrogenase (HSD), 11-, 17-, 21-hydroxylase and 11β-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.

Growth hormone-deficient patients show deterioration of insulin sensitivity and beta cell function. High-dose growth hormone treatment often induces further impairment of insulin sensitivity, leading to an increase in insulin and glucose levels or even, in cases of preexisting beta cell defect, to overt diabetes. However, low-dose treatment may improve insulin sensitivity, although data in humans with detailed metabolic phenotyping are as yet not available. We postulated that long-term low-dose growth hormone replacement, restoring IGF-1 to the low-normal range, might beneficially affect glucose metabolism.We studied prospectively the metabolic responses to 24 and 48 weeks of growth hormone treatment in a small group of six adults with severe growth hormone deficiency (four men, two women; age 40-59 years; BMI 30.2 +/- 1 kg/m(2); mean growth hormone dose 0.3 +/- 0.04 mg/day). All participants underwent an oral glucose tolerance test, euglycaemic-hyperinsulinaemic clamp and hyperglycaemic-hyperinsulinaemic clamp plus i.v. L: -arginine on three occasions. Insulin sensitivity was measured by calculating the M value during the steady state of the euglycaemic-hyperinsulinaemic clamp. Insulin secretion and clearance were estimated from AUC(C-peptide), AUC(insulin) and their ratio at each phase of the hyperglycaemic-hyperinsulinaemic clamp.Growth hormone significantly improved insulin sensitivity (M value 13.8 +/- 2.6 [baseline] vs 19.6 +/- 2.6 [24 weeks] and 23.7 +/- 1.9 [48 weeks] micromol kg(-1) min(-1); p0.01). Although the insulin response to glucose and arginine decreased slightly, the disposition index, integrating insulin sensitivity and secretion, significantly increased (p0.01), indicating an improvement in whole-body glucose metabolism. Insulin clearance was not affected during treatment (p0.05).Our data indicate that long-term low-dose growth hormone treatment may improve insulin sensitivity and whole-body glucose metabolism in adults with severe growth hormone-deficiency.

Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr94-to-Ala amino acid replacement (Ala/Ala94) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr94) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps ( n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic-hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala94 mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid-exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP ( P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala94 carriers (0.46 ± 0.05 vs. 0.59 ± 0.05 mg·kg−1·min−1, P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala94 carriers compared with wild types ( P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala94-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L-FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes.

Plasma retinol-binding protein 4 (RBP4) may be a new adipokine linked to obesity-induced insulin resistance and type 2 diabetes. The impact of diabetic nephropathy on plasma RBP4 levels, however, is not known. We tested the hypothesis that microalbuminuria is associated with elevated plasma concentrations of RBP4 in type 2 diabetic subjects. Retinol, its binding protein and transthyretin (TTR) were measured in the plasma and urine of 62 type 2 diabetic subjects, 26 of whom had microalbuminuria. The results were compared to 35 healthy control subjects. Despite no differences in plasma retinol, concentrations of the RBP4 were significantly elevated in plasma of diabetic patients and significantly higher in those with microalbuminuria. The higher plasma levels of the binding protein in subjects with microalbuminuria were accompanied by both significantly elevated plasma TTR and increased urinary levels of RBP4. There were no correlations of plasma-binding protein levels and parameters of insulin resistance. Our study suggests that plasma RBP4 levels in type 2 diabetic patients are affected by incipient nephropathy. Therefore, further studies evaluating RBP4 as a regulator of systemic insulin resistance and type 2 diabetes will need to take renal function into consideration.

Lipid-lowering therapy is associated with reduced cardiovascular risk. The aim of the present study was to investigate whether lipid-lowering therapy might be associated with changes in the concentrations of metabolically important hormone concentrations. We performed a randomised cross-over open-label trial with atorvastatin (10 mg/day) and fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men, 8 women, age 60.0+/-6.8 years, body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus and mixed hyperlipoproteinaemia. Plasma ghrelin (RIA, Phoenix Pharmaceuticals, Mountain View, CA, USA), adiponectin (ELISA, Biovendor, Heidelberg, Germany) as well as resistin (ELISA, Linco Research, St. Charles, MO, USA) concentrations were measured before and after atorvastatin as well as before and after fenofibrate. Ghrelin (462+/-84 pg/ml before vs. 464+/-102 pg/ml after atorvastatin, n.s.; 454+/-85 pg/ml before vs. 529+/-266 pg/ml after fenofibrate, n.s.), resistin (24.4+/-7.4 pg/ml before vs. 23.7+/-9.1 pg/ml after atorvastatin, n.s.; 23.4+/-8.2 pg/ml before vs. 19.9+/-5.5 pg/ml after fenofibrate, n.s.), adiponectin (10.89+/-5.33 pg/ml before vs. 12.41+/-5.75 pg/ml after atorvastatin, n.s.; 12.58+/-9.87 pg/ml before vs. 10.27+/-5.23 pg/ml after fenofibrate, n.s.) and insulin levels did not change significantly during lipid-lowering therapy. In patients with type 2 diabetes and mixed hyperlipoproteinaemia, short-term atorvastatin as well as fenofibrate therapy had no significant effects on adiponectin, ghrelin or resistin levels.

Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation.Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY.Total plasma PYY levels (PYY(1-36) + PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY(3-36) levels were measured in 17 lean and 15 obese individuals.Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects.Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.

The consumption of arabinoxylan, a soluble fibre fraction, has been shown to improve glycemic control in type 2 diabetic subjects. Soluble dietary fibre may modulate gastrointestinal or adipose tissue hormones regulating food intake. The present study investigated the effects of arabinoxylan consumption on serum glucose, insulin, lipids, leptin, adiponectin and resistin in subjects with impaired glucose tolerance. In a randomized, single-blind, controlled, crossover intervention trial, 11 adults consumed white bread rolls as either placebo or supplemented with 15 g arabinoxylan for 6 weeks with a 6-week washout period. Fasting serum glucose, insulin, triglycerides, unesterified fatty acids, apolipoprotein A1 and B, adiponectin, resistin and leptin were assessed before and after intervention. Fasting serum glucose, serum triglycerides and apolipoprotein A-1 were significantly lower during arabinoxylan consumption compared to placebo (p=0.029, p=0.047; p=0.029, respectively). No effects of arabinoxylan were observed for insulin, adiponectin, leptin and resistin as well as for apolipoprotein B, and unesterified fatty acids. In conclusion, the consumption of AX in subjects with impaired glucose tolerance improved fasting serum glucose, and triglycerides. However, this beneficial effect was not accompanied by changes in fasting adipokine concentrations.

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.The objective was to study effects of FFAs on adrenal production of androgen precursors in vivo.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.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.DHEA, androstenedione, 17-OH-progesterone, testosterone, estrone, LH, FSH, ACTH, and cortisol were measured.The adrenal androgen precursors DHEA and androstenedione showed a circadian decline during saline/heparin infusion (P0.05 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 (P0.05, 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.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.

Objective: It is well known that i.m. glucagon administration stimulates GH and cortisol release in humans, although the mechanisms are unclear. These effects are similar to those described for ghrelin on somatotroph and corticotroph function. The aim of the present study was to investigate the role of ghrelin in mediating the stimulatory effects of glucagon and to evaluate the effect of glucagon on ghrelin secretion. Design and methods: We studied the endocrine and metabolic response to i.m. glucagon administration in 24 subjects (14 men, 10 women; age 19–65 years; body mass index, 25.3 ± 1 kg/m2), who were shown to have an intact anterior pituitary function as evaluated before enclosure. Results: Serum ghrelin concentrations fell significantly at 30, 60, 120 and 180 min after glucagon administration (means ± s.e.m.; baseline, 377.9 ± 34.5 pg/ml; nadir, 294.6 ± 28.3 pg/ml (60 min); P < 0.01). Conversely, i.m. glucagon elicited an increase in GH (baseline, 1.5 ± 0.4 μg/l; peak, 14.2 ± 2.7 μg/l (180 min); P < 0.01) and cortisol concentrations (baseline, 452.6 ± 35.2 nmol/l; peak, 622.1 ± 44 nmol/l (180 min); P < 0.01). The changes in ghrelin concentration at both 120 and 180 min were still significant after correction for glucose and insulin (P < 0.05). Conclusions: We show that i.m. glucagon decreases ghrelin significantly. Therefore, the already known stimulatory effects of i.m. glucagon on cortisol and GH are not mediated by a change in ghrelin concentrations. The mechanisms underlying the ghrelin suppression after i.m. glucagon are unlikely to include glucose or insulin variations and need to be further elucidated.

