Daily adjustment of glucocorticoids by patients with adrenal insufficiency.

BACKGROUND: Patients with adrenal insufficiency (AI) require lifelong glucocorticoid (GC) replacement. AI patients need to adjust GC dosage in response to stressful events and illness in order to prevent life-threatening adrenal crisis (AC). AIM: To evaluate self-management of patients with AI. METHODS: Four German centres, which are using patient's diary as part of their routine clinical practice, instructed AI patients to prospectively document any discomfort, intercurrent illness or stressful events as well as changes in GC therapy on a daily basis. Diaries of 80 patients (44 females, 52.9 ± 15.9 years, 34 primary AI) were collected and analysed. A symptom score sheet was used to evaluate severity of discomfort. RESULTS: In total, 34 074 patient days (93.4 years) were recorded. 4622 days with discomfort were documented. On 35% of those days (n = 1621), patients increased their GC dose (4.8% of all days). Patients who recorded discomfort had a median of four episodes of discomfort, which lasted a median of 2 days. Women documented significantly more episodes of discomfort than men (P = 0.014). Low-to-median symptom scores resulted in GC increase by 50%-60%, whereas high symptom scores and/or fever resulted in doubling GC daily dose. However, dose increase was only 55% in situations indicating gastrointestinal (GI) infection. CONCLUSION: Severe discomfort did not always result in dose increase, especially in GI infection. However, low symptom scores resulted in an inappropriate GC increase in some patients. This underscores an urgent need for improved training methods. Keeping daily records might be a useful tool for continued and individualized patient education.

Incidence of myocardial infarction and stroke in acromegaly patients: results from the German Acromegaly Registry.

PURPOSE: Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension. In this study, we examine if the incidence of myocardial infarction (MI) and stroke differ from that of the general population. METHODS: Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed (n = 479, 56% female, 46 years old at diagnosis, 5549 person-years from diagnosis). Standardized incidence ratios (SIR) were calculated as compared to the general population. RESULTS: MI and stroke incidences were very close to those of the general population with an SIR (95% CI) of 0.89 (0.47-1.52, p = 0.80) for MI and 1.17 (0.66-1.93, p = 0.61) for stroke. Acromegaly was uncontrolled in 16% of patients with MI or stroke versus 21% in those without (p = 0.56). Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without (94 vs. 43%, p < 0.001). No association was seen between radiation therapy and stroke. CONCLUSIONS: For acromegaly patients being treated at specialized centres, the incidence of MIs and strokes does not seem to differ from the general population. Certainty regarding such statements requires large, prospective studies however.

Achievement of treatment goals for secondary prevention of myocardial infarction or stroke in 29,325 patients with type 2 diabetes: a German/Austrian DPV-multicenter analysis.

BACKGROUND: To analyze whether medical care is in accordance with guidelines for secondary prevention of myocardial infarction (MI), or stroke in patients with type 2 diabetes from Germany and Austria. METHODS: 29,325 patients (≥ 20 years of age) with type 2 diabetes and MI, or stroke, documented between 2006 and 2015 were selected from the Diabetes-Patienten-Verlaufsdokumentation database. We analyzed medication, clinical characteristics, and lifestyle factors according to national secondary prevention guidelines in patients with MI, or stroke, separately. RESULTS: HbA1C <7.5 % was achieved in 64.9 % (MI), and in 61.1 % (stroke) of patients. LDL <100 mg/dl was documented in 56.2 % (MI), and in 42.2 % (stroke). Non-smoking was reported in 92.0 % (MI), and in 93.1 % (stroke), physical activity in 9.6 % (MI), and 5.5 % (stroke). Target values of blood pressure (<130/80 mmHg in MI, 120/70-140/90 in stroke) were reached in 67.0 % (MI), and in 89.9 % (stroke). Prescription prevalence of inhibitors of platelet aggregation (IPA) was 50.7 % (MI), and 31.7 % (stroke). 57.0 % (MI), and 40.1 % (stroke) used statins, 65.1 % (MI), and 65.8 % (stroke) used any type of antihypertensives, and ACE inhibitors were prescribed in 49.7 % (MI), and 41.3 % (stroke). A body mass index (BMI) <27 kg/m(2) and the use of beta blockers were only recommended in subjects with MI. Of the patients with MI, 32.0 % had a BMI <27 kg/m(2), and 59.5 % used beta blockers. CONCLUSIONS: Achievement of treatment goals in secondary prevention of MI, or stroke in subjects with type 2 diabetes needs improvement. Target goals were met more frequently in patients with MI compared to subjects with stroke. Especially the use of IPA was very low in patients with stroke. There remains great potential to reduce the risk of repeated macrovascular events and premature death, as well as to increase patients' quality of life.

