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Purpose Bariatric surgery reduces mortality in patients with severe obesity and is predominantly performed in women. Therefore, an analysis of sex-specific differences after bariatric surgery in a population-based dataset from Austria was performed. The focus was on deceased patients after bariatric surgery. Materials and Methods The Austrian health insurance funds cover about 98% of the Austrian population. Medical health claims data of all Austrians who underwent bariatric surgery from 01/2010 to 12/2018 were analyzed. In total, 19,901 patients with 107,806 observed years postoperative were eligible for this analysis. Comorbidities based on International Classification of Diseases (ICD)-codes and drug intake documented by Anatomical Therapeutical Chemical (ATC)-codes were analyzed in patients deceased and grouped according to clinically relevant obesity-associated comorbidities: diabetes mellitus (DM), cardiovascular disease (CV), psychiatric disorder (PSY), and malignancy (M). Results In total, 367 deaths were observed (1.8%) within the observation period from 01/2010 to 04/2020. The overall mortality rate was 0.34% per year of observation and significantly higher in men compared to women (0.64 vs. 0.24%; p p p = 0.034), whereas malignant diseases (36%) were more frequent in women (30 vs. 41%; p = 0.025). Conclusion After bariatric surgery, short-term mortality as well as long-term mortality was higher in men compared to women. In deceased patients, diabetes was more common in men, whereas malignant diseases were more common in women. Graphical abstract

Background Biliary phosphatidylcholine (PtdC) concentration plays a role in the pathogenesis of bile duct diseases. In vivo phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) at 7 T offers the possibility to assess this concentration noninvasively with high spectral resolution and signal intensity. Purpose Comparison of PtdC levels of cholangiopathic patient groups to a control group using a measured T1 relaxation time of PtdC in healthy subjects. Study type Case control. Subjects Two patient groups with primary sclerosing cholangitis (PSC, 2f/3 m; age: 43 ± 7 years) and primary biliary cholangitis (PBC, 4f/2 m; age: 57 ± 6 years), and a healthy control group (CON, 2f/3 m; age: 38 ± 7 years). Ten healthy subjects for the assessment of the T1 relaxation time of PtdC. Field strength/sequence A 3D phase-encoded pulse-acquire 31 P-MRSI sequence for PtdC quantification and a 1D image-selected in vivo 31 P spectroscopy for T1 estimation at 7 T, and a T2-weighted half-Fourier single-shot turbo spin echo MRI sequence for volumetry at 3 T. Assessment Calculation of gallbladder volumes and PtdC concentration in groups using hepatic gamma-adenosine triphosphate signal as an internal reference and correction for insufficient relaxation of PtdC with a T1 value assessed in healthy subjects. Statistical tests Group comparison of PtdC content and gallbladder volumes of the PSC/PBC and CON group using Student's t-tests with a significance level of 5%. Results PtdC T1 value of 357 ± 85 msec in the gallbladder. Significant lower PtdC content for the PSC group, and for the female subgroup of the PBC group compared to the CON group (PSC/CON: 5.74 ± 0.73 mM vs. 9.64 ± 0.97 mM, PBC(f)/CON: 5.77 ± 1.44 mM vs. 9.64 ± 0.97 mM). Significant higher gallbladder volumes of the patient groups compared to the CON group (PSC/CON: 66.3 ± 15.8 mL vs. 20.9 ± 2.2 mL, PBC/CON: 49.8 ± 18.2 mL vs. 20.9 ± 2.2 mL). Data conclusion This study demonstrated the application of a 31 P-MRSI protocol for the quantification of PtdC in the human gallbladder at 7 T. Observed differences in PtdC concentration suggest that this metabolite could serve as a biomarker for specific hepatobiliary disorders. Level of evidence 2 TECHNICAL EFFICACY STAGE: 3.

Purpose In our centre, specialized high dose multivitamin supplementation designed to meet the needs of patients after gastric bypass surgery is routinely recommended in the early postoperative period. The aim of the present study was to analyse whether iron supplementation prescribed in clinical practice is sufficient in both sexes and whether multivitamin supplementation standardized for women might potentially lead to iron overload in men. Materials/Methods This was a retrospective study covering the period up to 36 months after bariatric surgery. Three groups were compared (men, premenopausal and postmenopausal women). The iron status was evaluated employing serum ferritin concentrations. Results A total of 283 patients who had at least one follow-up visit between January 2015 and April 2018 at a specialized academic outpatient centre were included (71 men, 130 premenopausal women, 82 postmenopausal women). Thirty-six months after surgery, 33.3%, 68.4% and 54.5% of the men, pre- and postmenopausal women, respectively, were iron deficient. The preoperative prevalence of excess ferritin levels was 13.7% in premenopausal, 3.0% in postmenopausal women, 5.7% in men and declined in the following months. Conclusion Iron deficiency is very common after gastric bypass surgery, and even high dosages of multivitamin and mineral supplements might not be sufficient to prevent the development of iron deficiency. Men, pre- and postmenopausal women differ in their prevalence of iron deficiency which demands adapted iron dosage regimens based on the sex and the age. Iron overload is rare in all observed groups and highest in premenopausal women. Graphical abstract

ZusammenfassungDer primäre Hyperaldosteronismus (Morbus Conn) ist die häufigste Ursache einer sekundären Hypertonie. Der Nachweis einer erhöhten Aldosteronproduktion bei unterdrückter Reninfreisetzung ist wegweisend für die Diagnose. Als Screeningtest hat sich die Aldosteron-Renin-Ratio etabliert. Bei Erhöhung dieser Ratio sollte ein Bestätigungstest durchgeführt werden. Eine Bildgebung der Nebennieren mittels CT folgt als nächster Schritt. Zur Bestimmung der Lateralisierung der erhöhten Aldosteronproduktion und vor geplanter Adrenalektomie sollte ein Nebennierenvenensampling durchgeführt werden. Da dies für den interventionellen Radiologen eine technisch sehr anspruchsvolle Intervention ist und die Erfolgsraten durchwachsen sind, kann ein Cortisol-Schnelltest verwendet werden, der die intraoperative Beurteilung der korrekten Abnahmestelle unterstützen kann.

Objective: Similar to pregnant women, women taking an oral contraceptive (OC) might have elevated iodine requirements due to the altered hormonal state. This is the first study aimed at investigating the prevalence of iodine deficiency and possible influences of OC intake on urine creatinine and iodine levels in young women. Methods: One hundred fifty-five women between the age of 18 and 35 years (62 taking an OC and 93 controls) participated in a cross-sectional pilot study at the Medical University of Vienna, which included a 1-spot urine sample and a questionnaire on OC intake as well as a food questionnaire. Results: The median urinary iodine concentration (UIC) in this study was 68 μg/L (41, 111 μg/L) suggesting an inadequate iodine status in the women according to the WHO guidelines. Median UIC (OC: 89 μg/L, IQR 55–120; control: 59 μg/L, IQR 39–91, p = 0.010) and urine creatinine (OC: median = 99.0 μg/L, IQR 74.9–175.5; control: 77.0 μg/L, IQR 49.6–147.2, p = 0.030) levels were significantly higher in OC women than in the control group. UIC corrected for urine creatinine was comparable between both groups. Conclusion: With similar creatinine-corrected UICs in both groups, OC intake might not have a significant impact on iodine status. However, the low median UIC in a vulnerable group of young women potentially conceiving in the following years points at the necessity of optimizing the iodine intake in the Austrian population and reiterates the insufficiency of the current iodine supplementation measures.

