We aimed to investigate the effects of a high protein content and a low glycemic index (HPLGI) diet during pregnancy on offspring body composition and metabolic health at 9 years of age. We conducted a randomized controlled trial in pregnant women with a pre-pregnancy BMI of 28–45 kg/m2 who were randomly assigned to either an HPLGI diet or a moderate-protein, moderate-glycemic-index (MPMGI) diet. Of the 208 live-born offspring, 114 were followed up at 9 years of age. Offspring blood samples were collected following an overnight fast, and continuous glucose monitoring data were obtained for up to 14 days. Body composition was assessed using dual-energy X-ray absorptiometry and magnetic resonance imaging. Offspring in the HPLGI group exhibited 0.30 mmol/L (P = 0.033) higher total cholesterol, 0.24 mmol/L (P = 0.031) higher LDL-cholesterol, and 0.03 g/cm2 (P = 0.017) higher bone mineral density than those in the MPMGI group. LDL-cholesterol trajectories from birth to 9 years of age indicated that group differences in LDL-cholesterol increased with age and manifested later in life. Glucose homeostasis and adipose tissue mass did not differ significantly between groups. An HPLGI diet during pregnancy may negatively affect offspring total cholesterol and LDL-cholesterol. This underscores the need to investigate the long-term consequences of high-protein diets and the underlying mechanisms.

OBJECTIVE:To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). METHODS:Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication. RESULTS:High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat. CONCLUSIONS:BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets.

Individuals who undergo pancreatic resection are at increased risk of developing hepatic steatosis. Glucagon is a key regulator of hepatic glucose, amino acids, and lipid metabolism, and the change in circulating glucagon is suggested to contribute to the pathogenesis of postoperative steatotic liver disease. Here, we aimed to elucidate hepatic and metabolic changes induced by pancreatic resection. Fifty individuals scheduled to undergo pancreatic surgery were recruited and evaluated by blood samples and a liver biopsy obtained during surgery. One year after surgery, 21 eligible participants (15 following pancreaticoduodenectomy, 6 following total pancreatectomy) met for a follow-up visit, with the remaining being excluded because of recurrent disease, comorbidities, or death. Follow-up MRS indicated increased liver fat in 12 of 19 participants despite a mean numerical decrease in body weight. Five eligible participants underwent a liver biopsy at follow-up, demonstrating increased liver fat content (largest individual increase: 80 percentage points). Circulating glucagon and C-peptide were significantly reduced at follow-up, with no detection of either following total pancreatectomy. No significant changes in fasting plasma glucose or HbA1c were observed, attributed to relevant exogenous insulin supplementation. Amino acids were markedly increased after both pancreaticoduodenectomy and total pancreatectomy, correlating negatively with remnant endocrine pancreatic function. In conclusion, our data suggest that reduced circulating glucagon levels may contribute to the increased liver fat content and hyperaminoacidemia observed after pancreatic resection. ARTICLE HIGHLIGHTS:Previous studies have demonstrated increased risk of hepatic steatosis in patients following pancreatic resection, which might be linked to decreased pancreatic function. Here, we evaluated liver fat content, circulating pancreatic hormones, amino acids, and more, before and 1 year after either total pancreatectomy or pancreaticoduodenectomy. At 1-year follow-up, we found increased liver fat content in more than half (63%) of the participants, evaluated both by liver histology and magnetic resonance imaging. The participants were characterized by hyperaminoacidemia, which correlated negatively with remnant endocrine pancreatic function. These findings further elucidate the relationship between glucagon, circulating amino acids, and hepatic metabolism.