Systemic ghrelin concentration falls rapidly after nutrient ingestion in vivo. The effect incretins on ghrelin secretion in humans remains unclear. We quantified circulating ghrelin concentrations under hyperglycemic conditions combined with infusion of gastric inhibitory polypeptide (GIP) and arginine.Eight healthy volunteers were studied with a hyperglycemic clamp followed by addition of GIP (2 pmol.kg(-1).min(-1), 60-115 min) and an arginine-bolus and -infusion (10 mg.kg(-1).min(-1), 90-115 min).Hyperglycemia alone increased circulating insulin concentrations (p0.01), and decreased ghrelin concentrations to 89.8% of basal (p=0.208). GIP-infusion resulted in circulating insulin concentration of 1109+/-942 pmol/l (p0.02) and no further decrease of ghrelin (86.2% of baseline, p=0.050). Under arginine- and GIP-infusion together, insulin concentrations increased progressively to 3005+/-1604 pmol/l (p0.01) without further decreasing in ghrelin concentrations (98.9% of baseline, p=0.575).Hyperglycemic hyperinsulinemia and further increases of hyperinsulinemia to supraphysiological and high supraphysiological concentrations under GIP- and arginine-infusion do not significantly decrease ghrelin concentrations in healthy subjects. Moreover, there is no dose-dependent suppression of ghrelin by insulin in the hyperglycemic condition. Neither GIP nor arginine affected ghrelin release.

Retinal photocoagulation reduces the incidence of severe visual loss in proliferative diabetic retinopathy (PDR). Reduced levels of VEGF/VPF might result in an improved function of the blood-retina barrier and cause a decrease of blood derived intraocular growth factors such as IGF-I. This study investigates whether retinal photocoagulation is able to normalize the concentrations of IGF-I, IGF-II and IGF-BP3 in the vitreous humor of patients undergoing vitrectomy. Levels of IGFs and the permeability marker, albumin, were measured in serum and vitreous of 52 patients. Three groups were compared: controls without proliferating eye disease (n = 19) and patients with PDR with (PDR+; n = 25) and without (PDR-; n = 8) previous retinal photocoagulation. IGF-I, IGF-II, IGF-BP3 and albumin were determined by immunological methods and were confirmed to be increased in patients with PDR compared to controls. Retinal photocoagulation influenced neither the intraocular concentration of the permeability marker albumin (PDR+: 253.2 +/- 46 mg/dl; PDR-: 256.4 +/- 66.5 mg/dl) nor the levels of IGFs (PDR+: IGF-I: 1.2 +/- 0.1 ng/ml; p = 0.38; IGF-II: 34.8 +/- 2.2 ng/ml; p = 0.1; IGF-BP3: 75.7 +/- 9.7 ng/ml; p = 0.27; PDR-: IGF-I: 1.1 +/- 0.2ng/ml; IGF-II: 29.3 +/- 5.2 ng/ml; IGF-BP3: 61.5 +/- 18.3 ng/ml). Systemic levels of albumin and IGFs were not changed significantly by retinal photocoagulation. These results demonstrate that previous retinal photocoagulation in patients undergoing vitrectomy does not functionally reestablish the blood-retina barrier despite decreases in VEGF/VPF. The lack of influence on intraocular concentrations of the serum-derived growth factors, IGF-I, IGF-II and IGF-BP3, might in part explain the failure of previous photocoagulation in the investigated patients. These results suggest that a combined treatment with retinal photocoagulation and growth hormone-lowering drugs, such as somatostatin analogues, could be a useful treatment, which may prevent further loss of visual acuity in patients with PDR.

Thyroid dysfunction has been shown to be associated with insulin resistance (IR). This may involve peripheral thyroid hormone metabolism, which is assumed to be reflected by the ratio triiodothyronine/reverse triiodothyronine (T3/rT3-ratio). To explore a potential association between the T3/rT3-ratio and IR we investigated pairs which differed in IR, but were matched by sex, age, body mass index (BMI), and thyroid stimulating hormone (TSH). For this purpose, matched pair analyses were embedded into a cross sectional study group. 22 pairs were matched from either the first or the third tertile of HOMA%S of a cohort of 353 euthyroid subjects with normal glucose metabolism who did not take any medication. The T3/rT3-ratio was compared in the matched pairs. The T3/rT3-ratio was significantly increased in the insulin resistant subjects compared to their insulin sensitive partners (8.78 ± 0.47 vs. 7.33 ± 0.33, p=0.019). Furthermore the T3/rT3-ratio was lower in men compared to women (p for the within-subject effect=0.046) both in the insulin sensitive and the insulin resistant subjects. Here we show that the T3/rT3-ratio, which is supposed to reflect the tissue thyroid hormone metabolism, is significantly increased in insulin resistant subjects. This further supports a link between thyroid function and IR.

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, 5α-dihydrotestosterone, estrone, and 17β-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3β,17β-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16α-hydroxy-DHEA and 5-androstene-3β,16α,17β-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.

