GHRH and GLP-1 receptor agonism promote human β-cell survival and improve glucose homeostasis in diabetic mice.

Type 1 diabetes (T1D) is characterized by progressive loss of pancreatic β cell mass driven by inflammatory cytokine-induced apoptosis. Although glucagon-like peptide-1 receptor (GLP-1R) agonists improve β cell function and survival, their efficacy may be limited under hyperglycemic conditions. Growth hormone-releasing hormone receptor (GHRH-R) agonists have emerged as potential β cell-protective agents through activation of cAMP-dependent signaling pathways. Here, we investigated the effects of the GHRH-R agonist MR-409, alone or in combination with the GLP-1R agonist exendin-4 (Ex-4), on β cell survival and glucose homeostasis. In human islets, combined MR-409 and Ex-4 treatment enhanced glucose-stimulated insulin secretion and increased CREB phosphorylation. The combination also reduced cytokine-induced apoptosis, with decreased caspase 3/7 activity compared with MR-409 alone and reduced BAX protein levels compared with either individual treatment. MR-409 alone increased IRS2 protein levels, consistent with activation of pro-survival signaling pathways. In a multiple low-dose streptozotocin (STZ) mouse model, MR-409, Ex-4, and their combination improved glucose homeostasis and increased β cell mass compared with vehicle-treated mice. However, the combination did not confer additional metabolic benefit over single treatments. Notably, MR-409 treatment was associated with greater improvements in glucose tolerance and insulin levels. These findings support further investigation of GHRH receptor agonism as a strategy to preserve β-cell survival under diabetogenic stress.