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

Scaling Propensity of Water

The commonly used Saturation Index calculated at 10°C (SI10) is not suitable for practical situations. New parameters have been developed for simple and rapid analysis of calcium carbonate precipitation (scaling) phenomena which occur during the heating of drinking water: TPCC90 (Theoretically Precipitable Calcium Carbonate at 90°C) SI90 (Saturation Index at 90°C) NI (Nucleation Index) PPCC (Practically Precipitable Calcium Carbonate) Both TPCC90 and SI90 describe the hydrodynamic driven force for the scaling reaction. The nucleation index indicates at what rate calcium carbonate precipitation is accelerated by nuclei present in the water. Finally, the PPCC is a measurement under practical conditions, determining the rate of scaling. The suitability of these parameters for predicting scaling was assessed and detailed results are presented in this publication

The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage

Liraglutide and sitagliptin have no effect on intestinal microbiota composition : A 12-week randomized placebo-controlled trial in adults with type 2 diabetes

Aim: Preclinical data suggest that treatment with either glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors could change the intestinal microbiome and thereby contribute to their beneficial (cardio)metabolic effects. Therefore, our study aimed to investigate the effects of these agents on microbiota composition in adults with type 2 diabetes (T2D). Methods: A total of 51 adults with T2D (mean +/- SD: age 62.8 +/- 6.9 years, BMI 31.8 +/- 4.1 kg/m(2), HbA(1c) 7.3 +/- 0.6%) treated with metformin and/or sulphonylureas were included in the 12-week randomized, double-blind trial. Patients were given the GLP-1 receptor agonist liraglutide (1.8 mg sc) or the DPP-4 inhibitor sitagliptin (100 mg), or matching placebos, once daily for 12 weeks. Faecal samples were collected at baseline and at 12 weeks after the start of the intervention. Microbiota analyses were performed by 16S rRNA gene-sequencing analysis. Bile acids were measured in faeces and plasma. Results: Liraglutide decreased HbA(1c) by 1.3% (95% CI: -1.7 to -0.9) and tended to reduce body weight (-1.7 kg, 95% CI: -3.6 to 0.3), but increased faecal secondary bile acid deoxycholic acid. Sitagliptin lowered HbA(1c) by 0.8% (95% CI: -1.4 to -0.4) while body weight remained stable (-0.8 kg, 95% CI: -2.7 to 1.0), but increased faecal levels of cholic acid, chenodeoxycholic acid and ursodeoxycholic acid. However, neither liraglutide nor sitagliptin affected either alpha or beta diversity of the intestinal microbiota, nor were changes in microbial composition related to clinical parameters. Conclusion: These data suggest that the beneficial effects of liraglutide and sitagliptin on glucose metabolism, body weight and bile acids, when used as add-on therapies to metformin or sulphonylureas, are not linked to changes in the intestinal microbiota (NCT01744236). (C) 2021 The Authors. Published by Elsevier Masson SAS.Peer reviewe

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

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