Elucidating the role of inhibitory G‐protein, Gz, in β‐cell preservation and regeneration (1062.3)

Abstract

Type 1 diabetes (T1D) occurs when β‐cell death causes insufficient β‐cell mass to maintain normoglycemia. Although select T1D patients are candidates for transplantation, no pharmaceutical cure for T1D exists. Such cures would augment the residual β‐cell mass had by most, if not all, T1D patients. We showed the α subunit of the heterotrimeric Gz protein, Gαz, inhibits production of cAMP, a second messenger proposed to potentiate β‐cell function and mass. In an obesity‐linked T2D model, we demonstrated islets from Gαz‐null mice have constitutively increased β‐cell cAMP production, insulin secretion, and replicative capacity. We hypothesized Gαz‐null mice subjected to chemical induction of T1D would have improved β‐cell replication, survival, and, ultimately, mass, especially when treated with drugs known to stimulate cAMP production. To test our hypothesis, we induced diabetes in mice with streptozotocin. The Gαz‐null mutation partially protected against hyperglycemia, as did treatment with the known cAMP potentiator, exendin‐4. Combining the Gαz‐null mutation with exendin‐4 treatment was completely protective. These pancreas sections had both increased β‐cell replication and decreased apoptosis. In vitro assays with novel Gαz variants are pinpointing critical downstream signaling pathways. Overall, our results support targeting Gαz signaling to preserve and regenerate functional β‐cell mass.Grant Funding Source: Supported by the Juvenile Diabetes Research Foundation