Synergy Between Gαz Deficiency and GLP-1 Analog Treatment in Preserving Functional β-Cell Mass in Experimental Diabetes

A defining characteristic of type 1 diabetes mellitus ( T1DM) pathophysiology is pancreatic beta-cell death and dysfunction, resulting in insufficient insulin secretion to properly control blood glucose levels. Treatments that promote beta-cell replication and survival, thus reversing the loss of beta-cell mass, while also preserving beta-cell function, could lead to a real cure for T1DM. The alpha-subunit of the heterotrimeric G(z) protein, G alpha(z), is a tonic negative regulator of adenylate cyclase and downstream cAMP production. cAMP is one of a few identified signaling molecules that can simultaneously have a positive impact on pancreatic islet beta-cell proliferation, survival, and function. The purpose of our study was to determine whether mice lacking G alpha(z) might be protected, at least partially, from beta-cell loss and dysfunction after streptozotocin treatment. We also aimed to determine whether G alpha(z) might act in concert with an activator of the cAMP-stimulatory glucagon-like peptide 1 receptor, exendin-4 ( Ex4). Without Ex4 treatment, G alpha(z)-null mice still developed hyperglycemia, albeit delayed. The same finding held true for wild-type mice treated with Ex4. With Ex4 treatment, G alpha(z)-null mice were protected from developing severe hyperglycemia. Immunohistological studies performed on pancreas sections and in vitro apoptosis, cytotoxicity, and survival assays demonstrated a clear effect of G alpha(z) signaling on pancreatic beta-cell replication and death; beta-cell function was also improved in G alpha(z)-null islets. These data support our hypothesis that a combination of therapies targeting both stimulatory and inhibitory pathways will be more effective than either alone at protecting, preserving, and possibly regenerating beta-cell mass and function in T1DM.