Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study DOI Creative Commons
Marie Winther‐Sørensen, Sara L. Garcia,

Andreas Bartholdy

et al.

Diabetologia, Journal Year: 2024, Volume and Issue: 67(8), P. 1602 - 1615

Published: May 6, 2024

Abstract Aims/hypotheses Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, dual agonists of their receptors currently being explored for treatment obesity metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals type 2 diabetes but also observed MASLD. GLP-1 reported to be largely unaffected or even reduced similar conditions. We investigated potential determinants plasma proglucagon associations receptor signalling diseases based on data UK Biobank. Methods used exome sequencing Biobank ~410,000 white participants identify variants grouped them known predicted signalling. Data estimated using Olink technology were available a subset cohort (~40,000). determined BMI, fat (quantified by MRI) performed survival analyses investigate if elevated predicts development. Results Obesity, MASLD associated independently each other. Baseline risk development over 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n =1562; p =1.3×10 −12 ). This association was magnitude across strata BMI. Carriers cAMP had (β 0.847; 0.04, 1.66; =17; =0.04), carriers frameshift mutation higher compared wild-type reference group 0.504; 0.03, 0.98; =11; =0.04). Conclusions/interpretation Our findings support suggestion that is involved MASLD, development, influenced genetic variation receptor, obesity, Determining molecular pathways downstream activation may guide biased GLP-1/glucagon co-agonist improved benefits. availability All coding through https://github.com/nicwin98/UK-Biobank-GCG Graphical

Language: Английский

Targeting the incretin system in obesity and type 2 diabetes mellitus DOI
Saleem Ansari, Bernard Khoo, Tricia Tan

et al.

Nature Reviews Endocrinology, Journal Year: 2024, Volume and Issue: 20(8), P. 447 - 459

Published: April 17, 2024

Language: Английский

Citations

38
Glucose-dependent insulinotropic polypeptide (GIP) DOI Creative Commons
Timo D. Müller, Alice E. Adriaenssens,

Bo Ahrén

et al.

Molecular Metabolism, Journal Year: 2025, Volume and Issue: 95, P. 102118 - 102118

Published: Feb. 28, 2025

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in maintenance of glucose tolerance healthy humans. Until recently GIP had not been developed as a therapeutic thus has overshadowed by other incretin, glucagon-like peptide 1 (GLP-1), which is basis for several successful drugs to treat diabetes obesity. However, there rekindling interest biology recent years, great part due pharmacology demonstrating that both GIPR agonism antagonism may be beneficial treating obesity diabetes. This apparent paradox reinvigorated field, led new lines investigation, deeper understanding GIP. In this review, we provide detailed overview on multifaceted nature discuss implications signal modification various diseases. Following its classification hormone, emerged pleiotropic hormone with variety metabolic effects outside endocrine pancreas. The numerous render interesting candidate development pharmacotherapies obesity, diabetes, drug-induced nausea bone neurodegenerative disorders.

Language: Английский

Citations

3
Islet hormones at the intersection of glucose and amino acid metabolism DOI
Phillip J. White, Nicolai J. Wewer Albrechtsen, Jonathan E. Campbell

et al.

Nature Reviews Endocrinology, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Language: Английский

Citations

2
The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation DOI
Konstantinos Stefanakis, Michail Kokkorakis, Christos S. Mantzoros

et al.

Metabolism, Journal Year: 2024, Volume and Issue: unknown, P. 156057 - 156057

Published: Oct. 1, 2024

Language: Английский

Citations

15
Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis DOI Creative Commons
Eric Lawitz,

Mandy Fraessdorf,

Guy Neff

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(5), P. 837 - 846

Published: June 8, 2024

Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated pharmacokinetic and safety profile survodutide people with cirrhosis.

Language: Английский

Citations

14
Non-canonical hepatic androgen receptor mediates glucagon sensitivity in female mice through the PGC1α/ERRα/mitochondria axis DOI Creative Commons
Jie Chen, Yuanyuan Wu,

Wanyu Hao

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115188 - 115188

Published: Jan. 1, 2025

Language: Английский

Citations

1
Glucagon resistance and metabolic-associated steatotic liver disease: a review of the evidence DOI
Emma Rose McGlone,

Steve Bloom,

Tricia Tan

et al.

