Does semaglutide reduce alcohol intake in Danish patients with alcohol use disorder and comorbid obesity? Trial protocol of a randomised, double-blinded, placebo-controlled clinical trial (the SEMALCO trial).

Introduction: Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies.

Metabolic and Hormonal Responses to Isomaltulose Ingestion Before or During Sustained Submaximal Exercise in Adults with Type 1 Diabetes Using Automated Insulin Delivery Systems.

Objectives: This article compares metabolic, pancreatic, and gut-derived hormone responses to isomaltulose ingestion, before versus during submaximal sustained exercise, in adults with type 1 diabetes (T1D) using automated insulin delivery systems.

Methods: In a randomized, cross-over trial, eight participants with T1D being treated with automated insulin pumps (five females, age: 47 ± 16 years, BMI: 27.5 ± 3.

Plasma concentration of gastrointestinal hormones and subjective appetite ratings after diet or bariatric surgery: 1-year results from the DISGAP study.

Objective: Long-term weight loss outcomes are contrasting between bariatric surgery and dietary restriction alone. This is the first study to investigate changes in gastrointestinal (GI) hormones involved in appetite regulation, and subjective appetite feelings, at 1-year follow-up, after initial weight loss induced by a very-low energy (VLED) alone (controls), or with bariatric surgery.

Methods: Patients scheduled for Sleeve Gastrectomy (SG) (n = 19) or Roux-en-Y gastric Bypass (RYGB) (n = 19), and controls (n = 16) were recruited.

Gastrointestinal hormones and subjective ratings of appetite after low-carbohydrate vs low-fat low-energy diets in females with lipedema - A randomized controlled trial.

Background: Ketosis seems to attenuate, or prevent, the rise in both ghrelin concentrations and subjective hunger ratings that follow weight loss. However, most of the previous studies have employed very-low energy diets (VLED) and are therefore limited in terms of generalizability.

Objectives: To compare changes in ghrelin plasma concentrations after a low-carbohydrate (LCD) versus an isocaloric low-fat low energy diet (LED) in females with lipedema.

Weight Loss Induces Changes in Vitamin D Status in Women with Obesity but not in Men: a Randomized Clinical Trial.

Context: Obesity is associated with low vitamin D and recent studies have suggested a difference in vitamin D metabolism between females and males.

Objective: The aim of this study was to investigate the effects of weight loss on vitamin D status in individuals with obesity, and secondarily, whether vitamin D metabolism differs between women and men.

Methods: Secondary analysis from a randomized placebo-controlled trial, designed to investigate the efficacy of 52 weeks of treatment with either liraglutide, exercise or combined, compared with placebo on weight loss maintenance after an 8-week low-calorie diet-induced weight loss in 195 individuals with obesity (BMI 32-43 kg/m2).

Annual Prize Lecture 2024: Endogenous physiological mechanisms as basis for the treatment of obesity and type 2 diabetes.

In 1964, it was proven that postprandial insulin secretion is largely regulated by gut hormones and, in 1973, it was proposed that a gut hormone would also regulate appetite and food intake. Several gut hormones were tested for metabolic actions with disappointing results until the discovery of the proglucagon derivative, glucagon-like peptide-1 (GLP-1). This peptide from the distal intestine has preserved activity on insulin secretion in people with type 2 diabetes and turned out to regulate both secretion and motility in the gastrointestinal tract and importantly, appetite and food intake, thus functioning as an efficient 'ileal brake' hormone.

Glucagon receptor activation contributes to the development of kidney injury.

The underlying causes of diabetic kidney disease are still largely unknown. New insights into the contributing causes of diabetic nephropathy are important to prevent this complication. Hyperglycemia and hypertension are some of the risk factors for diabetic nephropathy.

GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management.

The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15-25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules.

Alpha-cyclodextrin increases glucagon-like peptide-1 secretion in multiple models and improves metabolic status in mice.

Alpha-cyclodextrin (α-CD) is a non-absorbable and soluble fiber that causes weight loss. We studied whether this is due to an effect on GLP-1 secretion. In GLUTag cells, α-CD increased GLP-1 secretion up to 170% via adenylyl cyclase, phospholipase C, and L-type calcium channels dependent processes.

