J. Spranger

A dietary pattern protective against type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)--Potsdam Study cohort.

Aims/hypothesisThe aim of this study was to identify a dietary pattern associated with diabetes-related biomarkers and to investigate whether this pattern is associated with the incidence of type 2 diabetes.MethodsA nested case–control study of 192 cases of incident type 2 diabetes and 382 control subjects matched for sex and age was conducted. All subjects were participants in the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)—Potsdam Study. Dietary pattern score was derived using intake data on 48 food groups as exposure variables and the biomarkers HbA1c, HDL cholesterol, C-reactive protein and adiponectin as response variables in reduced rank regression. The association of the score with diabetes risk was estimated by conditional logistic regression analysis.ResultsA high score for the identified dietary pattern was characterised by a high intake of fresh fruit and a low intake of high-caloric soft drinks, beer, red meat, poultry, processed meat, legumes and bread (excluding wholegrain bread). Subjects with high scores had high plasma concentrations of HDL cholesterol and adiponectin and low plasma concentrations of HbA1c and C-reactive protein. After multivariate adjustment, the odds ratios for type 2 diabetes across increasing quintiles of the dietary pattern score were 1.0, 0.59, 0.51, 0.26 and 0.27, respectively (p=0.0006 for trend).Conclusions/interpretationA high score for the identified dietary pattern is associated with a more favourable biomarker profile and a substantially reduced incidence of type 2 diabetes.

Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women.

OBJECTIVE:Obesity is linked to the insulin resistance syndrome (IRS), type 2 diabetes (T2D) and cardiovascular disease. Markers of chronic subclinical inflammation such as high-sensitive C-reactive protein (hs-CRP) and interleukin 6 (IL-6) are closely related to insulin resistance and obesity. Recent evidence suggests that adiponectin, a protein whose circulating levels are decreased in obesity, has anti-inflammatory properties, and also appears to enhance potently insulin action and therefore appears to function as a signal produced by adipose tissue that influences whole-body glucose metabolism.SUBJECTS AND METHODS:We investigated the cross-sectional and longitudinal association of adiponectin with CRP and IL-6 in 41 morbidly obese women with different stages of glucose tolerance before and 17 months after significant weight loss induced by gastric surgery. Adiponectin was measured by RIA. CRP and IL-6 were determined by commercially available ELISA systems.RESULTS:Weight loss induced a significant shift from T2D (preoperatively 34% vs postoperatively 2%) to impaired glucose tolerance (IGT) (37% preoperatively vs 30% postoperatively) and normal glucose tolerance (NGT) (29% preoperatively vs 68% postoperatively). Preoperatively adiponectin levels were negatively correlated with CRP (r=−0.59, P<0.0006), IL-6 (r=−0.42, P<0.02) and leukocytes (r=−0.41, P<0.007). After gastroplasty, adiponectin concentrations increased significantly (15.4±8.2 vs 19.8±6.2 μg/ml, P<0.005) associated with changes of weight and body mass index (r=−0.45, P<0.007; r=−0.35, P<0.04). Furthermore, preoperative CRP was significantly associated with changes in adiponectin even after adjustment for sex, age, preoperative body mass index (BMI) impaired glucose metabolism and changes in BMI and changes in BMI (standardized beta 0.61, P=0.005).CONCLUSION:Levels of adiponectin, which are associated with markers of chronic subclinical inflammation, could be significantly increased after weight loss in morbidly obese patients. This increase was more pronounced in patients with NGT compared to those with T2D and IGT. Preoperative levels of CRP are predictive for changes of adiponectin after weight loss.

Release of the angiogenesis inhibitor angiostatin in patients with proliferative diabetic retinopathy : association with retinal photocoagulation

Aims/hypothesis. Proliferative diabetic retinopathy is a major debilitating disease causing most cases of blindness in humans in the Western world. Photocoagulation is the established therapy of proliferative diabetic retinopathy, although the molecular mechanisms of its effects are still not known. Recently angiostatin has been characterized as a potent inhibitor of neovascularization. Apart from a possible down-regulation of angiogenic cytokines, release of angiostatin could initiate the anti-angiogenic effects of retinal photocoagulation.¶Methods. We investigated the regulation of angiostatin and the angiogenic cytokines vascular endothelial growth factor and basic fibroblast growth factor in vivo by comparing vitreal concentrations of 18 control patients and 34 patients with proliferative diabetic retinopathy with and without previous photocoagulation. Concentrations of basic fibroblast growth factor and angiostatin were additionally measured in serum, while vascular endothelial growth factor is known to be regulated locally in the eye. Cytokines were measured by immunological methods.¶Results. Angiostatin could be detected in 2 out of 18 control patients and in 25 out of 34 diabetic patients (p < 0.00 001). Most importantly, production of angiostatin in human vitreous correlated significantly with previous retinal photocoagulation (p < 0.0001) in patients with proliferative diabetic retinopathy. Only two patients (one control and one diabetic) had detectable serum concentrations of angiostatin. Additionally patients with proliferative diabetic retinopathy and with previous photocoagulation had significantly lower concentrations of vascular endothelial growth factor (0.9 ± 0.1 ng/ml; p < 0.0001) than diabetic patients without previous photocoagulation (4.0 ± 0.8 ng/ml). The investigation of vitreal and serum basic fibroblast growth factor concentrations yielded no significant differences between the groups.¶Conclusion/interpretation. Angiostatin is not a regularly expressed angiogenesis inhibitor in human vitreous. The alterations we observed suggest that local release of angiostatin and down-regulation of vascular endothelial growth factor mediate the therapeutic effects of retinal photocoagulation in proliferative diabetic retinopathy. [Diabetologia (2000) 43: 1404–1407]

The many faces of ghrelin: new perspectives for nutrition research?