Journal of Endocrinology, Journal Year: 2024, Volume and Issue: 261(3)

Published: April 3, 2024

Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon a key metabolic regulator, and its actions include the reduction of fat through direct indirect means. Chronic glucagon signalling deficiency hyperaminoacidaemia, hyperglucagonaemia increased circulating levels glucagon-like peptide (GLP-1) fibroblast growth factor 21 (FGF-21). Reduction in activity decreases hepatic amino acid triglyceride catabolism; effects improved glucose tolerance, plasma cholesterol fat. Conversely, infusion healthy volunteers leads to output, decreased acids urea production, energy expenditure. Patients share many hormonal characteristics models deficiency, suggesting that they could be resistant glucagon. Although studies patients obesity and/or MASLD, some evidence expected effect on catabolism may attenuated. Taken together, this supports notion resistance exists contribute pathogenesis MASLD. Further warranted investigate metabolism

Language: Английский

Citations

8
Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective DOI Creative Commons
Yansong Fu, Zhipeng Wang, Hong Qin

et al.

Metabolites, Journal Year: 2024, Volume and Issue: 14(4), P. 218 - 218

Published: April 12, 2024

Metabolic-associated fatty liver disease (MAFLD), characterized primarily by hepatic steatosis, has become the most prevalent worldwide, affecting approximately two-fifths of global population. The pathogenesis MAFLD is extremely complex, and to date, there are no approved therapeutic drugs for clinical use. Considerable evidence indicates that various metabolic disorders play a pivotal role in progression MAFLD, including lipids, carbohydrates, amino acids, micronutrients. In recent years, medicinal properties natural products have attracted widespread attention, numerous studies reported their efficacy ameliorating subsequently alleviating MAFLD. This review aims summarize metabolic-associated pathological mechanisms as well regulate pathways alleviate

Language: Английский

Citations

8
Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males DOI Creative Commons

Dorte B. Zilstorff,

Michael M. Richter, Jens Hannibal

et al.

BMC Endocrine Disorders, Journal Year: 2024, Volume and Issue: 24(1)

Published: March 14, 2024

Abstract Background Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic production. Furthermore, glucagon enhances protein lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) are gut endocrine meals control homeostasis by potentiating insulin secretion inhibiting food intake. Both intake have been reported be affected circadian rhythms vice versa. In this study, we investigated whether the of glucagon, GLP-1 GIP was rhythms. Methods A total 24 healthy men with regular sleep schedules were examined for h at hospital ward 15 wakefulness 9 sleep. Food standardized, samples obtained every third hour. Plasma concentrations measured, data analyzed rhythmometric statistical methods. Available on plasma C-peptide also included. Results GLP-1, GIP, fluctuated diurnal 24-h rhythm, highest levels day lowest night: ( p < 0.0001, peak time 18:26 h), 17:28 18:01 17.59 23:26 h). As expected, found significant correlations between but did not find GIP. Conclusions Our results demonstrate that under meal conditions similar many free-living individuals, observed higher daytime evening than overnight. These findings underpin disturbed rhythm as potential risk factor diabetes obesity. Trial registration ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023.

Language: Английский

Citations

6
Glucagon-Like Peptide-1 Based Therapies: A New Horizon in Obesity Management DOI Creative Commons
Jang Won Son, Soo Lim

Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 39(2), P. 206 - 221

Published: April 16, 2024

Obesity is a significant risk factor for health issues like type 2 diabetes and cardiovascular disease. It often proves resistant to traditional lifestyle interventions, prompting need more precise therapeutic strategies. This has led focus on signaling pathways neuroendocrine mechanisms develop targeted obesity treatments. Recent developments in management have been revolutionized by introducing novel glucagon-like peptide-1 (GLP-1) based drugs, such as semaglutide tirzepatide. These drugs are part of an emerging class nutrient-stimulated hormone-based therapeutics, acting incretin mimetics target G-protein–coupled receptors GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon. vital regulating body fat energy balance. The development multiagonists, including GLP-1–glucagon GIP–GLP-1–glucagon receptor agonists, especially with the potential glucagon activation, marks advancement field. review covers clinical efficacy various GLP-1-based exploring challenges future directions management.

Language: Английский

Citations

5