Effect of ghrelin on glucose tolerance, gut hormones, appetite, and food intake after sleeve gastrectomy.

Ghrelin is an appetite-stimulating hormone secreted from the gastric mucosa in the fasting state, and secretion decreases in response to food intake. After sleeve gastrectomy (SG), plasma concentrations of ghrelin decrease markedly. Whether this affects appetite and glucose tolerance postoperatively is unknown.

The Severity of DSS-Induced Colitis Is Independent of the SCFA-FFAR2/3-GLP-1 Pathway Despite SCFAs Inducing GLP-1 Secretion via FFAR2/3.

Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and 3 (FFAR2 and 3) expressed on enteroendocrine L-cells. Fiber-deficient diets are associated with decreased intestinal function and decreased colonic GLP-1 and GLP-2 content.

Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids.

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo.

Bone remodeling in survivors of pediatric hematopoietic stem cell transplantation: Impact of heavy resistance training.

Background: Early-onset osteoporosis is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT). It remains unknown if physical training can improve bone formation in these patients, as the transplantation procedure may cause sustained dysregulation of the bone-forming osteoblast progenitor cells.

Objective: We aimed to explore the effect of resistance training on bone remodeling in long-term survivors of pediatric HSCT.

Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge.

Background And Purpose: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus.

The impact of short-term eucaloric low- and high-carbohydrate diets on liver triacylglycerol content in males with overweight and obesity: a randomized crossover study.

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.

Effect of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide on alcohol consumption in alcohol-preferring male vervet monkeys.

Rationale: Glucagon-like peptide-1 (GLP-1) receptor agonists reduce alcohol consumption in rodents and non-human primates. Semaglutide is a new long-acting GLP-1 receptor agonist, widely used in the clinic against type 2 diabetes and obesity. It is also reported to reduce alcohol intake in rodents.

L-valine is a powerful stimulator of GLP-1 secretion in rodents and stimulates secretion through ATP-sensitive potassium channels and voltage-gated calcium channels.

Background: We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release from the upper part of the rat small intestine. This makes L-valine an interesting target for nutritional-based modulation of GLP-1 secretion. However, the molecular mechanism of L-valine-induced secretion remains unknown.

Glucagon agonism in the treatment of metabolic diseases including type 2 diabetes mellitus and obesity.

Type 2 diabetes mellitus (T2DM) is associated with obesity and, therefore, it is important to target both overweight and hyperglycaemia. Glucagon plays important roles in glucose, amino acid and fat metabolism and may also regulate appetite and energy expenditure. These physiological properties are currently being exploited therapeutically in several compounds, most often in combination with glucagon-like peptide-1 (GLP-1) agonism in the form of dual agonists.

Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node.

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear.

Methods And Results: We employed a large animal model, the female landrace pig, and used multiple in vivo and ex vivo approaches including pharmacological challenges, electrophysiology, and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate.

Impact of Synbiotic Intake on Liver Metabolism in Metabolically Healthy Participants and Its Potential Preventive Effect on Metabolic-Dysfunction-Associated Fatty Liver Disease (MAFLD): A Randomized, Placebo-Controlled, Double-Blinded Clinical Trial.

Synbiotics modulate the gut microbiome and contribute to the prevention of liver diseases such as metabolic-dysfunction-associated fatty liver disease (MAFLD). This study aimed to evaluate the effect of a randomized, placebo-controlled, double-blinded seven-week intervention trial on the liver metabolism in 117 metabolically healthy male participants. Anthropometric data, blood parameters, and stool samples were analyzed using linear mixed models.

Effects of 3 months of 10-h per-day time-restricted eating and 3 months of follow-up on bodyweight and cardiometabolic health in Danish individuals at high risk of type 2 diabetes: the RESET single-centre, parallel, superiority, open-label, randomised controlled trial.

Background: Time-restricted eating (TRE) has been suggested to be a simple, feasible, and effective dietary strategy for individuals with overweight or obesity. We aimed to investigate the effects of 3 months of 10-h per-day TRE and 3 months of follow-up on bodyweight and cardiometabolic risk factors in individuals at high risk of type 2 diabetes.

Methods: This was a single-centre, parallel, superiority, open-label randomised controlled clinical trial conducted at Steno Diabetes Center Copenhagen (Denmark).