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Background: Intrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions. Objectives: We hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism. Methods: A randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation. Results: Eleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: −46.6, −24.1) from 4.9% [2.4–11.0] (median interquartile range) to 2.9% [1.4–6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged. Conclusions: Reduced carbohydrate and increased fat intake for 4 d induced a marked red

Background: The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health. Methods: In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.4 ± 4.3 years, BMI 24.5 ± 2.5 kg/m2) participated. The intervention involved oral intake of carrageenan (250 mg) or placebo in the morning and in the evening and each intervention lasted 2 weeks. The primary outcome measured was insulin sensitivity (using oral glucose tolerance test [OGTT] and hyperinsulinaemic-euglycaemic clamp). Additional end-points included whole body and hepatic insulin sensitivity, MRI-measured brain inflammation and insulin resistance, intestinal permeability (via lactulose-mannitol test and plasma zonulin levels), and gut microbiome composition. Immune-cell activation and pro-inflammatory cytokine release from peripheral blood mononuclear cells were measured. Results: Overall insulin sensitivity did not show significant differences between the treatments. However, interactions between BMI and treatment were observed (OGTT-based insulin sensitivity index: p=0.04, fasting insulin resistance:p=0.01, hepatic insulin sensitivity index: p=0.04). In overweight participants, carrageenan exposure resulted in lower whole body and hepatic insulin sensitivity, a trend towards increased brain inflammation, and elevated C-reactive protein (CRP) and IL-6 levels compared to placebo. Additionally, carrageenan was associated with increased intestinal permeability. In vitro natural killer (NK-)cell activation and increased pro-inflammatory cytokine release were found after carrageenan exposure in the participant’s peripheral blood mononuclear cells. Conclusions: These findings sug

Background: In humans, intraduodenal infusion of L-tryptophan (Trp) increases plasma concentrations of gastrointestinal hormones and stimulates pyloric pressures, both key determinants of gastric emptying and associated with potent suppression of energy intake. The stimulation of gastrointestinal hormones by Trp has been shown, in preclinical studies, to be enhanced by extracellular calcium and mediated in part by the calcium-sensing receptor. Objectives: This study aim was to determine whether intraduodenal calcium can enhance the effects of Trp to stimulate gastrointestinal hormones and pyloric pressures and, if so, whether it is associated with greater suppression of energy intake, in healthy males. Methods: Fifteen males with normal weight (mean ± standard deviation; age: 26 ± 7 years; body mass index: 22 ± 2 kg/m2), received on 3 separate occasions, 150-min intraduodenal infusions of 0, 500, or 1000 mg calcium (Ca), each combined with Trp (load: 0.1 kcal/min, with submaximal energy intake-suppressant effects) from t = 75–150 min, in a randomized, double-blind, crossover study. Plasma concentrations of GI hormones [gastrin, cholecystokinin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and peptide tyrosine-tyrosine (PYY)], and Trp and antropyloroduodenal pressures were measured throughout. Immediately postinfusions (t = 150–180 min), energy intake at a standardized buffet-style meal was quantified. Results: In response to calcium alone, both 500- and 1000-mg doses stimulated PYY, while only the 1000-mg dose stimulated GLP-1 and pyloric pressures (all P < 0.05). The 1000-mg dose also enhanced the effects of Trp to stimulate cholecystokinin and GLP-1, and both doses stimulated PYY but, surprisingly, reduced the stimulation of GIP (all P < 0.05). Both doses substantially and dose dependently enhanced the effects of Trp to suppress energy intake (Ca-0+Trp: 1108 ± 70 kcal; Ca-500+Trp: 961 ± 90 kcal; and Ca-1000