OBJECTIVE Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP). RESEARCH DESIGN AND METHODS Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90–180 min (MR1), and 300–390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques. RESULTS Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg−1 min−1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg−1 min−1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (−3.28 ± 0.49 vs. −2.53 ± 0.56 μmol kg−1 min−1; P = n.s.) or T2DM-P and T2DM-D (−0.74 ± 0.23 vs. −1.21 ± 0.33 μmol kg−1 min−1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg−1 min−1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed. CONCLUSIONS The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.

Die Nebenniereninsuffizienz (NNI) ist eine seltene, unbehandelt jedoch potenziell lebensbedrohlich verlaufende Erkrankung. Aufgrund der vor allem anfanglich unspezifischen klinischen Symptomatik ist es fur die behandelnden Arztinnen und Arzte wichtig, die Moglichkeit einer NNI als Differenzialdiagnose bei zunehmender Schwache, Gewichtsabnahme, Mudigkeit, aber auch Hyponatriamie und Hypoglykamie in Betracht zu ziehen. Die Therapie der NNI ist eine moglichst physiologische Glukokortikoidsubstitution, wobei hier Hydrocortison aufgrund seiner kurzen Halbwertszeit der Vorzug gegeben werden sollte. Auf eine adaquate Dosisadaptierung bei Sondersituationen ist zur Vermeidung von Nebennierenkrisen unbedingt zu achten. Bei der primaren NNI ist zusatzlich noch die Mineralokortikoidtherapie von Relevanz, wahrend bei der sekundaren und tertiaren NNI die anderen Hypophysenhormonachsen kontrolliert und bei Bedarf im Verlauf substituiert werden sollten.

Objective Acetylcarnitine plays an important role in fat metabolism and can be detected in proton magnetic resonance spectra in skeletal muscle. An inverse relationship of acetylcarnitine to intramyocellular lipids and metabolic markers of chronic hyperglycemia has been suggested. This study aimed to compare the acetylcarnitine concentrations and intramyocellular lipids measured noninvasively by proton magnetic resonance spectroscopy (1H MRS) in the tibialis anterior and the soleus of three different groups of volunteers with a broad range of glycemic control. Methods Acetylcarnitine and intramyocellular lipid concentrations were measured in 35 individuals stratified into three groups according to glucose tolerance and/or manifestation of type 2 diabetes mellitus. All MRS measurements were performed on a 3-T MR system. Results The differences in patient phenotype were mirrored by increased intramyocellular lipids in the tibialis anterior and decreased acetylcarnitine concentrations in the soleus muscle of type 2 diabetes patients when compared with normal glucose-tolerant individuals. Results suggest that intramyocellular lipids mirror whole-body glucose tolerance better in the tibialis anterior muscle, whereas acetylcarnitine is a better discriminator in the soleus muscle. Conclusions This muscle-specific behavior of metabolites could represent different fiber compositions in the examined muscles and should be considered when planning future metabolic studies.

Background In severe obesity, hypogonadism in men and androgen excess in women are frequently observed. Sex hormones play an important role in body composition and glucose and lipid metabolism. However, whether pre-operative gonadal dysfunction impacts weight loss after bariatric surgery is not fully known. Methods A total of 49 men and 104 women were included in a retrospective analysis. Anthropometric characteristics, glucose and lipid metabolism, and androgen concentrations were assessed pre-operatively and 17.9 ± 11 or 19.3 ± 12 months post-operatively in men and women. Men with (HYPOmale) and without (controls: CONmale) pre-operative hypogonadism, as well as women with (HYPERfemale) and without (controls: CONfemale) pre-operative hyperandrogenemia, were compared. Results In men, pre-operative hypogonadism was present in 55% and linked to a higher body mass index (BMI): HYPOmale 50 ± 6 kg/m2 vs. CONmale 44 ± 5 kg/m2, p = 0.001. Bariatric surgery results in comparable changes in BMI in HYPOmale and CONmale − 16 ± 6 kg/m2 vs. − 14 ± 5 kg/m2, p = 0.30. Weight loss reversed hypogonadism in 93%. In women, androgen excess was present in 22%, independent of pre-operative BMI: CONfemale 44 ± 7 kg/m2 vs. HYPERfemale 45 ± 7 kg/m2, p = 0.57. Changes in BMI were comparable in HYPERfemale and CONfemale after bariatric surgery − 15 ± 6 kg/m2 vs. − 15 ± 5 kg/m2, p = 0.88. Hyperandrogenemia was reversed in 61%. Conclusions Besides being frequently observed, hypogonadism in men and androgen excess in women have no impact on post-surgical improvements in body weight and glucose and lipid metabolism. Weight loss resulted in reversal of hypogonadism in almost all men and of hyperandrogenemia in the majority of women.

Background Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, patients suffering from primary adrenal insufficiency (AI) have an increased mortality, mainly due to cardiovascular diseases. Only little knowledge exists on the contribution of MC substitution to the cardiovascular risk. Therefore, this study investigates the impact of plasma renin concentration on parameters of micro- and macrovascular function. Methods 26 patients with primary AI [female = 18, age: 51 (28; 78) years; BMI: 24 (18; 40) kg/m2; disease duration: 18 (5; 36) years] were included in this cross-sectional analysis. Intima media thickness (IMT) and pulse wave velocity (PWV) were investigated to assess macrovascular remodeling and arterial stiffness. Microvascular function was estimated by post-occlusive reactive hyperemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded. Patients were grouped according to their median plasma renin concentration of previous visits (Reninhigh vs Reninlow) and were compared to a group of healthy women [age: 44 (43; 46) years; BMI: 24.2 (21.8; 27.5)]. Results PWV was significantly higher in AI patients compared to controls [9.9 (5; 18.5) vs 7.3 (6.8; 7.7) m/s; p low time to peak perfusion was significantly longer [6.0 (3; 15) vs 3.5 (1.5; 11) s; p high and Reninlow. No impact of GC dose was observed. Conclusions Microvascular function is not impaired in patients with primary AI under adequate replacement therapy, although higher renin concentrations are associated with subclinical improvements. No relation between RAAS activity and macrovascular function is observed, while arterial stiffness might be increased in primary AI.

Context A substantial number of patients undergoing bariatric surgery are prescribed psychopharmacological medication. However, the impact of concomitant psychopharmacological medication on the frequency of relevant vitamin deficiencies in postoperative follow-up is not known. Methods Five hundred twenty-four patients with obesity who underwent bariatric surgery (January 2004 to September 2018) with follow-up of at least 12 months, were included in retrospective analysis. Postoperative follow-up visits between January 2015 and September 2019 were analyzed. Anthropometric and laboratory data were analyzed at the first documented follow-up visit after on average 39.5 ± 37.3 months and at every following visit during the observation period. Patients with prescribed psychopharmacological drugs (PD) were compared with patients without (control group, CON). Results Psychopharmacological medication was documented in 25% (132) of patients. In 59 patients documented prescription of more than one psychiatric drug was found, whereas psychopharmacological monotherapy was found in 73 patients. Frequencies of vitamin deficiencies were comparable between PD and CON (vitamin A: p = 0.852; vitamin D: p = 0.622; vitamin E: p = 0.901; folic acid: p = 0.941). Prevalence of vitamin B12 deficiency was rare (6% CON, 1% PD) but was significantly higher in CON (p = 0.023). A comparison of CON and POLY also showed no significant differences between the groups concerning prevalence of vitamin deficiencies. Conclusions Intake of psychopharmacological medication is highly prevalent in patients after bariatric surgery. Patients with psychopharmacological medication, who participate in structured follow-up care after bariatric surgery, are not at higher risk for vitamin deficiencies compared with controls.