Ghrelin is a powerful orexigenic gut hormone. Circulating concentrations of total ghrelin are downregulated by food intake in both acute and chronic hyperinsulinemic states. However, in blood des-acylated (des-acyl) ghrelin is the predominant form that has no orexigenic effects in humans. Circulating acyl-ghrelin has been shown to be suppressed post-prandially and by pharmacological hyperinsulinemia. However, up to now responses of circulating acyl-ghrelin to moderate hyperinsulinemic and hyperinsulinemic-hyperlipidemic clamp conditions have not been reported. Fourteen healthy subjects were investigated using two-stepped euglycemic-hyperinsulinemic clamps (40 mU insulin/ m2/min; mean 148+/-7 min till steady state, followed by 300 min lipid/heparin infusion). Responses of total ghrelin and acyl-ghrelin were measured at timed intervals throughout the clamps. Des-acyl-ghrelin concentrations were calculated by subtraction. Total ghrelin significantly decreased vs baseline concentrations (819+/-92 vs 564+/-58 pg/ml, p0.001), thereby confirming previous observations. Des-acyl ghrelin closely followed total ghrelin concentrations and significantly decreased vs baseline (772+/-92 vs 517+/-56 pg/ml, p0.001). In contrast, neither euglycemichyperinsulinemia nor euglycemic-hyperinsulinemic- hyperlipidemia suppressed acyl-ghrelin below baseline concentrations throughout the clamps (46+/-3 vs 47+/-8 pg/ml, p=0.90). In conclusion, moderate hyperinsulinemic and hyperinsulinemic- hyperlipidemic clamp conditions differentially modulated circulating total ghrelin and acylghrelin in humans. Factors other than changes in insulin and lipid concentrations are likely to contribute to the previously reported post-prandial reduction of circulating acyl-ghrelin.

Fragestellung: Es wird vermutet, dass das Cytokin Interleukin-6 eine kausale Rolle in der Entstehung von Diabetes mellitus Typ 2 (T2DM) spielt. In zahlreichen kleineren Studien wurden die zwei im Promoterbereich liegenden Einzelnukleotidpolymorphismen (SNPs) -174G>C (rs1800795) und -573G>C (rs1800796) des fur Interleukin-6 kodierenden IL6-Gens auf ihren Zusammenhang mit T2DM untersucht. Die vorliegenden Ergebnisse waren jedoch nicht eindeutig. Um den Zusammenhang zwischen den beiden IL6-Varianten und T2DM zu klaren, wurde eine auf Individualdaten beruhende Meta-Analyse publizierter und unpublizierter Studien initiiert. Methodik: Nach einer systematischen Literaturrecherche sowie Rekrutierung aller verfugbaren publizierten und unpublizierten Studien, wurden die Individualdaten im Studienzentrum (Institut fur Epidemiologie des Helmholtz Zentrum Munchen, Neuherberg) gesammelt und auf Plausibilitat gepruft. Studienspezifische Assoziationsschatzer zum Zusammenhang zwischen den IL6-Varianten und dem Phanotyp T2DM – und wo verfugbar dem Phanotyp Nuchternglucose – wurden mittels multivariablen Regressionsmodellen mithilfe der Statistiksoftware SAS Version 9.1 berechnet. Die Heterogenitat zwischen den studienspezifischen Schatzern wurde untersucht und die Schatzer mit der „inverse-variance fixed-effect“ Methode zusammengefasst, da die Heterogenitat sehr gering war. Ergebnisse: Der Analysedatensatz umfasste fur den dichotomen Phanotyp T2DM Individualdaten von uber 20.000 Teilnehmern aus 21 publizierten und unpublizierten Studien, fur den quantitativen Phanotyp Nuchternglucose Individualdaten von uber 10.000 Teilnehmern aus acht publizierten und unpublizierten Studien. Die GC- und CC-Genotypen des IL6–174G>C Polymorphismus waren mit einem erniedrigten T2DM-Risiko (OR=0.91; P=0.04) und erniedrigter Nuchternglucose assoziiert (beta=-0.09mmol/l; P=0.01). Es gab keinen Hinweis auf eine Assoziation zwischen IL6–573G>C and T2DM. Schlussfolgerungen: Die Assoziationen zwischen dem IL6–174 C-Allel und reduziertem T2DM-Risiko sowie erniedrigten Nuchternglucosespiegeln, die in dieser bisher grosten auf Individualdaten basierenden Assoziationsanalyse fur T2DM entdeckt wurden, liefern weitere Hinweise dafur, dass Immunmediatoren in kausalem Zusammenhang mit T2DM stehen.

