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Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill‐defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry‐based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual‐specific protein levels with wide‐ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte‐secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of −16% and +37%, respectively ( P  < 10 −13 ), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten‐protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases. Synopsis Longitudinal plasma proteome profiling of 52 obese individuals during weight loss and maintenance reveals 93 significantly altered proteins, including panels correlating with inflammation and insulin resistance. 1,294 plasma proteomes are measured by single‐run mass spectrometry. 93 significantly changed plasma proteins are detected upon weight loss. Global changes in the apolipoprotein family reflect metabolic risk. A ten‐protein low‐grade inflammation and an insulin resistance panel are defined. Graphical Abstract Longitudinal plasma proteome profiling of 52 obese individuals during weight loss and maintenance reveals 93 significantly altered proteins, including panels correlating with inflammation and insulin resistance.

Background Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. Methods This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo , moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model. Results The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (− 0.37, 95% CI − 0.58 to − 0.16, P < 0.001) and the combination treatment (− 0.48, 95% CI − 0.70 to − 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). Conclusion The combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments. Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716

Aims/hypothesisThe secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon.MethodsTo examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance.ResultsFasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon–alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels.Conclusions/interpretationThis cross-sectional study supports the existence of a liver–alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon–alanine index is suggested as a relevant marker for hepatic glucagon signalling.

Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation Camilla H. Andreasen 1 , Kirstine L. Stender-Petersen 1 , Mette S. Mogensen 1 , Signe S. Torekov 1 , Lise Wegner 1 , Gitte Andersen 1 , Arne L. Nielsen 1 , Anders Albrechtsen 2 , Knut Borch-Johnsen 1 3 4 , Signe S. Rasmussen 1 , Jesper O. Clausen 1 , Annelli Sandbæk 5 , Torsten Lauritzen 5 , Lars Hansen 6 , Torben Jørgensen 3 , Oluf Pedersen 1 4 and Torben Hansen 1 1 Steno Diabetes Center, Gentofte, Denmark 2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark 3 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark 4 Faculty of Health Science, University of Aarhus, Aarhus, Denmark 5 Department of General Practice, University of Aarhus, Aarhus, Denmark 6 Science and Medicine, Novo Nordisk, Bagsværd, Denmark Address correspondence and reprint requests to Camilla H. Andreasen, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13, DK-2820 Gentofte, Denmark. E-mail: cila{at}novonordisk.com Abstract OBJECTIVE— Three independent studies have shown that variation in the fat mass and obesity-associated ( FTO ) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. RESEARCH DESIGN AND METHODS— The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups. RESULTS— In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06–1.20], P = 9 × 10 −5 ). This association was abolished when adjusting for BMI (1.06 [0.97–1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13–1.24], P = 1 × 10 −12 ) and obesity (1.27 [1.20–1.34], P = 2 × 10 −16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity ( P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 ± 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers. CONCLUSIONS— We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation. BIGTT, β-cell function, insulin sensitivity, and glucose tolerance testing BIGTT-AIR, BIGTT acute insulin response BIGTT-Si, BIGTT insulin sensitivity index SDC, Steno Diabetes Center SNP, single-nucleotide polymorphism Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 17 October 2007. DOI: 10.2337/db07-0910. C.H.A. and K.L.S.-P. contributed equally to this article. K.B.-J. has received honorarium for invited lectures by Novo Nordisk, Bristol-Myers Squibb, Novartis, Pfizer, Hermedico, and AstraZeneca. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0910 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 10, 2007. Received July 4, 2007. DIABETES