Pre-pregnancy obesity is linked to an increased risk of adverse maternal and neonatal outcomes, and an increased likelihood of offspring obesity later in life. Accumulation of visceral adipose tissue (VAT) has been reported to be more detrimental to health outcomes than generalized obesity. Therefore, we investigated the association between maternal VAT and the metabolic health of offspring at birth. This study was a secondary analysis of a dietary randomized controlled trial. Magnetic resonance imaging was performed in gestational weeks (GW) 15, 32, and at birth in a cohort of 119 pregnant women with a pre-pregnancy body mass index ranging from 28–45 kg/m2. Offspring anthropometric measurements and cord blood samples were collected at birth. Linear regression models were applied to evaluate the association between maternal VAT and offspring outcomes. Analysis of covariance was utilized to compare offspring outcomes among mothers who exhibited either an increase or a decrease in VAT volume from GW 15 to birth. Absolute maternal VAT during pregnancy was not associated with birthweight; however, women who experienced a reduction in VAT volume during pregnancy entered pregnancy with a higher VAT volume and gave birth to heavier infants by 161 grams (95

OBJECTIVE:The study objective was to evaluate changes in abdominal adipose tissue and ectopic fat during pregnancy and their associations with gestational weight gain (GWG) in women with overweight/obesity. METHODS:This study was a secondary analysis of a randomized controlled trial. Magnetic resonance scans were performed during gestational week (GW) 15, GW 32, and around birth to measure abdominal subcutaneous (SAT) and visceral (VAT) adipose tissues, liver fat, and muscle fat. Linear mixed models and multivariable linear regression analyses were utilized, adjusting for prepregnancy BMI, parity, and randomization. RESULTS:Among 119 women, VAT and SAT decreased from GW 15 to GW 32 but rebounded at birth; final levels were lower than at GW 15. Liver fat and muscle fat did not change significantly. GWG was positively associated with changes in SAT but not with those in VAT, liver fat, or muscle fat. CONCLUSIONS:This study demonstrates dynamic changes in abdominal fat depots during pregnancy in women with overweight/obesity. The observed reduction in VAT and SAT during pregnancy and the association of GWG with SAT suggest that weight gain during pregnancy may be less metabolically harmful than outside pregnancy. Future research should investigate the mechanisms and long-term effects on maternal and child health.

Background: Steatotic liver disease (SLD) represents a multisystem disease and is a common complication of childhood obesity. We studied fat content at the abdominal level (liver, subcutaneous, and visceral) and the response to childhood obesity management. Methods: In this retrospective longitudinal study, 8-18-year-olds with a body mass index (BMI) z-score above 1.28 (corresponding to a BMI above the 90th percentile), as a proxy for obesity, were offered person-centered, family-oriented obesity management in a hospital setting and in a magnetic resonance (MR) scan. Liver fat content (LFC) was assessed by MR spectroscopy, whereas subcutaneous adipose tissue and visceral adipose tissue (VAT) were assessed by MR imaging. We conducted nonparametric tests to evaluate baseline-to-follow-up changes and comparisons between participants with and without an MR assessment. Additionally, a logistic regression model examined the association between changes in LFC and BMI z-score. Results: The study group comprised 1002 children and adolescents (52% females) with an MR assessment at baseline. The median age was 13.0 years, the median BMI was 28.4, and the BMI z-score was 2.90. At baseline, 378 (38%) exhibited SLD defined by an LFC above 1.5%. Among the 322 with a follow-up MR scan, 76% of the patients with SLD reduced their LFC. BMI z-score and VAT (both p < 0.001) were reduced during intervention. Conclusions: SLD is highly prevalent (38%) in children and adolescents with obesity. A chronic care obesity management model reduced the fat content in the liver, the visceral fat, and the degree of obesity.