The appetite-modulating peptide ghrelin is predominantly produced and secreted by the stomach and shows a strong growth hormone-releasing activity, which is mediated by the activation of the so-called growth hormone secretagogue type 1a receptor. Ghrelin is involved in the regulation of energy balance by increasing food intake and reducing fat utilization. Additionally, it stimulates lactotroph and corticotroph function, influences the pituitary gonadal axis, inhibits pro-inflammatory cytokine expression, controls gastric motility and acid secretion and influences pancreatic exocrine and endocrine function, as well as impacting on glucose metabolism. This review summarizes the known functions of ghrelin and its role in the regulation of the gut-brain axis.

Post-prandial decrease of human plasma ghrelin in the absence of insulin

Ghrelin is the most powerful orexigenic hormone in mammalian physiology. Ghrelin plasma concentrations increase prior to meal onset, but decrease post-prandially. We and others reported previously that insulin reduces circulating ghrelin levels and might therefore be a driving force for post-prandial suppression of ghrelin. To test the influence of insulin on post-prandial ghrelin regulation, a patient with Type 1 diabetes with complete insulin deficiency received a low glycemic index meal and subsequently an additional high glycemic index meal in the absence of insulin substitution. Subsequently, a sc injection of 0.08 IU Lispro insulin per kg body weight was given. Results were compared to those of a healthy control subject matched for sex, age and body mass index, which was undergoing the same test series (without Lispro bolus) in the presence of endogenous post-prandial insulin secretion. A substantial decrease of plasma ghrelin levels was observed in the insulin-deficient patient following low glycemic index carbohydrate load (27% plasma ghrelin decrease). The subsequent exposure to a high glycemic index meal resulted in a slight additional reduction of ghrelin levels (32% from baseline), while Lispro bolus did not induce further changes in circulating ghrelin (27% of baseline at termination). This post-prandial response was comparable to that of the healthy control subject (33% reduction after the first meal, 40% after the second meal). These data tentatively suggest that post-prandial secretion of ghrelin is not exclusively regulated by plasma insulin or plasma glucose but may depend on other metabolic factors yet to be identified.

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.

mRNA expression of ligands of the epidermal-growth-factor-receptor in the uterus

Six different ligands of the epidermal‐growth‐factor receptor (EGFR) have been identified in the past. In some cervical squamous‐cell carcinomas, an increased amount of proteins binding to the EGFR has been reported. In order to identify the mRNA of EGFR ligands (EGFRL), which might be over‐expressed in cervical and endometrial cancers, we performed semi‐quantitative reverse‐transcription/polymerase chain reactions (RT‐PCR) for all 6 EGFRL in RNA extracts of normal and malignant tissue samples of the human uterus. PCR products from RNA extracts of 83 patients were quantitated relative to the housekeeping gene and internal standard pyruvate dehydrogenase by analyzing the PCR kinetics of product synthesis. In extracts of normal cervix, the level of mRNA expression of the EGFRL was significantly higher than in endometrium. No significant difference was detected between normal cervix and cervical carcinomas. However, both in cervical and in endometrial cancers, mRNA expression was non‐parametrically distributed and in some cervical cancers overexpression of transforming growth factor alpha (TGF‐α), amphiregulin or EGF was observed. In endometrial cancers, mRNA levels of all EGFRL were higher than in normal endometrium. This increase was significant (p < 0.005) for TGF‐α and amphiregulin. Thus, TGF‐α mRNA is over‐expressed in approximately 10% of cervical cancers and in the majority of endometrial cancers. Since TGF‐α anti‐sense therapy might represent a future strategy in such cancers, we also determined the absolute level of TGF‐α mRNA expression by quantitative PCR using a cloned standard. Int. J. Cancer 72:581–586, 1997.© 1997 Wiley‐Liss, Inc.

Short-term therapy with atorvastatin or fenofibrate does not affect plasma ghrelin, resistin or adiponectin levels in type 2 diabetic patients with mixed hyperlipoproteinaemia

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.

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 11β‐hydroxysteroid‐dehydrogenase system (11β‐HSD).

Identification of an intracellular metabolic signature impairing beta cell function in the rat beta cell line INS-1E and human islets

Aims/hypothesisChronic hyperglycaemia promotes the progressive failure of pancreatic beta cells in patients with type 2 diabetes mellitus, a clinically highly relevant phenomenon known as glucotoxicity. The intracellular metabolic consequences of a chronically high availability of glucose in beta cells are, as yet, poorly understood in its full complexity.MethodsAn unbiased metabolite profiling analysis (GC-time-of-flight-MS) was used to identify the time course of core metabolite patterns in rat beta cell line INS-1E during exposure to high glucose concentrations and its relation to insulin expression.ResultsWe report here that pentose phosphate pathway (PPP) metabolites accumulate remarkably during chronic but not acute glucose treatment, indicating altered processing of glucose through the pentose phosphate pathway. Subsequent functional studies in INS-1E cells and human islets revealed that a disturbance in this pathway contributes to decreases in insulin gene expression and a lack of glucose-stimulated insulin secretion. These effects were found to depend on the activation of extracellular-regulated-kinase (ERK1/2). Long-term inhibition of 6-phosphogluconic acid dehydrogenase resulted in accumulation of PPP metabolites, induced ERK1/2 activation independently of high glucose and impaired beta cell function. In turn, inhibition of ERK1/2 overstimulation during chronic glucose exposure partly inhibited metabolite accumulation and restored beta cell function.Conclusions/interpretationBased on unbiased metabolite analyses, the data presented here provide novel targets, namely the inhibition of PPP metabolite accumulation towards the therapeutic goal to preserve and potentially improve beta cell function in diabetes.