Leader: Francesco Giorgino (UNIBA); Other collaborator(s): Irene Caruso (UNIBA); Celeste Lauriola (UNIBA)
We plan to investigate the mechanisms leading to progressive beta-cell dysfunction and death in ageing islets of individuals with type 2 diabetes and to investigate the pro-survival effects and signaling mechanisms of GLP-1 receptor agonists, novel dual and triple GLP-1/GIP/Glucagon agonists as well as new molecules such as irisin that could enhance and maintain beta-cell secretory function over time, thus modifying the disease trajectory. Given the frequent association of type 2 diabetes with cardiovascular disease and cognitive dysfunction, the prosurvival effects of these molecules on human cardiac, endothelial and neuronal/glial cell models will be also investigated.
Brief description of the activities and of the intermediate results: One researcher and one PhD student have been recruited. Experiments on human coronary artery (HCAEC) and brain microvasculature (HBMEC) endothelial cells are currently ongoing to assess the putative protective effect of GLP-1RA and GIP/GLP-1 dual receptor agonists on cytokine- and hypoxia-induced damages. To date, we identified the expression of GIP and GLP-1R in HCAEC and HBMEC via immunoblotting and real-time polymerase chain reaction. Also, the activity of these receptors was demonstrated by assessing CREB phosphorilation following treatment with semaglutide and GIP. Time-course and dose-response experiments have been performed to identify the best conditions for the following experiments.
We also found that pretreatment with semaglutide reduced TNF-alpha-induced autophagy in HCAEC in both normal and high glucose concentration. Experiments to evaluate the effects of semaglutide on TNF-alpha-induced autophagy in HBMEC under different glucose concentrations are ongoing. We plan to complete the experiments on TNF-alpha-induced damage by assessing autophagy in HBMEC, apoptosis and endoplasmic reticulum stress in both cell systems and to evaluate the effect of semaglutide and tirzepatide.
These experiments will also be replicated to assess the role of these incretin drugs in preventing hypoxia induced damage mediated by cobalt(II) chloride hexahydrate. We are also currently investigating predictors of effectiveness and time to failure of GLP1RA treatment and preliminary results indicate that simple variables such as baseline HbA1c rather than an hard clustering approach in phenotypes could be better in guiding treatment tailoring. We have also conducted an analysis of the adverse events of tirzepatide by mining the FDA post-marketing pharmacovigilance database, finding an overall safety profile similar to that of GLP-1RA and hinting at a lower tolerability in patients above 65 years.
Main policy, industrial and scientific implications: Our work could aid clinicians in tailoring treatment to patients' needs, maximizing their efficacy and safety and optimizing healthcare systems' resources. Understanding the mechanisms of distric specific cardiovascular protection of these drugs might also inform clinical choices in the light of patients' complications profile.
Brief description of the activities and of the intermediate results:
- Experiments on HBMEC and HCAEC are ongoing;
- Authorization from the Ministry of Health has been requested for the project on an animal model titled “Evaluation of the effects of tirzepatide administration on the restoration of beta-cell and testicular function in murine models of obesity/diabetes and hypogonadism";
- The cohort for the study on predictors of effectiveness and time to failure following treatment with GLP-1RA has been completed and statistical analysis is ongoing;
- The research paper regarding the analysis of the adverse events of tirzepatide by mining the FDA post-marketing pharmacovigilance database has been completed and submitted to the Journal of Endocrinological Investigation for peer review;
- A network meta-analysis comparing hybrid closed loop systems for automated insulin delivery in people With type 1 diabetes has been conducted and submitted for peer review;
Brief description of the activities and of the intermediate results:
- Experiments on HBMEC and HCAEC are ongoing;
- Authorization from the Ministry of Health has been obtained on 18 July 2024 for the project on an animal model titled “Evaluation of the effects of tirzepatide administration on the restoration of beta-cell and testicular function in murine models of obesity/diabetes and hypogonadism"; purchase of a stereomicroscope (Thermo Fisher) and a fluorimeter (ClarioStar).
- The manuscript for the retrospective study on predictors of effectiveness and time to failure following treatment with GLP-1RA has been completed and is about to be submitted for publication;
- The research paper regarding the analysis of the adverse events of tirzepatide by mining the FDA post-marketing pharmacovigilance database has been published in the Journal of Endocrinological Investigation, presented at the 60th EASD congress in Madrid (9th-12th September 2024) and selected for the press release and press conference of the Congress, covered by press on several online journal (i.e., Medscape https://www.medscape.com/viewarticle/tirzepatide-real-world-safety-profile-reassuring-so-far-2024a1000gnq?form=fpf);
- A network meta-analysis comparing hybrid closed loop systems for automated insulin delivery in people With type 1 diabetes has been published in Diabetes/Metabolism Research and Reviews.
Brief description of the activities and of the intermediate results:
- Experiments on HBMEC and HCAEC: are ongoing ;
- The manuscript for the retrospective study on predictors of effectiveness and time to failure following treatment with GLP-1RA has been completed and a cohort of SGLT-2i users have been set up;
- A meta-analysis of randomized controlled trials concerning patients with type 1 diabetes using once weekly insulins has been completed (PROSPERO CRD42024606874); manuscript in preparation.
Scientific papers:
- Di Molfetta S, Di Gioia L, Caruso I, Cignarelli A, Green SC, Natale P, Strippoli GFM, Sorice GP, Perrini S, Natalicchio A, Laviola L, Giorgino F. Efficacy and Safety of Different Hybrid Closed Loop Systems for Automated Insulin Delivery in People With Type 1 Diabetes: A Systematic Review and Network Meta-Analysis. Diabetes Metab Res Rev 2024 Sep;40(6):e3842.doi: 10.1002/dmrr.3842.
- Caruso I, Di Gioia L, Di Molfetta S, Caporusso M, Cignarelli A, Sorice GP, Laviola L, Giorgino F. The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. J Endocrinol Invest 2024 Aug 14.doi: 10.1007/s40618-024-02441-z.
- Caruso I, Di Gioia L, Di Molfetta S, Cignarelli A, Palmer SC, Natale P, Strippoli GFM, Perrini S, Natalicchio A, Laviola L, Giorgino F. Glucometabolic outcomes of GLP-1 receptor agonist-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis. EClinicalMedicine 2023 Sep 12:64:102181. doi: 10.1016/j.eclinm.2023.102181.
National/international conferences:
- Caruso I, Di Gioia L, Di Molfetta S, Caporusso M, Cignarelli A, Sorice GP, Laviola L, Giorgino F. The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. EASD 60th Annual Meeting, Madrid, 9th-13th September, 2024 (Short oral presentation)
- Giorgino F. 16th Annual International Conference of the D&CVD Study Group - GLP-1-based multiagonists and cardiovascular outcomes. Prague, 29-31 May, 2024. (Oral presentation)
- Giorgino F. 5th European Incretin Study Group Meeting - Incretin-based therapies and mental health: analysis of the Food and Drug Administration Adverse Events Reporting System (FAERS), Cambridge, 4-6 April, 2024 (Poster)