Context Craniopharyngioma is a sellar tumor associated with high rates of pituitary deficiencies (~98%) and hypothalamic obesity (~50%). Objective To determine the efficacy regarding long-term weight loss after bariatric surgery in obese craniopharyngioma patients with hypothalamic dysfunction. Design Retrospective case control study. Setting Multicenter international study. Patients and participants Obese craniopharyngioma patients (N = 16; of which 12 women) with a history of bariatric surgery [12 Roux-en-Y gastric bypass, 4 sleeve gastrectomy; median age of 21 years (range 15-52), median follow-up 5.2 years (range 2.0-11.3)] and age/sex/surgery/BMI-matched obese controls (N = 155). Main outcome measures Weight loss and obesity-related comorbidities up to 5 years after bariatric surgery were compared and changes in hormonal replacement therapy evaluated. Results Mean weight loss at 5-year follow-up was 22.0% (95% CI 16.1, 27.8) in patients versus 29.5% (28.0, 30.9) in controls (P = 0.02), which was less after Roux-en-Y gastric bypass (22.7% [16.9, 28.5] vs. 32.0% [30.4, 33.6]; P = 0.003) but at a similar level after sleeve gastrectomy (21.7% [–1.8, 45.2] vs. 21.8% [18.2, 25.5]; P = 0.96). No major changes in endocrine replacement therapy were observed after surgery. One patient died (unknown cause). One patient had long-term absorptive problems. Conclusions Obese patients with craniopharyngioma had a substantial mean weight loss of 22% at 5-year follow-up after bariatric surgery, independent of type of bariatric surgery procedure. Weight loss was lower than in obese controls after Roux-en-Y gastric bypass. Bariatric surgery appears effective and relatively safe in the treatment of obese craniopharyngioma patients.

Assessing the quality of life (QOL) for patients with type 2 diabetes is an essential part of diabetes management, especially for the evaluation of new antidiabetic treatments and glucose monitoring technologies. Accordingly, the aim of this study was to assess QOL according to treatment types. This cross-sectional study included 170 patients with type 2 diabetes from the region of Melk in Lower Austria. Of the patients 61 used only oral antidiabetic agents (OAD) and 109 patients were treated with insulin (with or without OAD). The QOL was assessed in patients using sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors). Among the 170 patients with type 2 diabetes 95 used SGLT2 inhibitors. The World Health Organization Quality of Life BREF (WHOQOL-BREF) assessment was used to assess QOL among these patients. The Mann–Whitney U-test was utilized in this study and a P value

Baritrische Eingriffe werden in den letzten Jahren vermehrt durchgefuhrt, damit steigt auch die Anzahl der Patienten, die eine lebenslange, ernahrungs-medizinische Nachsorge benotigen. Hierdurch soll praventiv einem Versorgungsmangel vorgebeugt werden. Spezialisierte Einrichtungen stosen an die Grenzen ihrer Kapazitat fur eine solche Nachsorge, wodurch immer mehr Arzte im niedergelassenen Bereich aufgesucht werden. Der Umfang einer Kontrolle wird uberblicksmasig in internationalen Leitlinien beschrieben und umfasst eine medizinische Kontrolle und Unterstutzung bei der Umsetzung der Ernahrungs- und Bewegungsempfehlungen. Fur den langfristigen Erfolg nach einer bariatrischen Operation ist ein strukturiertes, regelmasiges Nachsorgemanagement fur den Patienten auserst wichtig.

Background Depending on CYP21A2 genotype, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to biochemical alterations (including hyperandrogenism, hypocortisolism, and hypoaldosteronism) and a wide spectrum of phenotypic disease manifestation. The latter include life-threatening salt-wasting crises, prenatal virilization of genitalia in women (classic CAH [C-CAH]) as well as milder forms of the disease exclusively presenting with hirsutism, acne or reduced fertility (nonclassic CAH [NC-CAH]), and could influence sexual function and identity. Aim The present study evaluated sexual function, gender identification, and partner preference in women with C-CAH and NC-CAH. Methods In a cross-sectional cohort analysis, 35 female patients with CAH were divided into 2 groups: C-CAH (salt-wasting/simple virilizing; n = 17) and NC-CAH (n = 18) according to genotype and phenotype. Sexual function and sexual distress were assessed using established questionnaires, including the Female Sexual Function Index. Phenotype (defined by signs of hyperandrogenism) was assessed clinically (Ferriman-Gallwey score) and with the ovulatory function index. CYP21A2 genotype was determined by Sanger sequencing and multiplex ligation-dependent probe amplification. Sexual function was also separately analyzed in the context of clinical signs of androgenization in women with (n = 13) and without acne (n = 22). Outcomes The study outcomes were sexual function and sexual distress in relation to genotype, clinical signs of androgenization, and biochemical parameters. Results Women with NC-CAH had significantly lower orgasm scores, a trend toward lower sexual function with higher sexual distress, as well as biochemical evidence of hyperandrogenism (higher dehydroepiandrosterone sulfate and lower SHBG) and a trend toward more clinical signs of hyperandrogenism (hirsutism). Indicators of in utero and childhood androgen excess as well as the presence of acne in all patients were related to lower sexual function and higher sexual distress. Clinical signs of hyperandrogenism correlated well with cardiovascular and metabolic risk factors. Clinical Translation Women with NC-CAH and women with clinical signs of hyperandrogenism demonstrated higher distress compared to women with C-CAH and women without clinical signs of hyperandrogenism, respectively, regarding different aspects of sexual function. Conclusions These data underline the importance of early diagnosis and therapy initiation, especially in patients with NC-CAH.

Background and aims Growth differentiation factor 15 (GDF15) is a strong predictor of cardiovascular morbidity and mortality found to be both marker and target of impaired glucose metabolism. GDF15 increases following glucose administration and is up-regulated in obesity and diabetes. We investigate here the relationship between GDF15 and beta cell function. Methods and results In this cross-sectional study we evaluated GDF15 concentrations in 160 obese subjects (BMI 35–63 kg/m2, age 39.4 ± 18.6 years, m/f 38/122) who underwent a 75 g oral glucose tolerance test (OGTT). Based on the OGTT results, the cohort was divided into two groups: 1) normal fasting glucose and normal glucose tolerance (n = 80), 2) impaired fasting glucose, impaired glucose tolerance or type 2 diabetes (n = 80). The relationship of GDF15 to fasting and OGTT-based dynamic insulin sensitivity and insulin secretion parameters was evaluated. GDF15 was higher in the prediabetes and diabetes groups and correlated with HbA1c, glucose, insulin as well as baseline and dynamic indices of insulin sensitivity and estimated beta cell function. Multiple regression analysis revealed that age, waist-to-height ratio, glomerular filtration rate and prehepatic beta cell function, but not the grade of impairment of glucose metabolism, were independent predictors of GDF15. Subgroup analysis showed that of all parameters of glucose metabolism only C-peptide, fasting prehepatic beta cell function and insulinogenic index remained significantly related to GDF15 in both groups. Conclusion We conclude that in patients with severe obesity, GDF15 strongly relates to beta cell function and should be further investigated as a potential therapeutic target and biomarker guiding treatment options.