Activation of the Ca²+-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane.

The Ca(2+)-sensing receptor (CaSR) belongs to the G-protein-coupled receptor superfamily and plays essential roles in divalent ion homeostasis and cell differentiation. Because extracellular Ca(2+) is essential for the development of stable epithelial tight junctions (TJs), we hypothesized that the CaSR participates in regulating TJ assembly. We first assessed the expression of the CaSR in Madin-Darby canine kidney (MDCK) cells at steady state and following manipulations that modulate TJ assembly. Next, we examined the effects of CaSR agonists and antagonists on TJ assembly. Immunofluorescence studies indicate that endogenous CaSR is located at the basolateral pole of MDCK cells. Stable transfection of human CaSR in MDCK cells further reveals that this protein co-distributes with ß-catenin on the basolateral membrane. Switching MDCK cells from low-Ca(2+) medium to medium containing a normal Ca(2+) concentration significantly increases CaSR expression at both the mRNA and protein levels. Exposure of MDCK cells maintained in low-Ca(2+) conditions to the CaSR agonists neomycin, Gd(3+) or R-568 causes the transient relocation of the tight junction components ZO-1 and occludin to sites of cell-cell contact, while inducing no significant changes in the expression of mRNAs encoding junction-associated proteins. Stimulation of CaSR also increases the interaction between ZO-1 and the F-actin-binding protein I-afadin. This effect does not involve activation of the AMP-activated protein kinase. By contrast, CaSR inhibition by NPS-2143 significantly decreases interaction of ZO-1 with I-afadin and reduces deposition of ZO-1 at the cell surface following a Ca(2+) switch from 5 µM to 200 µM [Ca(2+)]e. Pre-exposure of MDCK cells to the cell-permeant Ca(2+) chelator BAPTA-AM, similarly prevents TJ assembly caused by CaSR activation. Finally, stable transfection of MDCK cells with a cDNA encoding a human disease-associated gain-of-function mutant form of the CaSR increases the transepithelial electrical resistance of these cells in comparison to expression of the wild-type human CaSR. These observations suggest that the CaSR participates in regulating TJ assembly.

Cystic fibrosis-related diabetes compared with type 1 and type 2 diabetes in adults.

BACKGROUND: With increasing life expectancy of patients with cystic fibrosis (CF), secondary diabetes becomes more prevalent. It appears to be the most common co-morbidity in persons with cystic fibrosis. Therefore, the objective of our study was to describe characteristics of cystic fibrosis-related diabetes compared with type 1 and 2 diabetes (T1DM/T2DM) in adults. METHODS: Data from 218 436 patients >18 years with cystic fibrosis (n = 401), T1DM (n = 32,409) or T2DM (n = 185 626) in the multicenter Diabetes-Patienten-Verlaufsdokumentation or prospective documentation of diabetes patients registry were analysed. RESULTS: Diabetes onset [median (interquartile range)] in cystic fibrosis [18.70 (15.50-25.30) years] was between T1DM [16.40 (10.50-31.80) years] and T2DM [58.50 (48.80-68.00) years], with female preponderance. Body mass index (BMI) and glycosylated haemoglobin (HbA1c ) were lowest (19.6 [18.1-21.5] kg/m(2) )/50 mmol/mol (6.73%) versus T1DM (24.4 [22.1-27.4])/62 mmol/mol (7.83%) vs. T2DM (29.6 [26.1-33.9])/54 mmol/mol (7.06%); all p < 0.01. A total of 78.6% of cystic fibrosis patients with diabetes received insulin. Insulin dose (0.74 IE/kg bodyweight) was not significantly different from T1DM (0.73) and T2DM (0.76). Frequency of vascular complications, adjusted for confounding effects, across the groups was different: Hypertension (CFRD 16.1% vs. T1DM 24.0% vs. T2DM 32.2%; all p < 0.01), retinopathy (CFRD 10.7% vs. T1DM 10.4% vs. T2DM 10.5%, not significant), nephropathy (CFRD 25.2% vs. T1DM 17.2% vs. T2DM 24.7%; only T1DM/T2DM; p < 0.01). CONCLUSION: CFRD is a uniquely complex entity with clear differences from T1DM and T2DM in adults.