The main objective of the study was to investigate the effects of prenatal exercise interventions on maternal body composition at 28 weeks gestation and 7–14 days after delivery. We also explored associations between physical activity (PA) per se and body composition. This study presents secondary outcomes of the FitMum randomized controlled trial, which included healthy inactive pregnant women at gestational age 15+0 weeks. They were randomized to structured supervised exercise training, motivational counselling on PA, or standard care. Maternal body composition was measured by doubly labeled water at 28 weeks gestation (n = 134) and by dual-energy X-ray absorptiometry scan 7–14 days after delivery (n = 117). PA, including moderate-to-vigorous-intensity PA (MVPA), active kilocalories, and steps, were measured continuously from inclusion to delivery by a wrist-worn activity tracker. One hundred fifty pregnant women were included with a median pre-pregnancy body mass index (BMI) of 24.1 (21.6–27.9) kg/m2. We found no differences between groups in fat mass, fat percentage or fat-free mass at 28 weeks gestation or 7–14 days after delivery. Visceral adipose tissue mass and bone mineral density measured 7–14 days after delivery did not differ between groups either. Linear regression analyses adjusted for pre-pregnancy BMI showed that a higher number of daily steps was associated with lower fat mass, fat percentage, and visceral adipose tissue mass at 28 weeks gestation and 7–14 days after delivery. Active kilocalories during pregnancy was positively associated with fat-free mass 7–14 days after delivery. Neither structured supervised exercise training nor motivational counselling on PA during pregnancy affected maternal body composition at 28 weeks gestation or 7–14 days after delivery compared to standard care. Interestingly, when adjusted for pre-pregnancy BMI, higher number of daily steps was associated with lower fat content during pregnancy and after d

It is not completely clear which organs are responsible for glucagon elimination in humans, and disturbances in the elimination of glucagon could contribute to the hyperglucagonemia observed in chronic liver disease and chronic kidney disease (CKD). Here, we evaluated kinetics and metabolic effects of exogenous glucagon in individuals with stage 4 CKD (n =16), individuals with Child-Pugh A-C cirrhosis (n = 16) and matched control individuals (n = 16), before, during and after a 60-minute glucagon infusion (4 ng/kg/min). Individuals with CKD exhibited a significantly lower mean metabolic clearance rate of glucagon (14.0 [95% CI 12.2;15.7] mL/kg/min) both compared to individuals with cirrhosis (19.7 [18.1;21.3] mL/kg/min, P < 0.001) and to control individuals (20.4 [18.1;22.7] mL/kg/min, P < 0.001). Glucagon half-life was significantly prolonged in the CKD group (7.5 [6.9;8.2] minutes) compared to individuals with cirrhosis (5.7 [5.2;6.3] minutes, P = 0.002) and control individuals (5.7 [5.2;6.3] minutes, P < 0.001). No difference in the effects of exogenous glucagon on plasma glucose, amino acids, or triglycerides was observed between groups. In conclusion, chronic kidney disease, but not liver cirrhosis leads to a significant reduction in glucagon clearance, supporting the kidneys as a primary site for human glucagon elimination.

OBJECTIVE: The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. METHODS: Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4 ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. RESULTS: Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. CONCLUSION: Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.

Background: Sarcopenia is thought to be underlined by age‐associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageing per se or other confounding factors. Methods: Lean and healthy young (n = 10, 22 ± 3 years, BMI; 23.4 ± 0.8 kg/m2) and old men (n = 10, 70 ± 3 years, BMI; 22.7 ± 1.3 kg/m2) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after and 60 and 180 min after EAA intake. Muscle samples were analysed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signalling. Results: Following exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was ~11% and ~28% lower in Young (p < 0.01). Absolute levels of muscle EAA and leucine peaked 60 min after exercise, with ~15 and ~21% higher concentrations in the exercising leg (p < 0.01) but with no difference between groups. MPS increased in both the resting (~0.035%·h−1 to 0.056%·h−1, p < 0.05) and exercising leg (~0.035%·h−1 to 0.083%·h−1, p < 0.05) with no difference between groups. Phosphorylation of S6K1Thr389 increased to a similar extent in the exercising leg in both groups but was 2.8‐fold higher in the resting leg of Old at the 60 min timepoint (p < 0.001). Phosphorylation of 4E‐BP1Ser65 increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (p < 0.001). However, phosphorylation of this site was on average 78% greater across all timepoints in Old (p < 0.01). Phosphorylation of eEF2Thr56 was reduced (~66% and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (p < 0.05). However, phosphorylation at this site was reduced by ~27% also in the resting leg at 60 min, an effect that was only seen in O