Cystic fibrosis-related diabetes (CFRD) is associated with adverse clinical outcomes and should be screened for by an annual oral glucose tolerance test (OGTT). Since pathophysiologic studies have mainly been performed in a pediatric/adolescent, nontransplanted collective, we aimed to assess parameters of insulin secretion and sensitivity in adult cystic fibrosis (CF) patients after lung transplantation (LT).Twelve adult CF patients after LT without known diabetes (33.3 ± 11.5 years; body mass index [BMI] 21.5 ± 3.3 kg/mIn the CF group, 4 patients were diagnosed with overt diabetes (CFRD) compared to CF patients without diabetes (CF-noDM), of whom 6 had indeterminate glycemia with 1-h glucose values200 mg/dL. The insulin peak after glucose load occurred after 30 minutes in CON, after 90 minutes in CF-noDM, and was missing in CFRD. Insulin sensitivity was comparable between the groups. Beta-cell glucose sensitivity was markedly reduced in CFRD (10.7 ± 5.8 pmol/min*mAdult CF patients after LT have profound disturbances in glucose metabolism, with a high rate of undetected diabetes and markedly delayed insulin secretion. Curbed beta-cell glucose sensitivity rather than insulin resistance explains postprandial hyperglycemia and is accompanied by abnormalities in lipid metabolism.AUC = area under the curve; BMI = body mass index; CF = cystic fibrosis; CFRD = cystic fibrosis-related diabetes; CFTR = cystic fibrosis transmembrane-conductance regulator; CF-TX = cystic fibrosis patients who underwent lung transplantation; CGM = continuous glucose monitoring; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; INDET = indeterminate glycemia; LDL = low-density lipoprotein; LT = lung transplantation; OGIS = oral glucose sensitivity index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index.

OBJECTIVE To evaluate the safety and efficacy of IONIS-GCGRRx, a 2′-O-methoxyethyl antisense oligonucleotide targeting the glucagon receptor (GCGR), and the underlying mechanism of liver transaminase increases in patients with type 2 diabetes on stable metformin therapy. RESEARCH DESIGN AND METHODS In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGRRx (50–200 mg) or placebo for 13 or 26 weeks. RESULTS Significant reductions in HbA1c were observed after IONIS-GCGRRx treatment versus placebo at week 14 (−2.0% 200 mg, −1.4% 100 mg, −0.3% placebo; P < 0.001) or week 27 (−1.6% 75 mg, −0.9% 50 mg, −0.2% placebo; P < 0.001). Dose-dependent increases in transaminases were observed with IONIS-GCGRRx, which were attenuated at lower doses and remained mostly within the normal reference range at the 50-mg dose. There were no other significant safety observations and no symptomatic hypoglycemia or clinically relevant changes in blood pressure, LDL cholesterol, or other vital signs. At week 14, IONIS-GCGRRx 100 mg did not significantly affect mean hepatic glycogen content compared with placebo (15.1 vs. −20.2 mmol/L, respectively; P = 0.093) but significantly increased hepatic lipid content (4.2 vs. −2.7%, respectively; P = 0.005) in the presence of transaminase increases. CONCLUSIONS IONIS-GCGRRx is a potent inhibitor of hepatic glucagon receptor expression with a potential to improve glycemic control at low weekly doses in combination with metformin. Significant reductions in HbA1c occurred across the full-dose range tested, with minimal transaminase elevations at lower doses. Furthermore, novel results suggest that despite inhibition of glycogenolysis after GCGR antagonism, IONIS-GCGRRx did not increase hepatic glycogen content.

ZusammenfassungPotentielle Funktionsstörungen der Schilddrüse treten bei bis zu 15 % aller Schwangeren auf und gehören damit zu den häufigsten Fragestellungen, mit denen ÄrztInnen im Rahmen der Betreuung von Frauen mit Kinderwunsch/Schwangerschaft in der klinischen Praxis konfrontiert sind. Die Grundzüge der neuen Empfehlungen der Fachgesellschaften und eine Auswahl der aktuellen wissenschaftlichen Literatur sollen hier diskutiert werden, um dem klinisch tätigen Arzt einen Überblick über neue Entwicklungen zu geben.

Objective: Sleeve gastrectomy (SG) has recently become the most commonly applied bariatric procedure worldwide. Substantial regaining of weight or severe reflux might compromise quality of life (QOL) after SG in the long-term follow-up. Long-term data on patients’ QOL is limited, even though the persistent improvement in QOL is one of the aims of bariatric surgery. The objective of this study was to present patients’ QOL 10 years after SG. Methods: Of 65 SG patients with a follow-up of ≥10 years after SG who were asked to fill out the Bariatric Quality of Life Index (BQL) and Short Form 36 (SF36) questionnaires, 48 (74%) completed them. This multicenter study was performed in a university hospital setting in Austria. Results: The BQL score revealed nonsignificant differences between the patients with > 50% or < 50% excess weight loss (EWL). It did show significant differences between patients with and without any symptoms of reflux. Patients with < 50% EWL scored significantly lower in 3/8 categories of SF36. Patients suffering from reflux had significantly lower scores in all categories. Conclusions: EWL and symptomatic reflux impair patients’ long-term QOL after SG.

Background One-anastomosis gastric bypass (OAGB) is a well-established treatment method in patients with morbid obesity. Its long-term impact on de novo reflux, anastomotic complications, and malnutrition needs further evaluation. Roux-en-Y gastric bypass (RYGB) is a technically feasible procedure in revisional bariatric surgery. This study presents our institutional data on conversion from OAGB to RYGB. Objective To determine the reasons for conversion, preoperative endoscopic findings, and feasibility of revisional bariatric surgery after OAGB. Setting University hospital in Austria METHODS: Retrospective analysis of a prospectively fed database. All patients undergoing OAGB between January 2012 and December 2019 were included. Screening was carried out for all patients needing conversion to RYGB. Percent total weight loss, percent excess weight loss, time to conversion, postoperative complications, and reasons for conversion were assessed. Results Eighty-two of 1,025 patients who underwent OAGB were converted laparoscopically to RYGB. Seven patients were converted early because of anastomotic/gastric tube leakage. Median time to late conversion was 29.1 ± 24.3 months, mean percent excess weight loss was 86.6% ± 33.1% and percent total weight loss was 35.1% ± 13.5%. Forty-two patients were converted because of reflux, 11 because of persistent marginal ulcers, 10 because of anastomotic stenosis, 9 because of malnutrition, and 3 because of weight regain. Seven patients showed Barrett's metaplasia in biopsies at the gastroesophageal junction before conversion. Conclusion Laparoscopic conversion from OAGB to RYGB is technically feasible with a moderate rate of postoperative complications. Severe (bile) reflux is a serious long-term complication after OAGB, with 4.1% of patients needing conversion to RYGB. Endoscopy after OAGB in patients showing clinical symptoms of gastroesophageal reflux disease is strongly advised to detect underlying pathologic changes.

Studies conflict concerning the use of enzyme immunoassays (EIA) for plasma free metanephrines (P-MNs) vs. other methods for pheochromocytoma/paraganglioma (PPGL) diagnosis. We compared commercially available EIAs for P-MNs with high-pressure liquid chromatography (HPLC) for 24 h-urinary MNs (U-MNs) and -catecholamines (U-CATs). 943 (565 female, 378 male) patients (54 PPGL, 889 Non-PPGL) were studied. Simultaneous measurements of all parameters analyzed at the central lab of our university hospital was mandatory for inclusion. Sensitivity of P-MNs (94.4%) was similar to that of U-MNs (100%), and both were higher than of U-CATs (77.8%), specificity of P-MNs (100%) higher than of U-MNs (73.6%), and similar to U-CATs (99.8%). With the recently proposed downward adjusted ULN of P-MNs to correct for the reported negative bias of the EIAs sensitivity (98.1%) raised non-significantly, but specificity decreased significantly (94.8%). Areas under receiver-operating characteristic curves indicated comparable diagnostic performance of P-MNs (0.989) vs. U-MNs (0.995), both better than U-CATs (0.956). In summary, the EIAs to measure P-MNs performed similarly to U-MNs by HPLC, and both better than U-CATs by HPLC. The post-test probability of PPGL given a positive test result was best for P-MNs, and higher than for the other pairs of analytes. Downward corrections of ULN of P-MNs did not improve test performances.

