The triacylglycerol lowering effect of fatty fish and fish oils is well recognized, however we re... more The triacylglycerol lowering effect of fatty fish and fish oils is well recognized, however we recently showed that salmon intake resulted in higher serum triacylglycerol concentration in obese Zucker fa/fa rats. Since effects of salmon fillet have never before been studied in rats, the objective of this study was to compare effects of salmon intake on serum lipids in hyperlipidemic obese rats with normolipidemic lean rats. Zucker fa/fa rats and Long-Evans rats were fed diets with 25% protein from baked salmon fillet and 75% protein from casein, or casein as sole protein source (control group) for four weeks. Serum triacylglycerol concentration was higher, and cholesterol and apolipoproteinB-100 concentrations were lower in Zucker fa/fa rats fed Baked Salmon Diet compared to Zucker fa/fa rats fed Control Diet, with no differences in serum triacylglycerol, cholesterol and apolipoproteinB-100 between Long-Evans rats fed Baked Salmon Diet or Control Diet. Serum triacylglycerol fatty ac...
Improved process technologies have allowed fishing vessels to utilize residuals from cod fillet p... more Improved process technologies have allowed fishing vessels to utilize residuals from cod fillet production (head, backbone, skin, cuttings, and entrails) and convert this to high-quality protein powders for human consumption. In this double-blind pilot study, 42 healthy overweight or obese adults were randomized to three experimental groups consuming tablets corresponding to 6 g/day of proteins from cod residuals as presscake meal (Cod-PC), presscake and stickwater meal (Cod-PCW), or placebo tablets (control) for eight weeks. The primary outcome of this study was changes in metabolites related to glucose regulation in overweight or obese healthy adults after intake of proteins from cod residuals. Cod-PC supplementation decreased postprandial serum nonesterified fatty acids (NEFA) concentration and increased gene expressions of diglyceride acyltransferase 1 and 2 in subcutaneous adipose tissue compared with controls. Fasting insulin increased while fasting NEFA and 120-min postprandi...
The metabolic effects associated with intake of different dietary protein sources are not well ch... more The metabolic effects associated with intake of different dietary protein sources are not well characterized. We aimed to elucidate how two diets that varied in main protein sources affected the fasting and postprandial serum metabolites and lipid species. In a randomized controlled trial with crossover design, healthy adults ( = 20) underwent a 4-week intervention with two balanced diets that varied mainly in protein source (lean-seafood versus non-seafood proteins). Nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry analyses were applied to examine the effects of the two diets on serum metabolites. In the fasting state, the lean-seafood diet period, as opposed to the non-seafood diet period, significantly decreased the serum levels of isoleucine and valine, and during the postprandial state, a decreased level of lactate and increased levels of citrate and trimethylamine -oxide were observed. The non-seafood diet significantly increased the fasting ...
Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the me... more Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genoty...
The Journal of clinical endocrinology and metabolism, 2018
The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital a... more The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays. Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healt...
The impact of dietary protein types on the gut microbiome is scarcely studied. The aim of the pre... more The impact of dietary protein types on the gut microbiome is scarcely studied. The aim of the present study was therefore to examine the effects of lean-seafood and non-seafood proteins on the gut microbiome composition and activity and elucidate potential associations to cardiovascular disease (CVD) risk factors. A cross-over intervention study in which 20 healthy subjects consumed two diets that varied in protein source was conducted.H NMR spectroscopy and 16S rDNA sequencing analyses were applied to characterize fecal metabolites and gut microbiota composition, respectively. A twofold increase in fecal trimethylamine excretion was observed after the lean-seafood diet period. Circulating TAG and the total- to HDL cholesterol ratio as well as circulating TMAO levels were each associated with specific gut bacteria. Following the non-seafood diet period, a decreased relative abundance of Clostridium cluster IV and a tendency towards an increased Firmicutes/Bacteroidetes ratio were fo...
Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity ... more Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity on clinical and histological phenotype is poorly understood. This study explored abdominal fat volumes and fat distribution quantified by computed tomography (CT), in relation to tumor characteristics and outcome. 227 EC patients with preoperative abdominal CT scans were included. Total abdominal fat volume (TAV), subcutaneous abdominal fat volume (SAV) and visceral abdominal fat volume (VAV) were quantified, and visceral fat percentage calculated (VAV%=[VAV/TAV]x100). Waist circumference (WC) and liver density (LD) were measured, and body mass index (BMI) calculated. Data for estrogen, progesterone and androgen receptor (ERα/PR/AR) expression by immunohistochemistry were available for 149 tumors, and global gene expression data for 105 tumors. High BMI, TAV, SAV, VAV and WC, and low LD, were associated with low grade endometrioid tumors and PR and AR positivity (all p≤0.03). High VAV% w...
The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although... more The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal (30LKKVMRR36) in the human enzyme. Substituting the residues KK31,32 and RR35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell.