[Treatment of acromegaly - data from the German Acromegaly Register]. / Therapie der Akromegalie ­ Daten aus dem Deutschen Akromegalie Register.

Acromegaly is a rare disease in which chronic growth hormone overproduction (usually from an anterior pituitary adenoma) leads to various systemic complications. The management of acromegaly and the comorbidities of the disease is complex and requires a multidisciplinary approach. Early diagnosis is extremely important, as then the chances of a complete cure are significantly higher. The operation is the therapy of first choice and should be performed at a specialized center with an experienced neurosurgeon. With good patient information and guidance, the drug therapy of acromegaly patients in specialized practices and clinics can usually lead to biochemical control and thereby normalization of mortality risk. As with numerous rare diseases, care in specialized centers and recording and evaluation in registry studies can contribute to better patient care and the optimization of therapy and diagnostic guidelines. We assume that with the help of the German Acromegaly Registry, which currently includes more than 2500 patients with acromegaly, we will be able to present a realistic picture of the care situation in Germany in the coming years.

Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey.

OBJECTIVE: Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. DESIGN: Nationwide retrospective collaborative study. PATIENTS: We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. MEASUREMENTS: Activating CaSR mutations and clinical and biochemical findings were evaluated. RESULTS: Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 µg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). CONCLUSION: This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79.

AIMS: Although the association of low serum testosterone levels with mortality has gained strength in recent research, there are few population-based studies on this issue. This study examined whether low serum testosterone levels are a risk factor for all-cause or cause-specific mortality in a population-based sample of men aged 20-79. METHODS AND RESULTS: We used data from 1954 men recruited for the prospective population-based Study of Health in Pomerania, with measured serum testosterone levels at baseline and 195 deaths during an average 7.2-year follow-up. A total serum testosterone level of less than 8.7 nmol/L (250 ng/dL) was classified as low. The relationships of low serum testosterone levels with all-cause and cause-specific mortality were analysed by Cox proportional hazards regression models. Men with low serum testosterone levels had a significantly higher mortality from all causes than men with higher serum testosterone levels (HR 2.24; 95% CI 1.41-3.57). After adjusting for waist circumference, smoking habits, high-risk alcohol use, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate, low serum testosterone levels continued to be associated with increased mortality (HR 2.32; 95% CI 1.38-3.89). In cause-specific analyses, low serum testosterone levels predicted increased risk of death from cardiovascular disease (CVD) (HR 2.56; 95% CI 1.15-6.52) and cancer (HR 3.46; 95% CI 1.68-6.68), but not from respiratory diseases or other causes. CONCLUSION: Low serum testosterone levels were associated with an increased risk of all-cause mortality independent of numerous risk factors. As serum testosterone levels are inversely related to mortality due to CVD and cancer, it may be used as a predictive marker.

A high normal TSH is associated with the metabolic syndrome.