Previous case–control studies have reported aberrations of the gut microbiota in individuals with prediabetes. The primary objective of the present study was to explore the dynamics of the gut microbiota of individuals with prediabetes over 4 years with a secondary aim of relating microbiota dynamics to temporal changes of metabolic phenotypes. The study included 486 European patients with prediabetes. Gut microbiota profiling was conducted using shotgun metagenomic sequencing and the same bioinformatics pipelines at study baseline and after 4 years. The same phenotyping protocols and core laboratory analyses were applied at the two timepoints. Phenotyping included anthropometrics and measurement of fasting plasma glucose and insulin levels, mean plasma glucose and insulin under an oral glucose tolerance test (OGTT), 2-h plasma glucose after an OGTT, oral glucose insulin sensitivity index, Matsuda insulin sensitivity index, body mass index, waist circumference, and systolic and diastolic blood pressure. Measures of the dynamics of bacterial microbiota were related to concomitant changes in markers of host metabolism. Over 4 years, significant declines in richness were observed in gut bacterial and viral species and microbial pathways accompanied by significant changes in the relative abundance and the genetic composition of multiple bacterial species. Additionally, bacterial-viral interactions diminished over time. Despite the overall reduction in bacterial richness and microbial pathway richness, 80 dominant core bacterial species and 78 core microbial pathways were identified at both timepoints in 99

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.

Context: Studies in heterogeneous groups of people with respect to sex, body mass index (BMI), and glycemic status (normoglycemia, impaired glucose tolerance, diabetes), indicate no relationship between liver fat accumulation and pancreatic insulin secretion. Objective: This work aimed to better understand the association of liver fat with insulin secretion. Methods: A cross-sectional analysis was conducted of 61 men with abdominal obesity who had high liver fat (HLF, >= 5.6% by magnetic resonance spectroscopy, n = 28) or low liver fat (LLF, n = 33), but were balanced on BMI, total body fat, visceral adipose tissue (VAT), and pancreatic fat. A frequently sampled 5-hour oral glucose tolerance test with 11 samples, in conjunction with mathematical modeling, was used to compute indices of insulin sensitivity and insulin secretion (oral minimal model). Results: Compared to individuals with LLF, those with HLF had significantly greater fasting glucose, insulin, C-peptide, and triglycerides; lower high-density lipoprotein cholesterol; but similar glycated hemoglobin A1c. Areas under the 5-hour curve for glucose, insulin, and C-peptide were greater in the HLF group than the LLF group (by similar to 10%, similar to 38%, and similar to 28%, respectively); fasting and total postprandial insulin secretion rates were approximately 37% and approximately 50% greater, respectively (all P < .05); whereas the insulinogenic index was not different. HLF participants had lower whole-body and hepatic insulin sensitivity, disposition index, and total insulin clearance than LLF participants (all P < .05). Conclusion: Accumulation of liver fat is associated with increased insulin secretion independently of total adiposity, abdominal fat distribution, and pancreatic fat. Thereby, hyperinsulinemia in fatty liver disease is partly because of insulin hypersecretion and partly because of impaired insulin clearance.

Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of persons with diabetes. Hyperglucagonemia may arise due to reduced hepatic amino acid turnover and ensuing elevations in glucagonotropic amino acids. We recently observed reduced glucagon sensitivity and hyperglucagonemia in individuals with obesity and hypothesized it to be a consequence of steatosis. Here, we evaluated whether reduced glucagon sensitivity could be induced by a short-term hypercaloric diet intervention designed to increase hepatic fat content in healthy individuals. We recruited 20 healthy, lean individuals (BMI: 23 ± 0.3 (mean ± SD) kg/m2) to follow a hypercaloric diet (~5,000 kcal/day) and a sedentary lifestyle for 2 weeks. Amino acid turnover in response to infusion of glucagon was assessed during a pancreatic clamp with somatostatin and basal insulin. Participants were examined before and after the lifestyle-intervention and again after 8 weeks to assess the reversibility of any metabolic changes. Hepatic steatosis was assessed by magnetic resonance spectroscopy. The intervention led to increases in body weight (3.5 [2.8;4.2] (mean [95% confidence interval]) kg, P < 0.0001) and hepatic fat content (382 [206;705]%, P < 0.001). Insulin resistance was evident with unchanged fasting blood glucose levels and a 56% increase in fasting insulin (P < 0.001). Glucagon infusion led to a decrease in the concentration of total amino acids, but the percentage change in total amino acids was reduced (−2.5 ± 0.5 vs. −0.2 ± 0.7%, P = 0.015) and the average slope of the total amino acid curve was less steep (−2.0 ± 1.2 vs. −1.2 ± 0.3 μM/min, P = 0.016) after the intervention compared to baseline. All metabolic changes were normalized at follow-up. Our results indicate that short-term unhealthy behavior increasing hepatic fat content causes a reversible resistance to the effect of glucagon on amino acid turnover in healthy individuals, which may explain hyperglucagonemia associated with obesity and diabetes. Disclosure M.P.Suppli: None. J.I.Bagger: Speaker's Bureau; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.