The prevalence of type 2 diabetes (T2D) is low in populations with a high fish intake; however pr... more The prevalence of type 2 diabetes (T2D) is low in populations with a high fish intake; however prospective studies with fish intake have shown positive, negative or no association between fish intake and the risk for T2D. The aim of this study was to investigate the effects of high intake of lean or fatty fish on glucose tolerance, leucocyte membrane fatty acid composition and leucocyte function in overweight/obese adults. In this randomised clinical trial, sixty-eight healthy overweight/obese participants consumed 750 g/week of either lean or fatty fish as dinners, or were instructed to continue their normal eating habits but to avoid fish intake (control group), for 8 weeks. Energy and macronutrient intake and physical activity were not changed within the groups during the study period. High intake of fatty fish, but not of lean fish, significantly improved glucose regulation 120 min postprandially (P=0·012), but did not affect fasting glucose concentration. A smaller increase in ...
Journal of the American Heart Association, Feb 3, 2017
Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been o... more Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris. This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl-, octanoyl-, palmitoyl-, propionyl-, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios (HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow-up, 10.0% of the patients died of...
Different aspects of dietary pattern, including macronutrient and food profiles, may affect visce... more Different aspects of dietary pattern, including macronutrient and food profiles, may affect visceral fat mass and metabolic syndrome. We hypothesized that consuming energy primarily from carbohydrate or fat in diets with similar food profiles would differentially affect the ability to reverse visceral adiposity and metabolic syndrome. Forty-six men (aged 30-50 y) with body mass index (in kg/m(2)) >29 and waist circumference >98 cm were randomly assigned to a very high-fat, low-carbohydrate (VHFLC; 73% of energy fat and 10% of energy carbohydrate) or low-fat, high-carbohydrate (LFHC; 30% of energy fat and 53% of energy carbohydrate) diet for 12 wk. The diets were equal in energy (8750 kJ/d), protein (17% of energy), and food profile, emphasizing low-processed, lower-glycemic foods. Fat mass was quantified with computed tomography imaging. Recorded intake of carbohydrate and total and saturated fat in the LFHC and VHFLC groups were 51% and 11% of energy, 29% and 71% of energy, a...
Objectives The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but mod... more Objectives The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. Design and methods Prospective study of DST was carried out in patients with suspected Cushing’s syndrome (CS) (n = 49), incidentaloma (n = 152) and healthy controls (n = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST (n = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST...
This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss... more This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n = 100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n = 45) and without (n = 30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up.
Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We exa... more Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted.
The triacylglycerol lowering effect of fatty fish and fish oils is well recognized, however we re... more The triacylglycerol lowering effect of fatty fish and fish oils is well recognized, however we recently showed that salmon intake resulted in higher serum triacylglycerol concentration in obese Zucker fa/fa rats. Since effects of salmon fillet have never before been studied in rats, the objective of this study was to compare effects of salmon intake on serum lipids in hyperlipidemic obese rats with normolipidemic lean rats. Zucker fa/fa rats and Long-Evans rats were fed diets with 25% protein from baked salmon fillet and 75% protein from casein, or casein as sole protein source (control group) for four weeks. Serum triacylglycerol concentration was higher, and cholesterol and apolipoproteinB-100 concentrations were lower in Zucker fa/fa rats fed Baked Salmon Diet compared to Zucker fa/fa rats fed Control Diet, with no differences in serum triacylglycerol, cholesterol and apolipoproteinB-100 between Long-Evans rats fed Baked Salmon Diet or Control Diet. Serum triacylglycerol fatty ac...
Improved process technologies have allowed fishing vessels to utilize residuals from cod fillet p... more Improved process technologies have allowed fishing vessels to utilize residuals from cod fillet production (head, backbone, skin, cuttings, and entrails) and convert this to high-quality protein powders for human consumption. In this double-blind pilot study, 42 healthy overweight or obese adults were randomized to three experimental groups consuming tablets corresponding to 6 g/day of proteins from cod residuals as presscake meal (Cod-PC), presscake and stickwater meal (Cod-PCW), or placebo tablets (control) for eight weeks. The primary outcome of this study was changes in metabolites related to glucose regulation in overweight or obese healthy adults after intake of proteins from cod residuals. Cod-PC supplementation decreased postprandial serum nonesterified fatty acids (NEFA) concentration and increased gene expressions of diglyceride acyltransferase 1 and 2 in subcutaneous adipose tissue compared with controls. Fasting insulin increased while fasting NEFA and 120-min postprandi...
The metabolic effects associated with intake of different dietary protein sources are not well ch... more The metabolic effects associated with intake of different dietary protein sources are not well characterized. We aimed to elucidate how two diets that varied in main protein sources affected the fasting and postprandial serum metabolites and lipid species. In a randomized controlled trial with crossover design, healthy adults ( = 20) underwent a 4-week intervention with two balanced diets that varied mainly in protein source (lean-seafood versus non-seafood proteins). Nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry analyses were applied to examine the effects of the two diets on serum metabolites. In the fasting state, the lean-seafood diet period, as opposed to the non-seafood diet period, significantly decreased the serum levels of isoleucine and valine, and during the postprandial state, a decreased level of lactate and increased levels of citrate and trimethylamine -oxide were observed. The non-seafood diet significantly increased the fasting ...
Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the me... more Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genoty...
The Journal of clinical endocrinology and metabolism, 2018
The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital a... more The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays. Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healt...
The impact of dietary protein types on the gut microbiome is scarcely studied. The aim of the pre... more The impact of dietary protein types on the gut microbiome is scarcely studied. The aim of the present study was therefore to examine the effects of lean-seafood and non-seafood proteins on the gut microbiome composition and activity and elucidate potential associations to cardiovascular disease (CVD) risk factors. A cross-over intervention study in which 20 healthy subjects consumed two diets that varied in protein source was conducted.H NMR spectroscopy and 16S rDNA sequencing analyses were applied to characterize fecal metabolites and gut microbiota composition, respectively. A twofold increase in fecal trimethylamine excretion was observed after the lean-seafood diet period. Circulating TAG and the total- to HDL cholesterol ratio as well as circulating TMAO levels were each associated with specific gut bacteria. Following the non-seafood diet period, a decreased relative abundance of Clostridium cluster IV and a tendency towards an increased Firmicutes/Bacteroidetes ratio were fo...
Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity ... more Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity on clinical and histological phenotype is poorly understood. This study explored abdominal fat volumes and fat distribution quantified by computed tomography (CT), in relation to tumor characteristics and outcome. 227 EC patients with preoperative abdominal CT scans were included. Total abdominal fat volume (TAV), subcutaneous abdominal fat volume (SAV) and visceral abdominal fat volume (VAV) were quantified, and visceral fat percentage calculated (VAV%=[VAV/TAV]x100). Waist circumference (WC) and liver density (LD) were measured, and body mass index (BMI) calculated. Data for estrogen, progesterone and androgen receptor (ERα/PR/AR) expression by immunohistochemistry were available for 149 tumors, and global gene expression data for 105 tumors. High BMI, TAV, SAV, VAV and WC, and low LD, were associated with low grade endometrioid tumors and PR and AR positivity (all p≤0.03). High VAV% w...
The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although... more The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal (30LKKVMRR36) in the human enzyme. Substituting the residues KK31,32 and RR35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell.
The prevalence of type 2 diabetes (T2D) is low in populations with a high fish intake; however pr... more The prevalence of type 2 diabetes (T2D) is low in populations with a high fish intake; however prospective studies with fish intake have shown positive, negative or no association between fish intake and the risk for T2D. The aim of this study was to investigate the effects of high intake of lean or fatty fish on glucose tolerance, leucocyte membrane fatty acid composition and leucocyte function in overweight/obese adults. In this randomised clinical trial, sixty-eight healthy overweight/obese participants consumed 750 g/week of either lean or fatty fish as dinners, or were instructed to continue their normal eating habits but to avoid fish intake (control group), for 8 weeks. Energy and macronutrient intake and physical activity were not changed within the groups during the study period. High intake of fatty fish, but not of lean fish, significantly improved glucose regulation 120 min postprandially (P=0·012), but did not affect fasting glucose concentration. A smaller increase in ...
Journal of the American Heart Association, Feb 3, 2017
Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been o... more Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris. This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl-, octanoyl-, palmitoyl-, propionyl-, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios (HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow-up, 10.0% of the patients died of...
Different aspects of dietary pattern, including macronutrient and food profiles, may affect visce... more Different aspects of dietary pattern, including macronutrient and food profiles, may affect visceral fat mass and metabolic syndrome. We hypothesized that consuming energy primarily from carbohydrate or fat in diets with similar food profiles would differentially affect the ability to reverse visceral adiposity and metabolic syndrome. Forty-six men (aged 30-50 y) with body mass index (in kg/m(2)) >29 and waist circumference >98 cm were randomly assigned to a very high-fat, low-carbohydrate (VHFLC; 73% of energy fat and 10% of energy carbohydrate) or low-fat, high-carbohydrate (LFHC; 30% of energy fat and 53% of energy carbohydrate) diet for 12 wk. The diets were equal in energy (8750 kJ/d), protein (17% of energy), and food profile, emphasizing low-processed, lower-glycemic foods. Fat mass was quantified with computed tomography imaging. Recorded intake of carbohydrate and total and saturated fat in the LFHC and VHFLC groups were 51% and 11% of energy, 29% and 71% of energy, a...
Objectives The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but mod... more Objectives The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. Design and methods Prospective study of DST was carried out in patients with suspected Cushing’s syndrome (CS) (n = 49), incidentaloma (n = 152) and healthy controls (n = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST (n = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST...
This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss... more This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n = 100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n = 45) and without (n = 30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up.
Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We exa... more Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted.
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Papers by Gunnar Mellgren