Objective Overweight and obesity in pregnant women have been associated with an increased risk of depression and anxiety, but the strength of these associations and the influence of confounders remain uncertain. Understanding these associations may help identify women at risk in early pregnancy and guide targeted support. This study aimed to quantify associations between maternal body mass index (BMI) and symptoms of depression, anxiety, and health-related quality of life (HRQoL) in early pregnancy and to assess whether they persisted after adjustment for confounders. Methods This secondary analysis pooled baseline data from three randomised controlled trials including women at gestational week 10 + 0 to 20 + 0: LIMIT (BMI ≥ 25.0 kg/m²), GRoW (BMI ≥ 25.0 kg/m²) and OPTIMISE (BMI ≥ 18.5 to ≤ 24.9 kg/m²). LIMIT and OPTIMISE randomised participants to lifestyle intervention or standard care. In GRoW all women received a lifestyle intervention and were randomised to metformin or placebo. At baseline, women completed questionnaires assessing symptoms of depression, anxiety, and HRQoL (SF-12 or SF-36). Results 2961 pregnant women (mean BMI: 29.3 kg/m 2 ; mean age: 30.1 years) completed at least one questionnaire, including 1815 (61%) from LIMIT, 513 (17%) from GRoW, and 633 (21%) from OPTIMISE. Higher BMI was associated with an increase in depressive and anxiety symptoms in unadjusted analyses. After adjustment, only the association with depressive symptoms remained significant (β = 0.05, 95% CI 0.02, 0.08). BMI was inversely associated with physical HRQoL (β SF−12 =-0.36, 95% CI -0.45, -0.27; β SF−36 =-0.18, 95% CI -0.25, -0.11). Mental HRQoL was positively associated with BMI using SF-12 (β SF−12  = 0.18, 95% CI 0.08, 0.29) but showed no association with BMI using SF-36 (β SF−36 =-0.07, 95% CI -0.15, 0.02). Conclusion Increasing BMI was associated with higher depressive symptoms and poorer physical HRQoL in early pregnancy, but effect sizes were small, inconsistent, and attenuated after adjustment, suggesting modest associations partly explained by confounding. These findings highlight the need for a holistic approach to supporting mental health in pregnant women with overweight or obesity, as multiple factors beyond body weight likely contribute. Trial registration Australian New Zealand Clinical Trials Registry; LIMIT (ACTRN12607000161426, 9 March 2007); OPTIMISE (ACTRN12614000583640, 30 May 2014); GRoW (ACTRN12612001277831, 10 December 2012).

Loss-of-function (LoF) mutations in KCNQ1 , encoding the voltage-gated K + channel K v 7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of K v 7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that K v 7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.

IntroductionThe global prevalence of people living with overweight has tripled since 1975 and more than 40% of Danish women enter pregnancy being overweight. With the increasing rates of obesity observed in children, adolescents and adults, there is an urgent need for preventive measures. Risk factors for childhood obesity include maternal overweight or obesity before conception and excessive weight gain during pregnancy. Interventions aimed at modifying maternal lifestyle during pregnancy have demonstrated minimal positive or no impact on the health of the children. The ‘healthy lifestyle before and during pregnancy to prevent childhood obesity — the PRE-STORK trial’ aims to provide insights into the effect of a lifestyle intervention initiated before conception and continued during pregnancy in women with overweight or obesity, on neonatal adiposity in their children.Methods and analysisIn this randomised, two-arm, parallel-group, controlled trial, we will include 360 women with overweight or obesity (aged 18–40; body mass index 25–44 kg/m2) and their partners. The women will be randomised to receive either standard of care or a lifestyle intervention focused on preconception body weight reduction, regular physical exercise, healthy diet and support from a mentor before and during pregnancy. The primary outcome is the difference in neonatal adiposity measured in their children at birth. Children conceived during the trial will constitute a birth cohort, monitoring the effects on their health until the age of 18 years.Ethics and disseminationThe trial has been approved by the Regional Committee on Health Research Ethics in the Capital Region of Denmark (identification number H-22011403) and will be conducted in agreement with the Declaration of Helsinki. All results, whether positive, negative and inconclusive, will be disseminated at national or international scientific meetings and in peer-reviewed scientific journals.Trial registration numberClinicalTrials.gov: NCT05578690 (October 2022).