OBJECTIVE: Obesity and insulin resistance are key features of the metabolic syndrome. In euthyroidism, the relationships between TSH and insulin resistance or the metabolic syndrome are less clear. We investigated the associations between TSH and the features and prevalence of the metabolic syndrome in euthyroid German subjects. METHODS: In a cross-sectional study, glucose metabolism was defined by an oral glucose tolerance test (oGTT) (except for those with evident diabetes) in 1333 subjects with TSH values between 0.3 and 4.5 mU/l who did not take any thyroid medication. Lipid parameters were measured, blood pressure and anthromopmetric parameters were taken, and insulin resistance was quantified as HOMA%S. RESULTS: TSH was weakly correlated with BMI (R = 0.061, P = 0.025). This association remained significant after adjustment for sex, age, and impaired glucose metabolism (P = 0.002). Subjects with a TSH in the upper normal range (2.5-4.5 mU/l, n = 119) had a significantly higher BMI (30.47 +/- 0.57 vs. 28.74 +/- 0.18 kg/m(2), P = 0.001) and higher fasting triglycerides (1.583 +/- 0.082 vs. 1.422 +/- 0.024 mmol/l, P = 0.023), and their likeliness for fulfilling the ATP III criteria of the metabolic syndrome was 1.7-fold increased (95% CI: 1.11- 2.60). CONCLUSION: In euthyroidism, subjects with a TSH in the upper normal range (2.5-4.5 mU/l) were more obese, had higher triglycerides, and had an increased likeliness for the metabolic syndrome. Therefore, a TSH below 2.5 mU/l is associated with a favourable metabolic profile. Whether lowering TSH to levels below 2.5 mU/l improves metabolism needs to be investigated in intervention trials.

CRH and SRIF have opposite effects on the Wnt/ß-catenin signalling pathway through PKA/GSK-3ß in corticotroph pituitary cells.

The Wnt/ß-catenin signalling pathway is involved in tumorigenesis including endocrine tumors. We investigated the Wnt/ß-catenin pathway's modulation by corticotropin-releasing hormone (CRH) and somatostatin or somatotropin release-inhibiting factor (SRIF) in mouse pituitary AtT-20 corticotroph cells. The Wnt/ß-catenin signalling pathway was activated by CRH and inhibited by SRIF. We provide evidence that cAMP/PKA signalling is involved affecting the GSK-3ß phosphorylation status at phospho-GSK-3ß (Ser9), thereby altering ß-catenin degradation downstream. Furthermore, CRH and SRIF showed concordant effects on cell proliferation. Our data demonstrate an important role of the Wnt/ß-catenin pathway in the proliferative control of pituitary corticotroph cells and describe a mechanism for its regulation by CRH and SRIF.

[Update - Calcium Metabolism]. / Update ­ Kalziumstoffwechsel.

A finely balanced control system keeps the extracellular calcium concentration within narrow limits. Disorders of calcium metabolism are often based on altered parathormone levels. Symptoms are not always clear, sometimes they are even missing: the more it is important to know possible associated diseases. The author presents basics, current diagnostics and concrete therapy options. Central hormone for the regulation of the calcium balance is the parathyroid hormone. With decreasing calcium, PTH leads to an increase in extracellular free calcium concentration in three ways. The classic symptoms of pHPT (polyuria, polydipsia, "stone, leg, and stomach pain") are rare now, as the condition is diagnosed much earlier. Treatment of choice in all symptomatic patients with pHPT is surgery. FHH and pHPT are both characterized by hypercalcaemia and increased parathyroid hormone. The differential diagnosis of urinary calcium excretion, which is usually lower in FHH but normal or elevated in pHPT, is crucial. In primary hypoparathyroidism, parathyroid failure interferes with calcium homeostasis at a central location. Consequences are hypocalcaemia, hyperphosphatemia and lack of active vitamin D. Due to increased urinary calcium excretion, patients with ADH are at high risk for kidney stones, nephrocalcinosis and the development of renal insufficiency. Recently, rhPTH 1-84 has been available for the treatment of hypoparathyroidism. However, long-term data is still lacking to provide a safe indication, considering potential effects and side effects.

Growth hormone response during oral glucose tolerance test: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls, and the role of gender, age, and body mass index.

