1. Glucagon-like peptide-1 gene therapy
Anne M Rowzee,Niamh X Cawley,John A Chiorini,Giovanni Di Pasquale Exp Diabetes Res . 2011;2011:601047. doi: 10.1155/2011/601047.
Glucagon-like peptide 1 (GLP-1) is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.
2. GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action
Matthew M Rankin,Ivona Bakaj,June Zhi Xu,Seunghun P Lee,Alessandro Pocai,James Littrell,Guozhang Xu,Jenson Qi Front Endocrinol (Lausanne) . 2021 May 14;12:652628. doi: 10.3389/fendo.2021.652628.
The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R functionin vitroandin vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.
3. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial
Julio Rosenstock,Marie-Louise Hartoft-Nielsen,Serge Jabbour,Thomas R Pieber,Oluf K H Hansen,Melanie Davies JAMA . 2017 Oct 17;318(15):1460-1470. doi: 10.1001/jama.2017.14752.
Importance:Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.Objectives:To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.Design, setting, and patients:Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.Interventions:Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.Main outcomes and measures:The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.Results:Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.Conclusions and relevance:Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.Trial registration:clinicaltrials.gov Identifier:NCT01923181.
4. Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials
Dario Bruzzese,Simona Dell'Aversana,Paola Gargiulo,Santo Dellegrottaglie,Ivana Iesu,Luca Esposito,Fabio Marsico,Stefania Paolillo,Francesco Renga,Pasquale Perrone Filardi,Caterina Marciano,Immacolata Esposito Eur Heart J . 2020 Sep 14;41(35):3346-3358. doi: 10.1093/eurheartj/ehaa082.
Aims:Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD.Methods and results:In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo.Conclusion:Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.