Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial

AIM/HYPOTHESIS: To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses. METHODS: In a randomised placebo-controlled double-blind (participants and the investigators who performed the studies and assessed the outcomes were blinded) dose-response intervention study, 32 healthy men (age 22 +/- 3 years; BMI 22.4 +/- 1.7 kg/m(2)) were allocated to prednisolone 7.5 mg once daily (n = 12), prednisolone 30 mg once daily (n = 12), or placebo (n = 8) for 2 weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp conducted in the Clinical Research Unit of the Academic Medical Centre, Amsterdam, the Netherlands RESULTS: Prednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30 mg increased fasting insulin levels (29 +/- 15 pmol/l). Prednisolone 7.5 mg and prednisolone 30 mg decreased the ability of insulin to suppress endogenous glucose production (by 17 +/- 6% and 46 +/- 7%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5 mg, but was decreased by prednisolone 30 mg by 34 +/- 6% (p < 0.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state (p = 0.062), but both prednisolone 7.5 mg and prednisolone 30 mg decreased insulin-mediated suppression of lipolysis by 11 +/- 5% and 34 +/- 6%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30 mg (5 +/- 2%; p = 0.06). No side effects were reported by the study participants. All participants completed the study and were analysed. CONCLUSIONS/INTERPRETATION: Not only at high doses but also at low doses, glucocorticoid therapy impaired intermediary metabolism by interfering with the metabolic actions of insulin on liver and adipose tissue. These data indicate that even low-dose glucocorticoids may impair glucose tolerance when administered chronically. TRIAL REGISTRATION: ISRCTN83991850

Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus : A post-hoc analysis of a 52-week randomised trial

Aims: To compare the effects of long-term treatment with the GLP-1RA exenatide twicedaily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. Methods: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean +/- SD age 60 +/- 8 years, HbA1c 7.5 +/- 0.9%, eGFR 86 +/- 16 mL/min/1.73m(2), median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 mg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albuminexcretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. Results: HbA1c-reductions were similar with exenatide (mean +/- SEM -0.80 +/- 0.10%) and iGlar (-0.79 +/- 0.14%; treatment-difference 0.02%; 95% CI - 0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P <0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 +/- 2.1 mL/min/1.73 m(2); P = 0.069) and iGlar (-2.7 +/- 1.2 mL/min/1.73 m(2); P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P <0.001), but did not affect blood pressure, lipids or plasma uric acid. Conclusions: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

Aims/hypothesis: This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. Methods: We included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min−1 1.73 m−2. Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined. Results: Of the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min−1 1.73 m−2, p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05). Conclusions/interpretation: Exenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients. Trial registration: ClincialTrials.gov NCT01744236 Funding: The research leading to these results has been funded from: (1) the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 – the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87

Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients

Aims: Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile. Materials and methods: A total of 57 type 2 diabetes patients (mean±SD age, 62.8±6.9years; BMI, 31.8±4.1kg/m2; HbA1c, 7.3%±0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236). Results: Neither liraglutide nor sitagliptin had an effect on gallbladder fast

Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial

AIMS/HYPOTHESIS: Glucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis. We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis in patients with type 2 diabetes. METHODS: In this 12 week, parallel, randomised, placebo-controlled trial, performed at the VU University Medical Center between July 2013 and August 2015, 52 overweight patients with type 2 diabetes treated with metformin and/or sulphonylurea agent ([mean ± SD] age 62.7 ± 6.9 years, HbA1c 7.3 ± 0.7% or 56 ± 1 mmol/mol) were allocated to once daily liraglutide 1.8 mg (n = 17), sitagliptin 100 mg (n = 18) or matching placebos (n = 17) by computer generated numbers. Both participants and researchers were blinded to group assignment. Hepatic fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS). Hepatic fibrosis was estimated using three validated formulae. RESULTS: One patient dropped out in the sitagliptin group owing to dizziness, but no serious adverse events occurred. At week 12, no between-group differences in hepatic steatosis were found. Liraglutide reduced steatosis by 10% (20.9 ± 3.4% to 18.8 ± 3.3%), sitagliptin reduced steatosis by 12.1% (23.9 ± 3.0% to 21.0 ± 2.7%) and placebo lessened it by 9.5% (18.7 ± 2.7% to 16.9 ± 2.7%). Neither drug affected hepatic fibrosis scores compared with placebo. CONCLUSIONS/INTERPRETATION: Twelve-week liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis in type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01744236 FUNDING : Funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282521 - the SAFEGUARD project

Perinatal exposure to polychlorinated biphenyls and dioxins through dietary intake

Polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo p-dioxins and dibenzofurans) are potentially hazardous compounds. Since food is the major source (>90%) for the accumulation of PCBs and dioxins in the human body, food habits in women determine the degree of fetal exposure and levels in human milk. In order to investigate an association between dietary intake and PCB and dioxin levels in human milk and PCB levels in maternal and cord plasma, the food intake of 418 Dutch women during pregnancy was recorded using semi-quantitative food frequency questionnaires. After adjusting for covariates, a weak association was found between the estimated dietary intake of 2,3,7,8-tetrachlorodibenzo p-dioxin (2,3,7,8-TCDD), dioxins, and planar PCBs and their corresponding levels in breast milk. The estimated dietary intake of 2,3,7,8-TCDD, dioxins, and planar PCBs was also related to the PCB levels in maternal and cord plasma. Dairy products accounted for about half and industrial oils for about a quarter of the estimated 2,3,7,8-TCDD, dioxin, and the planar PCB intake. It is concluded that the contribution of a pregnancy related diet to PCB and dioxin levels in human milk and to PCB levels in maternal and cord plasma is relatively low. Decrease of exposure to PCBs and dioxins of the fetus and the neonate probably requires long-term reduction of the intake of these pollutants. Substitution of normal cheese by low-fat cheese and the use of vegetable oils instead of fish oils in the preparation of foodstuffs by the food industry could contribute to a reduced intake of PCBs and dioxins

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

Aims/hypothesis: This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. Methods: We included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min−1 1.73 m−2. Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined. Results: Of the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min−1 1.73 m−2, p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05). Conclusions/interpretation: Exenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients. Trial registration: ClincialTrials.gov NCT01744236 Funding: The research leading to these results has been funded from: (1) the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 – the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87

27. New echocardiogram index alternatives to MAPSE and TAPSE z-scores in children

BackgroundMitral annular plane systolic excursion (MAPSE), and tricuspid annular plane systolic excursion (TAPSE) are relatively load independent longitudinal left ventricle (LV) and right ventricle (RV) measurement in both adults and children. Normal paediatric values of MAPSE and TAPSE unlike adults are based on inconvenient z-scores. We hypothesize novel indexes of (LSI) LV longitudinal systolic index and (RSI) RV longitudinal systolic index are BSA, age, gender independent and nullifies the need for MAPSE and TAPSE z-scores.MethodsNormal echocardiograms were retrospectively reviewed from 2009 to 2011. Ejection fraction, LV dimensions, MAPSE, and TAPSE were determined. LSI and RSI were calculated using MAPSE and TAPSE divided by LV length. Echocardiogram indices were correlated. Regression analysis was done for BSA, age, and gender.ResultsTwo hundred and one patients had normal ejection fractions (67.3;±5.1%). Mean MAPSE 10.4;±3.3mm, z-score −0.07;±1.2, and LSI 0.20;±0.03; Mean TAPSE 17.4;±5.4mm, z-score 0.74;±1.7, and RSI 0.34;±0.06. LSI and MAPSE z-scores correlated, r=0.73, p<0.001. Age, gender, and BSA did not correlate with LSI. RSI and TAPSE z-scores correlated with r=0.76, p<0.001. Age influences RSI, R2=0.58, p value <0.001, BSA and gender does not. RSI, with age stratification, is significantly decreased less than 2months.ConclusionLSI obviates need for-MAPSE z scores. RSI offers an additional non TAPSE z-score method to evaluate RV function, but does not nullify age effect. RSI, especially in the first two months is decreased

The influence of the cultural climate of the training environment on physicians' self-perception of competence and preparedness for practice

<p>Abstract</p> <p>Background</p> <p>In current supervisory practice, the learning environment in which the training of specialist registrars (SpRs) takes place is important. Examples of such learning environments are the hospital settings and/or geographical locations where training occurs. Our objective was to investigate whether the cultural climate of different learning environments influences physicians' perceived level of competence and preparedness for practice.</p> <p>Methods</p> <p>An electronic questionnaire was sent to an equal group of paediatricians who had trained in clinical settings located in Europe and the Caribbean. 30 items (Likert scale 1–4 = totally disagree-totally agree) were used to measure the level of preparedness of the respondents in 7 physician competencies.</p> <p>Results</p> <p>42 participants were included for analysis. The distribution of participants in both groups was comparable. The overall perception of preparedness in the Caribbean group was 2.93 (SD = 0.47) and 2.86 (SD = 0.72) in the European group. The European group felt less prepared in the competency as manager 1.81 (SD = 1.06) compared to their Caribbean counterparts 2.72 (SD = 0.66). The difference was significant (p = 0.006).</p> <p>Conclusion</p> <p>The training in the different environments was perceived as adequate and comparable in effect. The learning environment's cultural climate appeared to influence the physician's perception of their competencies and preparedness for clinical practice.</p