CONTEXT: Besides the measurement of IGF-I, GH suppression during an oral glucose tolerance test is recommended to assess the biochemical status in acromegaly. However, the development of highly sensitive and specific GH assays necessitates a critical reevaluation of criteria for diagnosis and follow-up of disease activity. OBJECTIVE: Our objective was to evaluate the between-method discrepancies in GH determinations by different immunoassays considering further confounders like age, gender, and body mass index (BMI). DESIGN, SUBJECTS, AND METHODS: We measured GH during a 75-g oral glucose tolerance test in 46 acromegaly patients (18 controlled, 28 uncontrolled; 19 men; 31-63 yr; BMI 26.4 +/- 0.4 kg/m(2)) and 213 healthy subjects (66 men; 20-76 yr; BMI 30 +/- 0.5 kg/m(2)), using three different commercially available assays [Immulite (Diagnostic Products Corp., Los Angeles, CA), Nichols (Nichols Institute Diagnostika GmbH, Bad Vilbel, Germany), and Diagnostic Systems Laboratories (Sinsheim, Germany)] that were calibrated against the recently recommended GH standards. RESULTS: Results from all assays strongly correlated (r = 0.8-0.996; P < 0.0001). However, the results obtained with the Immulite assay were, on average, 2.3-fold higher than those obtained with Nichols and 6-fold higher than those obtained with Diagnostic Systems Laboratories. Using cutoff limits of 1 microg/liter (Immulite) and 0.5 microg/liter (Nichols) identified 95% of patients with active disease and 78-80% of patients in remission. Basal and nadir GH levels were significantly higher in females than in males (Immulite 2.2 +/- 0.28 microg/liter vs. 0.73 +/- 0.15 microg/liter and 0.16 +/- 0.01 microg/liter vs. 0.08 +/- 0.01 microg/liter; P < 0.001, respectively). In multiple regression analysis, age, BMI, and gender were predictors for basal and nadir GH levels. CONCLUSION: Postglucose GH-nadir values are assay, gender, age, and BMI specific, indicating the need of individual cutoff limits for each assay.

Novel inactivating mutations of the calcium-sensing receptor: the calcimimetic NPS R-568 improves signal transduction of mutant receptors.

CONTEXT AND OBJECTIVE: Inactivating mutations in the calcium-sensing receptor (CaSR) gene cause neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH). The aims of the present study were the functional characterization of novel mutations of the CaSR found in FHH patients, the comparison of in vitro receptor function with clinical parameters, and the effect of the allosteric calcimimetic NPS R-568 on the signaling of mutant receptors. METHODS: Wild-type and mutant CaSRs (W530G, C568Y, W718X, M734R, L849P, Q926R, and D1005N) were expressed in human embryonic kidney 293 cells. Receptor signaling was studied by measuring intracellular free calcium in response to different concentrations of extracellular calcium ([Ca(2+)](o)). RESULTS: Four CaSR mutations (C568Y, W718X, M734R, and L849P) demonstrated a complete lack of a [Ca(2+)](o)-induced cytosolic Ca(2+) response up to 30 mm [Ca(2+)](o), whereas the CaSR mutants W530G, Q926R, and D1005N retained some sensitivity to [Ca(2+)](o). There was no significant relation between the in vitro calcium sensitivity, serum calcium, and intact PTH levels in the patients. Patients with C-terminal CaSR mutations had a calcium to creatine ratio above the established diagnostic threshold of 0.01 for FHH. The calcimimetic NPS R-568 enhanced the responsiveness to [Ca(2+)](o) in CaSR mutants of the extracellular domain (W530G and C568Y) as well as the intracellular C-terminal domain (Q926R and D1005N). CONCLUSION: Therefore, calcimimetics might offer medical treatment for symptomatic FHH patients, and more important, for patients with neonatal severe hyperparathyroidism that harbor calcimimetic-sensitive CaSR mutants.

Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain.

