Abstract
Disclosure: M. Gonzalez Medina:
None.
R. Louzada:
None.
V. Pita-Grisanti:
None.
M. Blandino:
None.
T. Cui:
None.
W. Sha:
Owner/Co-Owner; Self; WS. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs.
R. Cai:
Owner/Co-Owner; Self; R.C. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs.
A.V. Schally:
Owner/Co-Owner; Self; A.V.S. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs..
E. Bernal-Mizrachi:
None.
Patients with type 1 diabetes (T1D) have decreased functional β-cell mass due to inflammatory cell infiltration and cytokine-induced β-cell death. Clinical trials using a combination of immunomodulatory agents and β-cell protecting medications such as GLP1-R agonists (GLP1-Ra) are being considered. A potential limitation for the clinical efficacy of GLP1-R agonists is the loss of GLP-1-R at the cell surface in states of hyperglycemia. Hence, novel agents that enhance β-cell survival and proliferation through parallel pathways could improve responses to GLP1-R agonists and/or synergistically potentiate β-cell responses. Previous studies have demonstrated beneficial effects of growth hormone-releasing hormone receptor agonists (GHRH-Ra), such as MR-409 on islet preconditioning in transplantation models. Our previous studies showed that GHRH-Ra protects β-cells from autoimmune injury
in vitro
and improves glucose levels in a model of high-dose streptozotocin-induced diabetes via stimulation of the cAMP/PKA/CREB/IRS2 axis. However, the effects of combination of incretin-based therapy with GHRHRa on β-cell survival in T1D models have not yet been explored. Using the low-dose STZ model in C57/B6 mice, we investigated how MR-409 alone or in combination with GLP1-R agonists (Exendin-4 or Ex-4) promotes β-cell survival and prevents T1D. Low-dose STZ treated mice received daily MR-409 and Ex-4 injections, either alone or in combination for six weeks. We found that, STZ-treated mice that received either MR-409, Ex-4 or combination exhibited better glucose homeostasis while the combination failed to induce any additional effect. Interestingly, glucose tolerance and insulin levels were improved only in the MR-409-treated mice. β-cell mass was similarly increased in mice that received MR-409, Ex-4 and combination groups compared to the vehicle-treated. Further, treatment of human islets with MR-409 and/or Ex-4 induced insulin receptor substrate 2 (IRS2) expression, a master regulator of survival and growth in β-cells, while the combination of both therapies did not have any additional effect. Experiments in human islets exposed to proinflammatory cytokines treatment demonstrated that MR-409 and/or Ex-4 was associated with a decrease in β-cell death and improved insulin secretory function by activation of the cAMP/PKA/CREB/IRS2 axis. These studies demonstrate that although there was no evidence for a synergistic effect between MR-409 and Ex-4, MR-409 appears to have more potent effects on improving glucose tolerance and insulin levels when compared to the long-term effect of Ex-4 in a low-dose STZ model, suggesting that MR-409 could be an alternative therapeutic agent in the treatment of β-cell death in T1D.
Presentation:
6/2/2024