Background Patients with active acromegaly exhibit low hepatocellular lipid content (HCL) despite pronounced insulin resistance. This contrasts the strong association of insulin resistance with non-alcoholic fatty liver disease in the general population. Acromegaly may therefore help to elucidate antisteatotic pathways. Since low HCL in acromegaly might be caused by changes in oxidative substrate metabolism and interorgan crosstalk we investigated mitochondrial activity and plasma metabolomics as well as lipidomics in active acromegaly. Approach & Results Patients In this cross-sectional study, 15 patients with active acromegaly (ACRO) and 17 healthy controls (CON) matched for age, BMI, gender and body composition were included. All participants were invited to undergo 31P/1H-7T-MR-spectroscopy of the liver and skeletal muscle, as well as plasma metabolomic profiling and an oral glucose tolerance test. In comparison to CON, ACRO were insulin resistant, and showed significant lower HCL but their hepatic ATP-synthesis rate adjusted to HCL was significantly increased (h_kATP:0.19[0.14;0.24]vs0.28[0.22;0.34]s-1);p=0.024). Furthermore, the HCL-adjusted ratio of unsaturated to saturated intracellular fatty acids was decreased in ACRO (8.4%vs25.5% of HCL,p Conclusions The dissociation of hepatic lipid content and peripheral insulin resistance in acromegaly is associated with high mitochondrial activity as indicated by liver specific upregulation of the ATP-synthesis rate. This is paralleled by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a change in circulating carnitine species, also reflecting an increased mitochondrial activity. Our findings hint at potential direct effects of growth hormone excess on hepatic lipid and energy metabolism.

Bariatrische Operationen haben sich in der Behandlung der Adipositas als Therapieoption bewahrt. Zu den postoperativen Risiken gehort neben dem Dumpingsyndrom auch die postprandiale Hypoglykamie. Sie entwickelt sich oft erst einige Monate bis Jahre nach der Operation und kann in Einzelfallen mit bedrohlichen Symptomen wie Bewusstseinsstorungen und Krampfanfallen einhergehen. Als eine wichtige Ursache gilt die inkretininduzierte inadaquate postprandiale Hyperinsulinamie. Auch erhohte praoperative Konzentrationen von Insulin-like Growth Factor 1 (IGF-1) konnen mit einem erhohten Risiko fur die postprandiale Hypoglykamie verbunden sein. Grundlage der Therapie ist eine intensive diatologische Betreuung mit Identifikation der auslosenden Mahlzeiten. Schnell resorbierbare Kohlehydrate sollten generell vermieden werden. Medikamente wie Acarbose konnen den postprandialen Glukoseanstieg reduzieren und damit den Stimulus fur die Insulinsekretion minimieren. Insgesamt ist die postprandiale Hypoglykamie noch nicht ausreichend erforscht; die Entwicklung standardisierter diagnostischer Tests ist dringend erforderlich.

Background Hepatic disorders are often associated with changes in the concentration of phosphorus-31 (31 P) metabolites. Absolute quantification offers a way to assess those metabolites directly but introduces obstacles, especially at higher field strengths (B0 ≥ 7T). Purpose To introduce a feasible method for in vivo absolute quantification of hepatic 31 P metabolites and assess its clinical value by probing differences related to volunteers' age and body mass index (BMI). Study type Prospective cohort. Subjects/phantoms Four healthy volunteers included in the reproducibility study and 19 healthy subjects arranged into three subgroups according to BMI and age. Phantoms containing 31 P solution for correction and validation. Field strength/sequence Phase-encoded 3D pulse-acquire chemical shift imaging for 31 P and single-volume 1 H spectroscopy to assess the hepatocellular lipid content at 7T. Assessment A phantom replacement method was used. Spectra located in the liver with sufficient signal-to-noise ratio and no contamination from muscle tissue, were used to calculate following metabolite concentrations: adenosine triphosphates (γ- and α-ATP); glycerophosphocholine (GPC); glycerophosphoethanolamine (GPE); inorganic phosphate (Pi ); phosphocholine (PC); phosphoethanolamine (PE); uridine diphosphate-glucose (UDPG); nicotinamide adenine dinucleotide-phosphate (NADH); and phosphatidylcholine (PtdC). Correction for hepatic lipid volume fraction (HLVF) was performed. Statistical tests Differences assessed by analysis of variance with Bonferroni correction for multiple comparison and with a Student's t-test when appropriate. Results The concentrations for the young lean group corrected for HLVF were 2.56 ± 0.10 mM for γ-ATP (mean ± standard deviation), α-ATP: 2.42 ± 0.15 mM, GPC: 3.31 ± 0.27 mM, GPE: 3.38 ± 0.87 mM, Pi : 1.42 ± 0.20 mM, PC: 1.47 ± 0.24 mM, PE: 1.61 ± 0.20 mM, UDPG: 0.74 ± 0.17 mM, NADH: 1.21 ± 0.38 mM, and PtdC: 0.43 ± 0.10 mM. Differences found in ATP levels between lean and overweight volunteers vanished after HLVF correction. Data conclusion Exploiting the excellent spectral resolution at 7T and using the phantom replacement method, we were able to quantify up to 10 31 P-containing hepatic metabolites. The combination of 31 P magnetic resonance spectroscopy imaging data acquisition and HLVF correction was not able to show a possible dependence of 31 P metabolite concentrations on BMI or age, in the small healthy population used in this study. Level of evidence 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:597-607.

Sleeve gastrectomy (SG) has been the most frequently performed bariatric procedure worldwide since 2014. Therefore, it is vital to look at its outcomes in a long-term follow-up based on a large patient collective. Main points of discussion are weight regain, reflux, and patients’ quality of life at 10+ years after the procedure. The aim of this study is to present an update of data that have been published recently and, thus, achieve more conclusive results. The number of patients has been doubled, and the length of the follow-up is still 10+ years. Multi-center study, medical university clinic, Austria This study includes all patients who had SG before December 2006 at the participating bariatric centers. At 10+ years, non-converted patients (67%) were examined using gastroscopy, manometry, 24-hour pH-metry, and questionnaires. Patients’ history of weight, comorbidities, and reflux were established through interviews. At 10+ years after SG, the authors found a conversion rate of 33%, an %EWL in non-converted patients of 50.0 ± 22.5, reflux in 57%, and Barrett’s metaplasia in 14% of non-converted patients. Gastroscopies revealed that patients with reflux were significantly more likely to have de-novo hiatal hernia. A significantly lower quality of life was detected through GIQLI and BAROS in patients with reflux. The authors recommend gastroscopies at 5-year intervals after SG to detect the possible sequelae of reflux at an early stage. Conversion to Roux-en-Y-gastric bypass (RYGB) works well to cure patients from reflux but may not be as efficient at treating weight regain.