Objective: In obesity and type 2 diabetes, hyperglucagonaemia may be caused by elevated levels of glucagonotropic amino acids due to hepatic glucagon resistance at the level of amino acid turnover. Here, we investigated the effect of exogenous glucagon on circulating amino acids in obese and non-obese individuals with and without type 2 diabetes. Design: This was a post hoc analysis in a glucagon infusion study performed in individuals with type 2 diabetes (n = 16) and in age, sex, and body mass index-matched control individuals without diabetes (n = 16). Each group comprised two subgroups of eight individuals with and without obesity, respectively. Methods: All participants received a 1-h glucagon infusion (4 ng/kg/min) in the overnight fasted state. Plasma amino acid concentrations were measured with frequent intervals. Results: Compared to the control subgroup without obesity, baseline total amino acid levels were elevated in the control subgroup with obesity and in the type 2 diabetes subgroup without obesity. In all subgroups, amino acid levels decreased by up to 20% in response to glucagon infusion, which resulted in high physiological steady-state glucagon levels (mean concentration: 74 pmol/L, 95% CI [68;79] pmol/L). Following correction for multiple testing, no intergroup differences in changes in amino acid levels reached significance. Conclusion: Obesity and type 2 diabetes status was associated with elevated fasting levels of total amino acids. The glucagon infusion decreased circulating amino acid levels similarly in all subgroups, without significant differences the response to exogenous glucagon between individuals with and without obesity and type 2 diabetes. Significance statement The hormone glucagon stimulates glucose production from the liver, which may promote hyperglycaemia if glucagon levels are abnormally elevated, as is often seen in type 2 diabetes and obesity. Glucagon levels are closely linked to, and influenced by, the levels of circu

OBJECTIVE Insulin remains the only glucose-lowering treatment modality recommended for totally pancreatectomized patients. We investigated the effects of the sodium–glucose cotransporter 2 inhibitor empagliflozin on fasting and postprandial glucose concentrations in pancreatectomized patients and matched healthy control participants. RESEARCH DESIGN AND METHODS In a randomized, double-blind, placebo-controlled crossover study, 10 pancreatectomized patients and 10 matched control participants underwent two 3-h liquid mixed meal tests preceded by two doses of 25 mg empagliflozin (administered the night before and in the morning of the meal test) or placebo, respectively. Basal insulin was administered as usual, but bolus insulin was omitted before the meal test during experimental days. RESULTS Compared with placebo, empagliflozin lowered fasting plasma glucose (5.0 ± 0.4 vs. 7.9 ± 0.9 mmol/L [mean ± SEM], P = 0.007) and postprandial plasma glucose excursions as assessed by baseline-subtracted area under the curve (1,080 [733; 1,231] vs. 1,169 [1,036; 1,417] pmol/L × min [median (25th and 75th percentiles)], P = 0.014) in the pancreatectomized patients. In the control participants, empagliflozin lowered fasting plasma glucose compared with placebo (5.1 ± 0.1 vs. 5.5 ± 0.1 mmol/L, P = 0.008) without affecting postprandial glucose excursions significantly. The pancreatomy group exhibited greater postprandial glucagon excursions compared with the control group on both experimental days (P ≤ 0.015); no within-group differences between days were observed. CONCLUSIONS Empagliflozin administered the day before and immediately before a standardized liquid mixed meal test normalized fasting hyperglycemia and improved postprandial glucose tolerance in pancreatectomized patients., OBJECTIVE: Insulin remains the only glucose-lowering treatment modality recommended for totally pancreatectomized patients. We investigated the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on fasting and postprandial glucose concentrations in pancreatectomized patients and matched healthy control participants. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled crossover study, 10 pancreatectomized patients and 10 matched control participants underwent two 3-h liquid mixed meal tests preceded by two doses of 25 mg empagliflozin (administered the night before and in the morning of the meal test) or placebo, respectively. Basal insulin was administered as usual, but bolus insulin was omitted before the meal test during experimental days. RESULTS: Compared with placebo, empagliflozin lowered fasting plasma glucose (5.0 ± 0.4 vs. 7.9 ± 0.9 mmol/L [mean ± SEM], P = 0.007) and postprandial plasma glucose excursions as assessed by baseline-subtracted area under the curve (1,080 [733; 1,231] vs. 1,169 [1,036; 1,417] pmol/L × min [median (25th and 75th percentiles)], P = 0.014) in the pancreatectomized patients. In the control participants, empagliflozin lowered fasting plasma glucose compared with placebo (5.1 ± 0.1 vs. 5.5 ± 0.1 mmol/L, P = 0.008) without affecting postprandial glucose excursions significantly. The pancreatomy group exhibited greater postprandial glucagon excursions compared with the control group on both experimental days (P ≤ 0.015); no within-group differences between days were observed. CONCLUSIONS: Empagliflozin administered the day before and immediately before a standardized liquid mixed meal test normalized fasting hyperglycemia and improved postprandial glucose tolerance in pancreatectomized patients.