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  1. Article ; Online: Targeting the GLP-2 receptor in the management of obesity.

    Pálsson, Thorir G / Gilliam-Vigh, Hannah / Jensen, Benjamin A H / Jeppesen, Palle B / Lund, Asger B / Knop, Filip K / Nielsen, Casper K

    Peptides

    2024  Volume 177, Page(s) 171210

    Abstract: Recent advancements in understanding glucagon-like peptide 2 (GLP-2) biology and pharmacology have sparked interest in targeting the GLP-2 receptor (GLP-2R) in the treatment of obesity. GLP-2 is a proglucagon-derived 33-amino acid peptide co-secreted ... ...

    Abstract Recent advancements in understanding glucagon-like peptide 2 (GLP-2) biology and pharmacology have sparked interest in targeting the GLP-2 receptor (GLP-2R) in the treatment of obesity. GLP-2 is a proglucagon-derived 33-amino acid peptide co-secreted from enteroendocrine L cells along with glucagon-like peptide 1 (GLP-1) and has a range of actions via the GLP-2R, which is particularly expressed in the gastrointestinal tract, the liver, adipose tissue, and the central nervous system (CNS). In humans, GLP-2 evidently induces intestinotrophic effects (i.e., induction of intestinal mucosal proliferation and improved gut barrier function) and promotes mesenteric blood flow. However, GLP-2 does not seem to have appetite or food intake-reducing effects in humans, but its gut barrier-promoting effect may be of interest in the context of obesity. Obesity is associated with reduced gut barrier function, increasing the translocation of proinflammatory gut content to the circulation. This phenomenon constitutes a strong driver of obesity-associated systemic low-grade inflammation, which in turn plays a major role in the development of most obesity-associated complications. Thus, the intestinotrophic and gut barrier-improving effect of GLP-2, which in obese rodent models shows strong anti-inflammatory potential, may, in combination with food intake-reducing strategies, e.g., GLP-1 receptor (GLP-1) agonism, be able to rectify core pathophysiological mechanism of obesity. Here, we provide an overview of GLP-2 physiology in the context of obesity pathophysiology and review the pharmacological potential of GLP-2R activation in the management of obesity and related comorbidities.
    Language English
    Publishing date 2024-04-03
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 769028-9
    ISSN 1873-5169 ; 0196-9781
    ISSN (online) 1873-5169
    ISSN 0196-9781
    DOI 10.1016/j.peptides.2024.171210
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Separate and combined effects of long-term GIP and GLP-1 receptor activation in patients with type 2 diabetes: a structured summary of a study protocol for a double-blind, randomised, placebo-controlled clinical trial.

    Helsted, Mads M / Gasbjerg, Lærke S / Vilsbøll, Tina / Nielsen, Casper K / Forman, Julie L / Christensen, Mikkel B / Knop, Filip K

    BMJ open

    2023  Volume 13, Issue 2, Page(s) e065736

    Abstract: Introduction: Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, ... ...

    Abstract Introduction: Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D.
    Methods and analysis: In this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18-74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks' add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial.
    Ethics and dissemination: The present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.
    Trial registration numbers: NCT05078255 and U1111-1259-1491.
    MeSH term(s) Humans ; Incretins ; Diabetes Mellitus, Type 2/drug therapy ; Glucagon-Like Peptide-1 Receptor ; Blood Glucose Self-Monitoring ; Blood Glucose ; Glucose ; Randomized Controlled Trials as Topic
    Chemical Substances Incretins ; gastric inhibitory polypeptide receptor (D6H00MV7K8) ; Glucagon-Like Peptide-1 Receptor ; Blood Glucose ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2023-02-27
    Publishing country England
    Document type Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2599832-8
    ISSN 2044-6055 ; 2044-6055
    ISSN (online) 2044-6055
    ISSN 2044-6055
    DOI 10.1136/bmjopen-2022-065736
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Dasiglucagon Treatment for Postprandial Hypoglycemia After Gastric Bypass: A Randomized, Double-Blind, Placebo-Controlled Trial.

    Nielsen, Casper K / Øhrstrøm, Caroline C / Houji, Inas J K / Helsted, Mads M / Krogh, Liva S L / Johansen, Nicklas J / Hartmann, Bolette / Holst, Jens J / Vilsbøll, Tina / Knop, Filip K

    Diabetes care

    2023  Volume 46, Issue 12, Page(s) 2208–2217

    Abstract: Objective: Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon ...