Aktuelle Leitlinien empfehlen, im Rahmen der Abklarung einer Hyponatriamie eine primare Hypothyreose auszuschliesen. Die Evidenz aus groseren Studien und damit die Bedeutung fur den klinischen Alltag sind hierfur jedoch nicht eindeutig und durchaus kritisch zu hinterfragen. Es gibt verschiedene Erklarungsmechanismen, wie die Schilddrusenunterfunktion eine Hyponatriamie auslosen konnte. Ein Ansatz geht davon aus, dass der bei hypothyreoten Patienten erhohte ADH-Spiegel uber eine Wasserretention zu einer Hyponatriamie fuhren konnte. Ein weiterer Ansatz beruft sich auf eine reduzierte Herzfunktion, welche durch eine Schilddrusenunterfunktion ausgelost werden kann. Dies sowie mogliche Veranderungen in der Niere, insbesondere eine reduzierte glomerulare Filtrationsrate, konnten eine Hyponatriamie erklaren. Ob diese Mechanismen jedoch auch fur den medizinischen Alltag von Relevanz sind bzw. eine Schilddrusenunterfunktion alleine ausreicht, um eine klinisch relevante Hyponatriamie zu induzieren, ist unklar. Eine kurzlich von uns publizierte Studie an einem grosen Patientenkollektiv mit Hyponatriamie konnte keinen wesentlichen Einfluss einer Hypothyreose zeigen. In Zusammenschau der vielen Studien zu dieser Thematik lasst sich folgern, dass eine Hypothyreose als alleiniges Krankheitsbild, wenn uberhaupt, sehr selten fur eine klinisch relevante Hyponatriamie verantwortlich sein durfte. Bei Patienten mit einem verminderten Natriumspiegel gibt es viele alternative Ursachen, welche nicht ubersehen werden sollten.

Laparoscopic sleeve gastrectomy (SG) has become the most frequently performed bariatric procedure worldwide. De novo reflux might impact patients’ quality of life, requiring lifelong proton pump inhibitor medication. It also increases the risk of esophagitis and formation of Barrett’s metaplasia. Besides weight regain, gastroesophageal reflux disease (GERD) is the most common reason for conversion to Roux-en-Y gastric bypass. We performed 24-h pH metries, manometries, gastroscopies, and questionnaires focusing on reflux (GIQLI, RSI) in SG patients with a follow-up of more than 10 years who did not suffer from symptomatic reflux or hiatal hernia preoperatively. From a total of 53 patients, ten patients after adjustable gastric banding were excluded. From the remaining 43, six patients (14.0%) were converted to RYGB due to intractable reflux over a period of 130 months. Ten out of the remaining non-converted patients (n = 26) also suffered from symptomatic reflux. Gastroscopies revealed de novo hiatal hernias in 45% of the patients and Barrett’s metaplasia in 15%. SG patients suffering from symptomatic reflux scored significantly higher in the RSI (p = 0.04) and significantly lower in the GIQLI (p = 0.02) questionnaire. This study shows a high incidence of Barrett’s esophagus and hiatal hernias at more than 10 years after SG. Its results therefore suggest maintaining pre-existing large hiatal hernia, GERD, and Barrett’s esophagus as relative contraindications to SG. The limitations of this study—its small sample size as well as the fact that it was based on early experience with SG—make drawing any general conclusions about this procedure difficult.

Cardiovascular disease is the leading cause of death in general population. Besides well-known risk factors such as hypertension, impaired glucose tolerance and dyslipidemia, growing evidence suggests that hormonal changes in various endocrine diseases also impact the cardiac morphology and function. Recent studies highlight the importance of ectopic intracellular myocardial and pericardial lipid deposition, since even slight changes of these fat depots are associated with alterations in cardiac performance. In this review, we overview the effects of hormones, including insulin, thyroid hormones, growth hormone and cortisol, on heart function, focusing on their impact on myocardial lipid metabolism, cardiac substrate utilization and ectopic lipid deposition, in order to highlight the important role of even subtle hormonal changes for heart function in various endocrine and metabolic diseases.

To prove the feasibility and safety of a conversion to once-daily injected GLP1 agonist (lixisenatide) and long-acting basal insulin analogue (glargine) in patients with T2DM and poorly controlled glycemia previously treated with multiple injections of premixed insulins (iPremix) in an outpatient setting. Nine patients with T2DM currently receiving iPremix formulations and poor glycemic control were switched to once-daily injected lixisenatide (Lixi) and basal insulin analogue glargine (iGlar) for a 12-week period. Efficacy was defined as A1c reduction of at least 0.4% and weight loss of 0.5 kg or higher. Five of nine patients achieved A1c reductions of 0.4% (4 mmol/mol) or higher and six of nine patients a weight loss of 0.5 kg or higher. A mean A1C reduction of 0.5% ± 0.5% (6 mmol/mol) and mean weight loss of −1.4 ± 3.6 kg were observed in all patients. Total daily insulin dose after 12 weeks declined from 56 ± 26 IU with iPremix formulations to 47 ± 17 IU in patients taking combined iGlar and Lixi. Corrections with fast acting insulin glulisine (iGlu) were necessary in two patients on a regular basis and in four patients on an irregular basis (2.3 IU mean total daily dose). Two patients did not need additional iGlu. Postprandial glucose profiles were lower in the combined group compared with iPremix throughout the day, which resolved in the afternoon. No metabolic derangements occurred. Mild hypoglycemia and gastrointestinal symptoms were the most often reported adverse events affecting three patients. The conversion to once-daily injected GLP1 agonist Lixi and basal iGlar could safely be performed in an outpatient setting and was associated with better postprandial glycemic control throughout the day, except dinner, compared to iPremix. Clinical Trial Registration: EU clinical trials register EudraCT number 2013-005334-37 and ClinicalTrials.gov NCT02168491. Funding: Sponsored by the Medical University of Vienna and in part supported by Sanofi-Aventis.

Quality of life is becoming an important health outcome and among the main goals of every healthcare intervention. This study aims to assess the reliability of the German version of the World Health Organization Quality of Life-BREF instrument (WHOQOL-BREF) among Austrian patients with diabetes and examine the correlation to glycated hemoglobin (HbA1c).This was a cross-section study that involved 223 patients with diabetes who attended the diabetes center at Melk Hospital in Austria. The German version of the WHOQOL-BREF questionnaire was used to assess their quality of life from 2018 to 2019. The response to each question was scored from 1 to 5 (ranged from strongly disagree to strongly agree) on the Likert scale. The reliability of the WHOQOL-BREF instrument was assessed using the Cronbach's α, and the Spearman correlation coefficient was used to examine the correlation between the quality of life and the HbA1c.There were 208 valid WHOQOL-BREF questionnaires with a response rate of 93.7%. The overall observed Cronbach's α for WHOQOL-BREF was 0.86. The mean±standard deviation (SD) for the physical domain, psychological domain, social domain, and environmental domain were 61.9±19.1, 71.5±17.8, 71.0±19.6, and 81.3±11.1, respectively. There was a moderate but statistically significant negative correlation between HbA1c and the physical health domain (rs=-0.31, p0001). There was also a weak correlation between the HbA1c and other domains: psychological (rs=-0.23, p001), social relationships (rs=-0.15, p005) and environmental (rs=-0.23, p001).This study showed that the German form of the WHOQOL-BREF is a valid instrument to evaluate the quality of life among Austrian patients with diabetes. There was a moderate to weak negative association between WHOQOL-BREF and HbA1c.