Fragestellung: Chronisch hohe Glucosekonzentrationen fuhren in pankreatischen Betazellen und Inseln zur Verminderung der Insulinexpression und -sekretion, ein Phanomen, dass unter dem Namen Glucosetoxizitat bekannt ist. Trotz seiner moglichen Relevanz bei der Entstehung des Typ-2-Diabetes sind die zu Grunde liegenden Mechanismen bisher nicht genau geklart. Obwohl intensive Untersuchungen zur Regulation der Insulingenexpression stets neue Erkenntnisse liefern ist die Beteilung des Glucosestoffwechsels weitgehend unklar. Mithilfe von Metabolitenprofilanalysen wird der Frage nachgegangen, welche metabolischen Veranderungen durch hohe Glucosekonzentrationen in Betazellen induziert werden. Methodik: INS-1 Zellen wurden bei 3 mM oder 16 mM Glucose fur 48h kultiviert. Die Messung der Insulin mRNA Spiegel erfolgte mittels semiquantitativer real-time RT-PCR. Intrazellulare Metaboliten wurden mit Methanol:Chloroform:Wasser extrahiert und mittels GC-tofMS analysiert. Ergebnisse: Die Insulingenexpression ist unter chronisch hohen Glucosebedingungen signifikant vermindert (P

Fragestellung: Eine Adipositas und daraus resultierende Entgleisungen des Glucosestoffwechsels oder die Entstehung kardiovaskularer Erkrankungen, werden durch die Interaktion verschiedenster Umweltfaktoren und der individuellen genetischen Pradisposition verursacht. Varianten zu ermitteln, die im Zusammenhang mit diesen sehr heterogenen polygenetischen, metabolischen Erkrankungen stehen, ist Inhalt dieser Arbeit. Das Retinol-bindende Protein 4 (RBP4) stellt auf Grund experimenteller Daten, welche dieses Gen mit allen drei Krankheitsbildern in Verbindung bringt, ein kausales Kandidatengen dar. Methodik: Es wurden alle vier im RBP4-Gen vorkommenden htSNP's (haplotype tagging Single Nucleotide Polymorphism), mittels des TaqMan-Assays, in zwei unabhangigen Kohorten bestimmt. Die Querschnittsstudie MeSyBePo (Metabolisches Syndrom Berlin Potsdam), mit 1.895 Teilnehmern, beinhaltet eine umfangreiche anthropometrische und metabolische Charakterisierung, welche die Durchfuhrung eines OGTT einschliest. Die prospektive (Follow-Up 6,5 Jahre) Fall-Kohorten Studie EPIC-Potsdam (European Investigation into Cancer and Nutrition) mit insgesamt 1.250 Probanden, umfasste 408 Personen die entweder einen inzidenten Myokardinfarkt (n=155), einen Schlaganfall (n=163) oder eine transitorisch ischamische Attacke (n=90) protokollierten. Zugunsten einer besseren Ubersicht, werden hier nur die Ergebnisse des rs10882278 dargestellt, da dieser den deutlichsten Effekt zeigte. Ergebnisse: In beiden Kohorten kam es in Falle der Variante zu einer Erhohung des BMI, Huft- und Taillenumfangs und des prozentualen Fettanteils, welcher uber die Messung vier verschiedener Hautfalten kalkuliert wurde. Die WHR blieb dagegen unverandert. Auf den fur die MeSyBePo-Kohorte validierten Index der Insulinsekretion wurde kein Effekt detektiert, dagegen aber eine Verbesserung des Insulinsensitivitatsindizes. Auch der Dispositionsindex, welcher das hyperbolische Verhaltnis von Insulinsensitivitat zu Insulinsekretion reflektiert, war fur Trager der Variante verbessert. Auf den in dieser Kohorte bestimmten Serumspiegel von RBP4 hatte die Variante keinen Effekt. In Hinblick auf das Risiko einer kardiovaskularen Erkrankung zeigte sich auf den prospektiven Endpunkt Myokardinfarkt ein um 50% verringertes Risiko fur Trager des mutierten Allels (p=0,039). Schlussfolgerungen: Aufgrund der hier ermittelten Daten kann man spekulieren, dass der rs10882278 Polymorphismus des RBP4-Gens zwar eine Erhohung von Parametern der allgemeinen Korperzusammensetzung zur Folge hat, aber mehr zu Lasten des subkutanen Kompartiments, als das metabolisch negativere viszerale Depot. Dies konnte auch erklaren, warum es trotz Erhohung anthropometrischer Parameter durch die Variante zu einer Verbesserung des Glucosemetabolismus kommt und das Risiko fur einen Myokardinfarkt deutlich verringert wird. Diese Ergebnisse mussen in weiteren Studienkollektiven validiert werden.

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.