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Papers by Samuel van Nierop
Metabolism: clinical and experimental, 2019
BACKGROUND AND AIMS Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight l... more BACKGROUND AND AIMS Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement. METHODS We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement. RESULTS Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile acid species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandi...
Clinical nutrition, 2017
BACKGROUND & AIMS Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism... more BACKGROUND & AIMS Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism. The physiochemical properties of different BA species affect their enterohepatic dynamics and their affinity for bile acid receptors. The BA pool composition is altered in patients with type 2 diabetes and obesity. In this study we used a 2-week very-low-calorie diet (VLCD) to investigate the effects of weight loss on BA pool composition and postprandial dynamics. METHODS We performed mixed meal tests in obese, insulin resistant subjects before and after the VLCD. We measured postprandial plasma levels of glucose, insulin, BA and the BA-induced enterokine fibroblast growth factor 19 (FGF19). RESULTS The VLCD decreased weight by 4.5 ± 2.3 kg (p < 0.0001) within 14 days. Weight loss increased peak postprandial deoxycholate (DCA) levels (median [IQR]: 0.90 [0.90] vs. 1.25 [1.35] μmol/L; p = 0.045*). Other BA species, glucose, insulin and FGF19 levels and prandial excursions were not si...
The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of p... more The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus on the translation of preclinical studies into clinically applicable findings. Studies in rodents...
American Journal of Physiology-Endocrinology and Metabolism
Context: Bile acids, glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 19 (FGF19) play... more Context: Bile acids, glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1 and FGF19. Objective: First, we investigated the postprandial response to 40-hour fasting. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. Design: Two separate observational randomized crossover studies Subjects: Healthy lean male subjects Intervention: Study 1: a 4-hour mixed meal test after an overnight fast and a 40 hour fast. Study 2: a 4-hour mixed meal test with and without gDCA supplementation. Main outcome measures: postprandial glucose, insulin, bile acids, GLP-1, FGF19. Results: In study 1, 40 hours of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA lev...
Expert opinion on drug metabolism & toxicology, Jan 23, 2016
Knowledge of factors contributing to variation in drug metabolism is of vital importance to optim... more Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2). In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis. The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml-1h-1 (p=0.04) and exposure to omeprazole by 31 % from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by t...
The Journal of clinical endocrinology and metabolism, 2016
Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellul... more Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Bile acid and FGF-19 concentrations. Postprandial total bile acid concentrations increased with increasing meal fat content (P < .05), peaked after 1-2 hours, and were higher in T2D patie...
Nederlands Tijdschrift voor Diabetologie, 2013
Drug metabolism and disposition: the biological fate of chemicals, Jan 20, 2015
Experimental studies indicate that short-term fasting alters drug metabolism. However, the effect... more Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in human need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36h) on CYP450-mediated drug metabolism. In a randomized cross-over study design, nine healthy subjects ingested a cocktail consisting of five CYP-specific probe-drugs (caffeine [CYP1A2], S-warfarin [CYP2C9], omeprazole [CYP2C19], metoprolol [CYP2D6] and midazolam [CYP3A4]) on two occasions (control study after an overnight fast and after 36h of fasting). Blood samples were drawn for pharmacokinetic (PK) analysis using nonlinear mixed effects modeling (NONMEM). In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of CYP-isoforms corresponding with the five studied CYP-enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (p=0.03) a...
Clinical Nutrition, 2013
ABSTRACT
Critical Care Medicine, 2012
Objectives-Patients with diabetes mellitus (DM) form 23-30% of published cohorts of critically il... more Objectives-Patients with diabetes mellitus (DM) form 23-30% of published cohorts of critically ill patients. Conflicting published evidence links DM to both higher and lower mortality. Other cohort studies have suggest that DM protects against acute lung injury (ALI). We hypothesized that DM is an independent risk factor for mortality. We further hypothesized that DM is a risk factor for cardiac overload (CO) and not for ALI.