Background Bariatric metabolic surgery is a well-established treatment option associated with significant weight loss and an improvement of metabolic co-morbidities. However, the changes in gastrointestinal anatomy frequently result in nutritional deficiencies. Objective To evaluate the impact of biliopancreatic limb length in one-anastomosis gastric bypass (OAGB) on micronutrient and protein deficiencies. Setting University hospital, Austria. Methods All patients that were (1) undergoing OAGB between 2012 and 2014, and (2) had at least 3 postoperative follow-up visits were retrospectively analyzed. Systemic levels of parathyroid hormone, vitamins (A, D, E, and B12), folic acid, magnesium, calcium, iron, albumin, and ferritin were correlated to biliopancreatic limb length as follows: short limb (150 cm), intermediate limb (200 cm), and long limb (250 cm). Results A total of 155 patients fulfilled inclusion criteria (female/male: n = 111/44). OAGB led to a mean percent excess weight loss of 79.9 (±24.2) and a reduction of mean body mass index from 45.4 kg/m2 (±6.1 kg/m2) at baseline to 30.2 kg/m2 (±9.9 kg/m2). Preoperative deficiencies were seen in 25-hydroxy-vitamin D (93.8%), folic acid (27.6%), ferritin (4.1%), vitamin A (5.5%), and vitamin B12 (2.3%). In patients with long limb, systemic folic acid levels were significantly lower after 24 months postoperatively compared with short and intermediate limb (P Conclusion Nutritional deficiencies were common after OAGB without severe deficiencies in biliopancreatic limb lengths ranging from 150 to 250 cm. A trend can be observed with more pronounced deficiencies with intermediate and long limb lengths without significant differences for most micronutrients.

Background Increased fructose intake has been associated with metabolic consequences such as impaired hepatic lipid metabolism and development of nonalcoholic fatty liver disease (NAFLD). Objectives The aim of this study was to investigate the role of fructose in glucose and lipid metabolism in the liver, heart, skeletal muscle, and adipose tissue. Methods Ten healthy subjects (age: 28 ± 19 y; BMI: 22.2 ± 0.7 kg/m2) underwent comprehensive metabolic phenotyping prior to and 8 wk following a high-fructose diet (150 g daily). Eleven patients with NAFLD (age: 39.4 ± 3.95 y; BMI: 28.4 ± 1.25) were characterized as "positive controls." Insulin sensitivity was analyzed by a 2-step hyperinsulinemic euglycemic clamp, and postprandial interorgan crosstalk of lipid and glucose metabolism was evaluated, by determining postprandial hepatic and intra-myocellular lipid and glycogen accumulation, employing magnetic resonance spectroscopy (MRS) at 7 T. Myocardial lipid content and myocardial function were assessed by 1H MRS imaging and MRI at 3 T. Results High fructose intake resulted in lower intake of other dietary sugars and did not increase total daily energy intake. Ectopic lipid deposition and postprandial glycogen storage in the liver and skeletal muscle were not altered. Postprandial changes in hepatic lipids were measured [Δhepatocellular lipid (HCL)_healthy_baseline: -15.9 ± 10.7 compared with ± ΔHCL_healthy_follow-up: -6.9 ± 4.6; P = 0.17] and hepatic glycogen (Δglycogen_baseline: 64.4 ± 14.1 compared with Δglycogen_follow-up: 51.1 ± 9.8; P = 0.42). Myocardial function and myocardial mass remained stable. As expected, impaired hepatic glycogen storage and increased ectopic lipid storage in the liver and skeletal muscle were observed in insulin-resistant patients with NAFLD. Conclusions Ingestion of a high dose of fructose for 8 wk was not associated with relevant metabolic consequences in the presence of a stable energy intake, slightly lower body weight, and potentially incomplete absorption of the orally administered fructose load. This indicated that young, metabolically healthy subjects can at least temporarily compensate for increased fructose intake. This trial was registered at www.clinicaltrials.gov as NCT02075164.

The prevalence of obesity and metabolic syndrome increases in patients with type 1 diabetes mellitus (T1DM). In the general population this is linked with ectopic lipid accumulation in liver (HCL) and skeletal muscle (IMCL), representing hallmarks in the development of insulin resistance. Moreover, hepatic mitochondrial activity is lower in newly diagnosed patients with T1DM. If this precedes later development of diabetes related fatty liver disease is currently not known. This study aims to investigate energy metabolism in liver (kATP) and skeletal muscle (kCK) and its impact on HCL, IMCL, cardiac fat depots and heart function in 10 patients with long standing T1DM compared to 11 well-matched controls by 31P/1H magnetic resonance spectroscopy. HCL was almost 70% lower in T1DM compared to controls (6.9 ± 5% vs 2.1 ± 1.3%; p = 0.030). Also kATP was significantly reduced (0.33 ± 0.1 s−1vs 0.17 ± 0.1 s−1; p = 0.018). In T1DM, dose of basal insulin strongly correlated with BMI (r = 0.676, p = 0.032) and HCL (r = 0.643, p = 0.045), but not with kATP. In the whole cohort, HCL was significantly associated with BMI (r = 0.615, p = 0.005). In skeletal muscle kCK was lower in patients with T1DM (0.25 ± 0.05 s−1vs 0.31 ± 0–04 s−1; p = 0.039). No significant differences were found in IMCL. Cardiac fat depots as well as heart function were not different. Our results in patients with long standing T1DM show that HCL is lower compared to matched controls, despite reduced energy metabolism in liver and skeletal muscle.

Background In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin–angiotensin–aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity. Methods Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case–control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry. Results In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P r = 0.985; P Conclusions AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.

Medullary carcinoma (MTC) is an aggressive tumour that derives from the thyroid parafollicular calcitonin-secreting cells (C cells). Lymph node metastasis may occur early in disease pathogenesis and is one of the most important negative prognostic parameters. Surgery is the only curative therapy while chemotherapeutic options are limited. Neuroendocrine differentiated C cells may express somatostatin receptors (SSTR), which have a wide range of biological actions including inhibitory effects on cell survival and angiogenesis and antiproliferative effects on cancer cell lines. Moreover, they are a potential target for various somatostatin analogues. Aim of this study was to analyse the protein expression of SSTR2A and 5 in MTCs with or without the presence of lymph node metastases in correlation with various clinicopathological parameters. This retrospective immunohistochemical analysis included 97 patients with medullary thyroid carcinomas. Protein expression was detected by immunohistochemistry for somatostatin receptors 2A and 5. Various clinicopathological parameters, such as Ki-67 proliferation index or presence of desmoplasia, were included for statistical analysis. SSTR2A protein expression significantly correlated with the presence of lymph node metastases (p = 0.009), locally advanced MTCs staged according to the TNM (p < 0.001) and degree of desmoplasia (p = 0.029). Although SSTR5 protein expression significantly correlated with advanced stages of MTCs (p = 0.023) and degree of desmoplasia (p = 0.020), no correlation was found with the presence of lymph node metastases. Our results provide additional information concerning the aggressiveness of MTCs and reveal that a high SSTR2A and SSTR5 expression might be a poor prognostic feature.

Background/aims: \ud Uncertainty still exists on the earliest beta-cell defects at the bases of the type 2 diabetes. We assume that this depends on the inaccurate distinction between fasting and post-load glucose homeostasis and aim at providing a description of major beta-cell functions across the full physiologic spectrum of each condition.\ud \ud Methods: \ud In 1320 non-diabetic individuals we performed an OGTT with insulin secretion modeling and a euglycemic insulin clamp, coupled in subgroups to glucose tracers and IVGTT; 1038 subjects underwent another OGTT after 3.5 years. Post-load glucose homeostasis was defined as mean plasma glucose above fasting levels (δOGTT). The analysis was performed by two-way ANCOVA.\ud \ud Results: \ud Fasting plasma glucose (FPG) and δOGTT were weakly related variables (stβ = 0.12) as were their changes over time (r = −0.08). Disruption of FPG control was associated with an isolated and progressive decline (approaching 60%) of the sensitivity of the beta-cell to glucose values within the normal fasting range. Disruption of post-load glucose control was characterized by a progressive decline (approaching 60%) of the slope of the full beta-cell vs glucose dose-response curve and an early minor (30%) decline of potentiation. The acute dynamic beta-cell responses, neither per se nor in relation to the degree of insulin resistance appeared to play a relevant role in disruption of fasting or post-load homeostasis. Follow-up data qualitatively and quantitatively confirmed the results of the cross-sectional analysis.\ud \ud Conclusion: \ud In normal subjects fasting and post-load glucose homeostasis are largely independent, and their disruption is sustained by different and specific beta-cell defects.