IntroductionThe aim of this study is to investigate the effects of time-restricted eating (TRE) on change in body weight and describe changes in behaviour and metabolism in individuals at high risk of type 2 diabetes.Methods and analysisThe REStricted Eating Time (RESET) study is a randomised controlled parallel-group open-label trial. 100 women and men with (1) overweight (body mass index (BMI)≥25 kg/m2) and prediabetes (glycated haemoglobin 39–47 mmol/mol); or (2) obesity (BMI≥30 kg/m2) will be randomised to a control group (habitual living) or TRE (self-selected 10-hours eating window within the period from 06:00 to 20:00 in a 1:1 ratio. Testing is scheduled at baseline and after 6 weeks (mid-intervention), 3 months (post-intervention) and 6 months (follow-up). The primary outcome is change in body weight after 3 months of intervention. Secondary outcomes include changes in body composition; measures of glucose metabolism including glycaemic variability, hormones and metabolites; subjective and metabolic markers of appetite, food preferences and reward; dietary intake; physical activity, sleep, chronotype; gastric emptying, gastrointestinal transit time and motility; respiratory and glycolytic capacities; the plasma proteome and metabolome; blood pressure, resting heart rate and heart rate variability; and resting energy expenditure and substrate oxidation. Motivation and feasibility will be examined based on interviews at baseline and after 3 months. After the 3-month intervention, a 3-month follow-up period and subsequent testing are scheduled to assess maintenance and longer-term effects.Ethics and disseminationThe study has been approved by the Ethics Committee of the Capital Region of Denmark (H-18059188) and the Danish Data Protection Agency. The study will be conducted in accordance with the Declaration of Helsinki. Results from the study will address whether TRE is effective and feasible in improving health outcomes in individuals at risk of lifestyle-related diseases and can potentially inform the design of feasible health recommendations.Trial registration numberNCT03854656.

Pathogenic mutations in the melanocortin-4 receptor (MC4R) are associated with obesity, increased linear growth, and higher bone mass in children, and rodent studies have indicated an effect of the MC4R on bone turnover. Furthermore, GLP-1 receptor agonists (GLP-1 RAs) may influence bone metabolism. However, these associations have not been assessed in adults with pathogenic MC4R mutations. Thus, we wished to assess the impact of the MC4R on bone mass and metabolism. Secondly, we wished to investigate the impact of the GLP-1 RA liraglutide on bone mass in adults with pathogenic MC4R mutations. 17 patients with obesity-causing MC4R mutations (BMI: 35.5 ± 7.6) and 35 matched control participants with common obesity (BMI: 34.3 ± 7.1) underwent a DEXA scan for assessment of bone mineral density (BMD), bone mineral apparent density [BMAD = (BMD/√(bone area)], and bone turnover markers (BTMs). Individuals with a BMI above 28 (14 MC4R mutation carriers and 28 matched control participants) underwent 16 weeks treatment with liraglutide 3.0 mg. The MC4R group had higher BMD [mean difference: 0.065 g/m2 (− 0.008 to 0.138), p = 0.03], but BMAD and BTMS were not different compared to the control group. In response to liraglutide, BMAD increased in the control group, compared to no change in the MC4R group [mean group difference: 0.0007 (0.0001–0.001), p = 0.04]. In conclusion, BMD is increased in MC4R causal obesity compared to common obesity, but when corrected for body size (BMAD), bone mass was not increased, and no evidence of an influence of the MC4R on bone metabolism in adults was found. Liraglutide treatment did not change bone metabolism in MC4R causal obesity, but increased bone mass as measured by BMAD in common obesity.

Background The voltage-gated potassium channel Kv7.1 encoded by KCNQ1 is located in both cardiac myocytes and insulin producing beta cells. Loss-of-function mutations in KCNQ1 causes long QT syndrome along with glucose-stimulated hyperinsulinemia, increased C-peptide and postprandial hypoglycemia. The KCNE1 protein modulates Kv7.1 in cardiac myocytes, but is not expressed in beta cells. Gain-of-function mutations in KCNQ1 and KCNE1 shorten the action potential duration in cardiac myocytes, but their effect on beta cells and insulin secretion is unknown. Case presentation Two patients with atrial fibrillation due to gain-of-function mutations in KCNQ1 (R670K) and KCNE1 (G60D) were BMI-, age-, and sex-matched to six control participants and underwent a 6-h oral glucose tolerance test (OGTT). During the OGTT, the KCNQ1 gain-of-function mutation carrier had 86% lower C-peptide response after glucose stimulation compared with matched control participants (iAUC 360min  = 34 pmol/l*min VS iAUC 360min  = 246 ± 71 pmol/l*min). The KCNE1 gain-of-function mutation carrier had normal C-peptide levels. Conclusions This case story presents a patient with a gain-of-function mutation KCNQ1 R670K with low glucose-stimulated C-peptide secretion, additionally suggesting involvement of the voltage-gated potassium channel KCNQ1 in glucose-stimulated insulin regulation.