Aims Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver–α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver–α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. Methods We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1 H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Results Individuals with NAFLD ( n = 52) had higher plasma glucagon concentrations than individuals without NAFLD ( n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. Conclusion MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.

Objectives: Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men. Methods: In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures. Results: Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI −0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed. Conclusions: In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insul in resistance or other glucometabolic perturbations.

Background & aims: In recent years, epidemiological studies have reported links between the consumption of fermented dairy products, such as yogurt, and health; however, evidence from human intervention trials is scarce and inconsistent. We aimed to investigate the effect of consumption of four different types of dairy products (two fermented and two non-fermented) on liver fat (primary outcome) and metabolic risk markers in males with abdominal obesity. Methods: In this parallel randomized controlled trial with four arms, 100 males aged 30-70 years, with body mass index 28.0-45.0 kg/m(2), and waist circumference >= 102 cm underwent a 16-weeks intervention where they were instructed to consume 400 g/day of either milk, yogurt, heat-treated yogurt, or acidified milk as part of their habitual diet. Liver fat was measured by magnetic resonance imaging. Results: In the complete case analyses (n = 80), no effects of the intervention or differences between groups were detected in anthropometry or body composition including liver fat. Moreover, no effects were detected in inflammatory markers. Main effects of time were detected in blood pressure (decrease; P < 0.001), insulin (decrease; P < 0.001), C-peptide (decrease; P = 0.040), homeostatic model assessment for insulin resistance (decrease; P < 0.001), total cholesterol (decrease; P = 0.016), low-density lipoprotein (decrease; P = 0.033), high-density lipoprotein (decrease; P = 0.006), and alanine transaminase (decrease; P = 0.019). Interactions between group and time failed to reach significance. Conclusions: In conclusion, findings from our study do not confirm that fermented yogurt products are superior in reducing liver fat or improving metabolic risk markers compared to non-fermented milk products. In fact, all intervention products (both fermented yogurt products and non-fermented milk products) did not affect liver fat and caused largely similar modest favorable changes in some metabolic risk markers. The study was registered at www. (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND & AIMS:Genome-wide association studies have identified steatogenic variants that also showed pleiotropic effects on cardiometabolic traits in adults. We investigated the effect of eight previously reported genome-wide significant steatogenic variants, individually and combined in a weighted genetic risk score (GRS), on liver and cardiometabolic traits, and the predictive ability of the GRS for hepatic steatosis in children and adolescents. APPROACH & RESULTS:Children and adolescents with overweight (including obesity) from an obesity clinic group (n = 1768) and a population-based group (n = 1890) were included. Cardiometabolic risk outcomes and genotypes were obtained. Liver fat was quantified using 1 H-MRS in a subset of 727 participants. Variants in PNPLA3, TM6SF2, GPAM and TRIB1 were associated with higher liver fat (p < .05) and with distinct patterns of plasma lipids. The GRS was associated with higher liver fat content, plasma concentrations of alanine transaminase (ALT), aspartate aminotransferase (AST) and favourable plasma lipid levels. The GRS was associated with higher prevalence of hepatic steatosis (defined as liver fat ≥5.0%) (odds ratio per 1-SD unit: 2.17, p = 9.7E-10). A prediction model for hepatic steatosis including GRS alone yielded an area under the curve (AUC) of 0.78 (95% CI 0.76-0.81). Combining the GRS with clinical measures (waist-to-height ratio [WHtR] SDS, ALT, and HOMA-IR) increased the AUC up to 0.86 (95% CI 0.84-0.88). CONCLUSIONS:The genetic predisposition for liver fat accumulation conferred risk of hepatic steatosis in children and adolescents. The liver fat GRS has potential clinical utility for risk stratification.

Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes. This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48–97 mmol/mol (6.5–11%), BMI >25 kg/m2, eGFR >30 ml min−1 [1.73 m]−2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev). Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] −1.9 [−3.5, −0.3] mmol/mol [−0.18 (−0.32, −0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] −0.8 [−1.2, −0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] −4.1 [−5.9, −2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] −18 [−29, −6]%, p < 0.01) and liver fat content (by mean [95% CI] −26 [−45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets. Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies. ClinicalTrials.gov NCT03814694. The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.

Alternate-day fasting induces oscillations in energy stores. We hypothesized that repeated oscillations increases insulin secretion and sensitivity, and improve metabolic health in patients with obesity with or without type 2 diabetes (T2DM). Twenty-three male patients fasted every other day for 30 h for 6 weeks. Experiments included resting energy expenditure, continuous glucose monitoring, intravenous glucose tolerance test, euglycemic hyperinsulinemic clamp, body composition, hepatic triglyceride content, muscle biopsies which were performed at baseline, during 3 weeks without allowed weight loss, and after additional 3 weeks with weight loss. Bodyweight decreased ∼1% and further ∼3% during weeks one to three and four to six, respectively ( p < 0.05). Only minor changes in fat mass occurred in weeks 1–3. With weight loss, visceral fat content decreased by 13 ± 3% and 12 ± 2% from baseline in patients with and without T2DM, respectively ( p < 0.05). Hepatic triglyceride content decreased by 17 ± 9% and 36 ± 9% (with diabetes) and 27 ± 8% and 40 ± 8% (without diabetes) from baseline to week 3 and week 6, respectively (all p < 0.05). Muscle lipid and glycogen content oscillated with the intervention. Glucose homeostasis, insulin secretion and sensitivity was impaired in patients with T2DM and did not change without weight loss, but improved ( p < 0.05) when alternate day fasting was combined with weight loss. In conclusion, alternate-day fasting is feasible in patients with obesity and T2DM, and decreases visceral fat and liver fat deposits. Energy store oscillations by alternate-day fasting do not improve insulin secretion or sensitivity per se . Clinical Trial registration: ( ClinicalTrials.gov ), (ID NCT02420054).

AIM:To evaluate the effect of curcumin treatment on hepatic fat content in obese individuals. MATERIALS AND METHODS:In a double-blind, parallel-group trial, 37 obese, non-diabetic individuals were randomized to placebo or curcumin treatment for 6 weeks. Curcumin was dosed as lecithin-formulated tablet; 200 mg twice daily. The primary endpoint was hepatic fat content as assessed by magnetic resonance spectroscopy (MRS). Other endpoints included anthropometric measurements, hepatic biomarkers including FibroScan measurements, metabolic variables, inflammation markers, appetite measures and ad libitum food intake. RESULTS:Baseline characteristics (mean ± SD) were age 46 ± 14 years, hepatic fat content 12.2% ± 8.8% points, body mass index 38.8 ± 6.1 kg/m2 and waist circumference 125.8 ± 12.3 cm. After 6 weeks of treatment with curcumin, hepatic fat content was changed by -0.86% points (95% CI -3.65; 1.94) compared with 0.71% points (95% CI - 2.08; 3.51) with placebo, thus resulting in a non-significant estimated treatment difference of -1.57% points (95% CI -5.36; 2.22, P = .412). Compared with placebo, curcumin treatment caused small reductions in fasting plasma glucose (estimated treatment difference [ETD] - 0.24 mmol/L [95% CI -0.45; -0.03]), triglycerides (ETD [percentage change] -20.22% [95% CI -33.21; -6.03]) and gamma glutamyltransferase (ETD [percentage change] -15.70% [95% CI -23.32; -7.32]), but except for gamma glutamyltransferase, none of these differences remained statistically significant after adjusting for multiple testing. Treatment was well tolerated. CONCLUSIONS:Compared with placebo, curcumin treatment for 6 weeks had no significant effect on MRS-assessed hepatic fat content in obese individuals with primarily mild steatosis. Curcumin was well tolerated.