    Abstract Objective: Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and was recently shown to mitigate postbariatric hypoglycemia in experimental settings. Here, we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial.
    Research design and methods: We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital in Denmark. The study included 24 individuals who had undergone Roux-en-Y gastric bypass surgery (n = 23 women) with continuous glucose monitor-verified postbariatric hypoglycemia (≥15 min at <3.9 mmol/L three or more times per week) randomly assigned to two treatment periods of 4 weeks of self-administered subcutaneous dasiglucagon at 120 μg or placebo. The primary and key secondary outcomes were continuous glucose monitor-captured percentage of time in level 1 and 2 hypoglycemia (<3.9 and <3.0 mmol/L), respectively.
    Results: Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (-1.2 percentage points; 95% CI -2.0 to -0.5; P = 0.002) and time in level 2 hypoglycemia by 54% (-0.4 percentage points; 95% CI -0.6 to -0.2; P < 0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 min in 401 of 412 self-administrations, compared with 104 of 357 placebo self-administrations (97.3% vs. 29.1% correction of hypoglycemia rate; P < 0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea.
    Conclusions: Compared with placebo, 4 weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in individuals who had undergone Roux-en-Y gastric bypass surgery.
    MeSH term(s) Humans ; Female ; Glucagon ; Gastric Bypass/adverse effects ; Hypoglycemia/drug therapy ; Hypoglycemia/etiology ; Hypoglycemia/metabolism ; Blood Glucose/metabolism ; Double-Blind Method
    Chemical Substances dasiglucagon ; Glucagon (9007-92-5) ; Blood Glucose
    Language English
    Publishing date 2023-10-17
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article
    ZDB-ID 441231-x
    ISSN 1935-5548 ; 0149-5992
    ISSN (online) 1935-5548
    ISSN 0149-5992
    DOI 10.2337/dc23-1193
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1434: Show issues Location:
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  4. Article ; Online: Dasiglucagon Effectively Mitigates Postbariatric Postprandial Hypoglycemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

    Nielsen, Casper K / Øhrstrøm, Caroline C / Kielgast, Urd L / Hansen, Dorte L / Hartmann, Bolette / Holst, Jens J / Lund, Asger / Vilsbøll, Tina / Knop, Filip K

    Diabetes care

    2022  Volume 45, Issue 6, Page(s) 1476–1481

    Abstract: Objective: To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH).: Research design and ... ...

    Abstract Objective: To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH).
    Research design and methods: In a randomized, double-blind, placebo-controlled, crossover trial, 10 RYGB-operated participants with continuous glucose monitoring-verified PBH were randomly assigned to 3 trial days, each consisting of a 240-min standardized liquid mixed-meal test with the subcutaneous injection of placebo or 80 μg or 200 μg dasiglucagon.
    Results: Compared with placebo, treatment with both 80 and 200 μg dasiglucagon raised nadir plasma glucose (PG) (placebo: 3.0 ± 0.2 mmol/L [mean ± SEM]; 80 μg dasiglucagon: 3.9 ± 0.3 mmol/L, P = 0.002; 200 μg dasiglucagon: 4.5 ± 0.2 mmol/L, P = 0.0002) and reduced time in hypoglycemia (PG <3.9 mmol/L) by 70.0 min (P = 0.030 and P = 0.008).
    Conclusions: Single-dose administration of dasiglucagon effectively mitigated postprandial hypoglycemia.
    MeSH term(s) Blood Glucose ; Blood Glucose Self-Monitoring ; Cross-Over Studies ; Double-Blind Method ; Gastric Bypass/adverse effects ; Glucagon/analogs & derivatives ; Humans ; Hypoglycemia/drug therapy ; Hypoglycemia/etiology ; Hypoglycemia/prevention & control ; Insulin/therapeutic use
    Chemical Substances Blood Glucose ; Insulin ; dasiglucagon ; Glucagon (9007-92-5)
    Language English
    Publishing date 2022-06-23
    Publishing country United States
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 441231-x
    ISSN 1935-5548 ; 0149-5992
    ISSN (online) 1935-5548
    ISSN 0149-5992
    DOI 10.2337/dc21-2252
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1434: Show issues Location:
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