Metabolism: clinical and experimental, 2019
BACKGROUND AND AIMS Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight l... more BACKGROUND AND AIMS Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement. METHODS We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement. RESULTS Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile acid species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandi...
Clinical nutrition, 2017
BACKGROUND & AIMS Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism... more BACKGROUND & AIMS Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism. The physiochemical properties of different BA species affect their enterohepatic dynamics and their affinity for bile acid receptors. The BA pool composition is altered in patients with type 2 diabetes and obesity. In this study we used a 2-week very-low-calorie diet (VLCD) to investigate the effects of weight loss on BA pool composition and postprandial dynamics. METHODS We performed mixed meal tests in obese, insulin resistant subjects before and after the VLCD. We measured postprandial plasma levels of glucose, insulin, BA and the BA-induced enterokine fibroblast growth factor 19 (FGF19). RESULTS The VLCD decreased weight by 4.5 ± 2.3 kg (p < 0.0001) within 14 days. Weight loss increased peak postprandial deoxycholate (DCA) levels (median [IQR]: 0.90 [0.90] vs. 1.25 [1.35] μmol/L; p = 0.045*). Other BA species, glucose, insulin and FGF19 levels and prandial excursions were not si...
The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of p... more The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus on the translation of preclinical studies into clinically applicable findings. Studies in rodents...
American Journal of Physiology-Endocrinology and Metabolism
Context: Bile acids, glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 19 (FGF19) play... more Context: Bile acids, glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1 and FGF19. Objective: First, we investigated the postprandial response to 40-hour fasting. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. Design: Two separate observational randomized crossover studies Subjects: Healthy lean male subjects Intervention: Study 1: a 4-hour mixed meal test after an overnight fast and a 40 hour fast. Study 2: a 4-hour mixed meal test with and without gDCA supplementation. Main outcome measures: postprandial glucose, insulin, bile acids, GLP-1, FGF19. Results: In study 1, 40 hours of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA lev...
Expert opinion on drug metabolism & toxicology, Jan 23, 2016
Knowledge of factors contributing to variation in drug metabolism is of vital importance to optim... more Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2). In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis. The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml-1h-1 (p=0.04) and exposure to omeprazole by 31 % from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by t...
The Journal of clinical endocrinology and metabolism, 2016
Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellul... more Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Bile acid and FGF-19 concentrations. Postprandial total bile acid concentrations increased with increasing meal fat content (P < .05), peaked after 1-2 hours, and were higher in T2D patie...
Nederlands Tijdschrift voor Diabetologie, 2013
Drug metabolism and disposition: the biological fate of chemicals, Jan 20, 2015
Experimental studies indicate that short-term fasting alters drug metabolism. However, the effect... more Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in human need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36h) on CYP450-mediated drug metabolism. In a randomized cross-over study design, nine healthy subjects ingested a cocktail consisting of five CYP-specific probe-drugs (caffeine [CYP1A2], S-warfarin [CYP2C9], omeprazole [CYP2C19], metoprolol [CYP2D6] and midazolam [CYP3A4]) on two occasions (control study after an overnight fast and after 36h of fasting). Blood samples were drawn for pharmacokinetic (PK) analysis using nonlinear mixed effects modeling (NONMEM). In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of CYP-isoforms corresponding with the five studied CYP-enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (p=0.03) a...
Clinical Nutrition, 2013
ABSTRACT
Critical Care Medicine, 2012
Objectives-Patients with diabetes mellitus (DM) form 23-30% of published cohorts of critically il... more Objectives-Patients with diabetes mellitus (DM) form 23-30% of published cohorts of critically ill patients. Conflicting published evidence links DM to both higher and lower mortality. Other cohort studies have suggest that DM protects against acute lung injury (ALI). We hypothesized that DM is an independent risk factor for mortality. We further hypothesized that DM is a risk factor for cardiac overload (CO) and not for ALI.