The molecular mechanism of the action of lithium salts in the treatment of bipolar disorder is not well understood. As their therapeutic action requires chronic treatment, adaptive neuronal processes are suggested to be involved. The molecular basis of this are changes in gene expression regulated by transcription factors such as CREB (cAMP-response-element-binding protein). CREB contains a transactivation domain, in which Ser119 is phosphorylated upon activation, and a bZip (basic leucine zipper domain). The bZip is involved in CREB dimerization and DNA-binding, but also contributes to CREB transactivation by recruiting the coactivator TORC (transducer of regulated CREB). In the present study, the effect of lithium on CRE (cAMP response element)/CREB-directed gene transcription was investigated. Electrically excitable cells were transfected with CRE/CREB-driven luciferase reporter genes. LiCl (6 mM or higher) induced an up to 4.7-fold increase in 8-bromo-cAMP-stimulated CRE/CREB-directed transcription. This increase was not due to enhanced Ser119 phosphorylation or DNA-binding of CREB. Also, the known targets inositol monophosphatase and GSK3beta (glycogen-synthase-kinase 3beta) were not involved as specific GSK3beta inhibitors and inositol replenishment did not mimic and abolish respectively the effect of lithium. However, lithium no longer enhanced CREB activity when the CREB-bZip was deleted or the TORC-binding site inside the CREB-bZip was specifically mutated (CREB-R300A). Otherwise, TORC overexpression conferred lithium responsiveness on CREB-bZip or the CRE-containing truncated rat somatostatin promoter. This indicates that lithium enhances cAMP-induced CRE/CREB-directed transcription, conferred by TORC on the CREB-bZip. We thus support the hypothesis that lithium salts modulate CRE/CREB-dependent gene transcription and suggest the CREB coactivator TORC as a new molecular target of lithium.

Personality Traits and Physical Complaints in Patients With Acromegaly: A Cross Sectional Multi-Center Study With Analysis of Influencing Factors.

Objective: Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities. Design: Cross sectional, multicentric. Methods: 129 patients (M/W 65/64, 58.3 ± 12.7 years, 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented. Results: Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable. Conclusions: We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity.

Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40.

Free fatty acids (FFA) cause a rise in cytosolic free Ca2+ ([Ca2+]i) and stimulate insulin release from pancreatic beta-cells. The G-protein coupled receptor GPR40 can be activated by medium- and long-chain FFA. We investigated a potential role for GPR40 in the generation of the FFA-induced Ca2+ signal and insulin secretion. [Ca2+]i was measured in primary mouse beta-cells and in INS-1 cells, and insulin secretion was assessed from INS-1 cells. GPR40 expression was determined by RT-PCR and downregulation of GPR40 expression by siRNA transfection was carried out in INS-1 cells. A number of saturated, mono- and polyunsaturated medium- and long-chain FFA caused a rise in [Ca2+]i both in primary mouse beta-cells and in INS-1 cells. By contrast, the short-chain saturated caproic acid was ineffective at concentrations up to 300 microM. In INS-1 cells, the FFA-induced Ca2+ signal required mobilization of internal Ca2+ and Ca2+ influx through voltage-sensitive Ca2+ channels. RT-PCR analysis revealed that GPR40 is expressed in INS-1 cells. Downregulation of GPR40 by specific siRNA treatment lead to a significant inhibition of the FFA-induced [Ca2+]i response and insulin secretion, indicating that the FFA-stimulated Ca2+ signal and insulin secretion involve activation of GPR40 in pancreatic beta-cells.

Adipocyte fatty acid-binding protein is associated with markers of obesity, but is an unlikely link between obesity, insulin resistance, and hyperandrogenism in polycystic ovary syndrome women.

OBJECTIVE: Many polycystic ovary syndrome (PCOS) women suffer from adiposity and insulin resistance (IR), which play an important role in the development and maintenance of PCOS. Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes, and circulating A-FABP has been associated with markers of obesity and IR. Thus, as observed with other adipose tissue derived factors, secreted A-FABP might be involved in the pathogenesis of obesity-associated disorders such as PCOS. DESIGN: Plasma A-FABP concentrations were measured in 102 non-diabetic PCOS women, and associations with markers of obesity, IR, inflammation, and hyperandrogenism were investigated by correlation and multiple linear regression analyses. The effect of lifestyle intervention on A-FABP was studied in a second cohort of 17 obese PCOS women. RESULTS: A-FABP correlated with body mass index (BMI; R = 0.694, P < 0.001), dual-energy X-ray-absorptiometry (DEXA) fat mass (R = 0.729, P < 0.001), DEXA lean body mass (R = 0.399, P = 0.001), HOMA %S (R = -0.435, P < 0.001), hsCRP (R = 0.355, P = 0.001), and free testosterone (fT; R = 0.230, P = 0.02). Adjusted for age, smoking, and glucose metabolism the association of A-FABP with HOMA %S was still significant (P < 0.001), whereas the associations with fT (P = 0.09) and hsCRP (P = 0.25) were not. Inclusion of BMI into the model abolished the impact of A-FABP on HOMA %S. In BMI-matched PCOS women (n = 20 pairs), neither HOMA %S (P = 0.3) nor fT (P = 0.6) were different despite different A-FABP levels (P < 0.001), and in 17 obese PCOS women undergoing a lifestyle intervention, changes in IR were not paralleled by changes in A-FABP. CONCLUSIONS: Circulating A-FABP was correlated with markers of obesity, but had no major impact on IR, inflammation, or hyperandrogenemia in PCOS women.