Little is known about changes in bone mineral density (BMD) following weight loss after one-anastomosis gastric bypass (OAGB) and the role of serum vitamin D and its supplementation on bone metabolism. We evaluated BMD after OAGB as a function of vitamin D supplementation with respect to a minimum threshold of 25-hydroxy-vitamin-D [25(OH)D] concentration, which could prevent or decelerate an eventual bone loss. Fifty bariatric patients who participated in the randomized controlled trial were included in this analysis. BMD and anthropometric measurements by DXA and laboratory parameters were assessed before (T0), at 6 (T6), and 12 months (T12) after surgery. OAGB resulted in a 36% total body weight loss with a decrease in body fat and an increase in lean body mass. A significant decrease in BMD was seen in lumbar spine by 7%, left hip 13%, and total body 1%, but not in forearm. Bone turnover markers increased significantly but with normal parathyroid hormone concentrations. Weight loss was not associated with changes in BMD. A serum 25(OH)D concentration > 50 nmol/l at T6 and T12 (adequate-vitamin-D-group; AVD) showed a significant lower bone loss, compared to the inadequate-vitamin-D-group (IVD

The prevalence of obesity is growing worldwide, and strategies to overcome this epidemic need to be developed urgently. Bariatric surgery is a very effective treatment option to reduce excess weight and often performed in women of reproductive age. Weight loss influences fertility positively and can resolve hormonal imbalance. So far, guidelines suggest conceiving after losing maximum weight and thus recommend conception at least 12–24 months after surgery. As limited data of these suggestions exist, further evidence is urgently needed as well for weight gain in pregnancy. Oral glucose tolerance tests for the diagnosis of gestational diabetes mellitus (GDM) should not be performed after bariatric procedures due to potential hypoglycaemic adverse events and high variability of glucose levels after glucose load. This challenges the utility of the usual diagnostic criteria for GDM in accurate prediction of complications. Furthermore, recommendations on essential nutrient supplementation in pregnancy and lactation in women after bariatric surgery are scarce. In addition, nutritional deficiencies or daily intake recommendations in pregnant women after bariatric surgery are not well investigated. This review summarizes current evidence, proposes clinical recommendations in pregnant women after bariatric surgery, and highlights areas of lack of evidence and the resulting urgent need for more clinical investigations.

Uninterrupted uptime is a critical aspect of Virtual Machines (VMs) offered by cloud hosting providers. Google's VMs run on top of rapidly changing infrastructure: we regularly update hardware and host software, and we must quickly respond to failing hardware. Frequent change is critical to both development velocity---deploying new versions of services and infrastructure---and the ability to respond rapidly to defects, including critical security fixes. Typically these updates would be disruptive, resulting in VM termination or restart. In this paper we present how we use VM live migration at scale to eliminate this disruption with minimal impact to the guest, performing over 1,000,0001migrations monthly in our production fleet, with 50ms median blackout, 300ms 99th percentile blackout.

Calcium metabolism changes in pregnancy and lactation to meet fetal needs, with increases in 1,25-dihydroxyvitamin D [1,25-(OH)2D] during pregnancy playing an important role. However, these changes rarely cause maternal hypercalcemia. When maternal hypercalcemia occurs, further investigation is essential, and disorders of 1,25-(OH)2D catabolism should be carefully considered in the differential diagnosis.A patient with a childhood history of recurrent renal stone disease and hypercalciuria presented with recurrent hypercalcemia and elevated 1,25-(OH)2D levels during pregnancy. Laboratory tests in the fourth pregnancy showed suppressed PTH, elevated 1,25-(OH)2D, and high-normal 25-hydroxyvitamin D levels, suggesting disordered vitamin D metabolism. Analysis revealed low 24,25-dihydroxyvitamin D3 and high 25-hydroxyvitamin D3 levels, suggesting loss of function of CYP24A1 (25-hydroxyvitamin-D3-24-hydroxylase). Gene sequencing confirmed that she was a compound heterozygote with the E143del and R396W mutations in CYP24A1.This case broadens presentations of CYP24A1 mutations and hypercalcemia in pregnancy. Furthermore, it illustrates that patients with CYP24A1 mutations can maintain normal calcium levels during the steady state but can develop hypercalcemia when challenged, such as in pregnancy when 1,25-(OH)2D levels are physiologically elevated.

SummaryBackground Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72-h fast. However, the prognostic value of parameters in the standardized 72-h fast on histopathological tumour criteria and clinical presentation has not been examined. Methods In thirty-three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki-67 index. Cut-off values for classical grading (Gclas) were set at G1clas≤2%, G2clas3–20% & G3clas>20% and for modified grading (Gmod) at G1mod 20%. Results When Gmod criteria were applied, the initial blood glucose was lower in GII/IIImod patients compared to GImod (2·8 ± 0·8 vs 3·8 ± 1·3 mmol/l; P = 0·046). Basal and end of fast levels of insulin (basal insulin 71 ± 61 vs 20 ± 16 mU/l; P

To demonstrate the overlap of the hepatic and bile phosphorus (31P) magnetic resonance (MR) spectra and provide evidence of phosphatidylcholine (PtdC) contribution to the in vivo hepatic 31P MRS phosphodiester (PDE) signal, suggested in previous reports to be phosphoenolpyruvate (PEP). Phantom measurements to assess the chemical shifts of PEP and PtdC signals were performed at 7 T. A retrospective analysis of hepatic 3D 31P MR spectroscopic imaging (MRSI) data from 18 and five volunteers at 3 T and 7 T, respectively, was performed. Axial images were inspected for the presence of gallbladder, and PDE signals in representative spectra were quantified. Phantom experiments demonstrated the strong pH-dependence of the PEP chemical shift and proved the overlap of PtdC and PEP (~2 ppm relative to phosphocreatine) at hepatic pH. Gallbladder was covered in seven of 23 in vivo 3D-MRSI datasets. The PDE gall/γ-ATPliver ratio was 4.8-fold higher (p = 0.001) in the gallbladder (PDEgall/γ-ATPliver = 3.61 ± 0.79) than in the liver (PDEliver/γ-ATPliver = 0.75 ± 0.15). In vivo 7 T 31P MRSI allowed good separation of PDE components. The gallbladder is a strong source of contamination in adjacent 31P MR hepatic spectra due to biliary phosphatidylcholine. In vivo 31P MR hepatic signal at 2.06 ppm may represent both phosphatidylcholine and phosphoenolpyruvate, with a higher phosphatidylcholine contribution due to its higher concentration. • In vivo 31 P MRS from the gallbladder shows a dominant biliary phosphatidylcholine signal at 2.06 ppm. • Intrahepatic 31 P MRS signal at 2.06 ppm may represent both intrahepatic phosphatidylcholine and phosphoenolpyruvate. • In vivo 31 P MRS has the potential to monitor hepatic phosphatidylcholine.