GHRH agonist MR-409 protects -cells from streptozotocin-induced diabetes

Patients with type 1 diabetes (T1D) suffer from insufficient functional (3-cell mass, which results from infiltration of inflammatory cells and cytokine-mediated (3-cell death. Previous studies demonstrated the beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH- R), such as MR -409 on preconditioning of islets in a transplantation model. However, the therapeutic potential and protective mechanisms of GHRH- R agonists on models of T1D diabetes have not been explored. Using in vitro and in vivo models of T1D, we assessed the protective propertie of the GHRH agonist, MR409 on (3 -cells. The treatment of insulinoma cell lines and rodent and human islets with MR -409 induces Akt signaling by induction of insulin receptor substrate 2 (IRS2), a master regulator of survival and growth in (3 -cells, in a PKA-dependent manner. The increase in cAMP/PKA/CREB/IRS2 axis by MR409 was associated with decrease in (3 -cell death and improved insulin secretory function in mouse and human islets exposed to proinflammatory cytokines. The assessment of the effects of GHRH agonist MR -409 in a model of T1D induced by low -dose streptozotocin showed that mice treated with MR -409 exhibited better glucose homeostasis, higher insulin levels, and preservation of (3 -cell mass. Increased IRS2 expression in (3-cells in the group treated with MR -409 corroborated the in vitro data and provided evidence for the underlying mechanism responsible for beneficial effects of MR -409 in vivo. Collectively, our data show that MR -409 is a novel therapeutic agent for the prevention and treatment of (3 -cells death in T1D.