Cereal fiber improves whole-body insulin sensitivity in overweight and obese women.

OBJECTIVE: Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that intake of purified insoluble oat fiber may improve whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS: A randomized, controlled, single-blind, cross-over study was performed, and 17 overweight or obese subjects with normal glucose metabolism were analyzed. After consumption of nine macronutrient-matched portions of fiber-enriched bread (white bread enriched with 31.2 g insoluble fiber/day) or control (white bread) over a time period of 72 h, whole-body insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Energy intake was individually adjusted by providing standardized liquid meals. Hydrogen breath tests were performed to control for dietary adherence. RESULTS: When analyzing the entire cohort, whole-body glucose disposal was improved after fiber consumption (M value 6.56 +/- 0.32 vs. 6.07 +/- 0.27 mg . min(-1) . kg(-1); P = 0.043). Thirteen subjects had increased hydrogen breath test concentrations after fiber consumption, indicating probable dietary adherence. Restricting analysis to these subjects, improvements in M value (6.85 +/- 0.34 vs. 6.06 +/- 0.32 mg . min(-1) . kg(-1); P = 0.003) and insulin sensitivity, expressed as M/I ratio (M value divided by mean serum insulin at steady state: 3.73 +/- 0.23 vs. 3.21 +/- 0.27; P = 0.02), after fiber consumption were more pronounced. Plasma lipids, serum magnesium, ghrelin, and adiponectin concentrations, as well as substrate utilization and body weight, were not significantly changed by fiber intake (P > 0.15). CONCLUSIONS: Increased insoluble dietary fiber intake for 3 days significantly improved whole-body insulin sensitivity. These data suggest a potential mechanism linking cereal fiber intake and reduced risk of type 2 diabetes.

The Effects of a Normal Rate versus a Slow Intervalled Rate of Oral Nutrient Intake and Intravenous Low Rate Macronutrient Application on Psychophysical Function - Two Pilot Studies.

Stomach distension and energy per time are factors influencing satiety. Moreover, different rates of nutrient intake induce different stomach distension. The goal of our studies was to elucidate the influence of different oral rates of nutrient intake (normal rate versus slow intervalled rate; study I) and intravenous low rate macronutrient application (protein, carbohydrate, fat) or placebo (study II) on psychophysical function. The pilot studies investigated the effects of 1) study I: a mixed nutrient solution (1/3 protein, 1/3 fat, 1/3 carbohydrates) 2) study II: intravenous macronutrient infusions (protein, carbohydrate, fat) or placebo on psychophysical function (mood, hunger, food craving, alertness, smell intensity ratings and hedonic ratings) in human subjects. In study I 10 male subjects (age range: 21-30 years) completed the study protocol participating in both test conditions and in study II 20 male subjects (age range: 19-41 years) completed the study protocol participating in all test conditions. Additionally, metabolic function was analyzed and cognitive and olfactory tests were conducted twice starting 100 min before the beginning of the intervention and 240 min after. Psychophysical (mood, hunger, fat-, protein-, carbohydrate-, sweets- and vegetable-craving), alertness and metabolic function tests were performed seven times on each examination day. Greater effects on hunger and food cravings were observed for normal rate of intake compared to slow intervalled rate of intake and intravenous low rate macronutrient application. Our findings potentially confirm that volume of the food ingested and a higher rate of energy per time contribute to satiety during normal rate of food intake, while slow intervalled rate of food intake and intravenous low rate macronutrient application showed no effects on satiation. Our results motivate the view that a certain amount of volume of the food ingested and a certain energy per time ratio are necessary to reduce hunger and food craving.