Targeting the GLP-2 receptor in the management of obesity.

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.

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

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.

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.

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.

Dasiglucagon Effectively Mitigates Postbariatric Postprandial Hypoglycemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

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.