BACKGROUND:Prepregnancy overweight and excessive gestational weight gain (GWG) increase the risk of complications and offspring obesity. OBJECTIVES:We aimed to investigate the effect of a high-protein low-glycemic index (HPLGI) diet on GWG, birth weight, and risk of gestational complications in pregnant women with obesity. METHODS:A total of 279 women with prepregnancy overweight or obesity (BMI: 28-45 kg/m2), between 18 and 45 y old, and in their late first trimester with singleton pregnancies, were randomly assigned to 1 of 2 ad libitum diets: a high-protein low-glycemic index diet (HPLGI: 25%-28% of energy from protein and glycemic index ≤ 55) and a moderate-protein moderate-glycemic index diet (MPMGI: 15%-18% of energy from protein and glycemic index ∼60). Diets were consumed from gestational week 15 and throughout pregnancy. Participants received dietary guidance by a clinical dietician 9 times to facilitate adherence. RESULTS:Out of 141 and 138 women randomly assigned to the HPLGI and MPMGI diets, 105 and 104 completed the intervention, respectively (75%). In the available case analyses, GWG was 6.8 ± 1.3 kg among women assigned the HPLGI diet and this was significantly lower, by -1.7 kg (95% CI: -2.8, -0.5 kg; P = 0.004), than the GWG of 8.5 ± 1.3 kg among women assigned the MPMGI diet. There were no significant differences between diets on major neonatal outcomes (birth weight and other anthropometric measures). The incidence of composite pregnancy complications was lower for the HPLGI than for the MPMGI diet (35.4% compared with 53.7%, respectively; P = 0.009), including cesarean delivery (15.4% compared with 28.8%, respectively; P = 0.03). There were no reported maternal, fetal, or neonatal deaths. Incidence of miscarriages (1%-2%) did not differ between groups. CONCLUSIONS:A moderate increase in dietary protein in conjunction with a reduction in glycemic index during the last 2 trimesters of pregnancy reduced GWG and limited complications and cesarean deliveries among women with overweight or obesity.

BACKGROUND:Diagnosis of nonalcoholic fatty liver disease in children and adolescents currently requires advanced or invasive technologies.OBJECTIVES:We aimed to develop a method to improve diagnosis, using body composition indices and liver biochemical markers.METHODS:To diagnose non-alcoholic fatty liver disease, 767 Danish children and adolescents underwent clinical examination, blood sampling, whole-body dual-energy X-ray absorptiometry scanning and proton magnetic resonance spectroscopy for liver fat quantification. Fourteen variables were selected as a starting point to construct models, narrowed by stepwise selection. Individuals were split into a training set for model construction and a validation test set. The final models were applied to 2120 Danish children and adolescents to estimate the prevalence.RESULTS:The final models included five variables in different combinations: body mass index-standard deviation score, android-to-gynoid-fat ratio, android-regional fat percent, trunk-regional fat percent and alanine transaminase. When validated, the sensitivity and specificity ranged from 38.6% to 51.7% and 87.6% to 91.9%, respectively. The estimated prevalence was 24.2%-35.3%. Models including alanine transaminase alongside body composition measurements displayed higher sensitivity.CONCLUSIONS:Body composition indices and alanine transaminase can be used to estimate non-alcoholic fatty liver disease, with 38.6%-51.7% sensitivity and 87.6%-91.9%, specificity, in children and adolescents with overweight (including obesity). These estimated a 24.2%-35.3% prevalence in 2120 patients.