GABAergic regulation of pancreatic islet cells: Physiology and antidiabetic effects

Diabetes occurs when pancreatic β‐cell death exceeds β‐cell growth, which leads to loss of β‐cell mass. An effective therapy must have two actions: promotion of β‐cell replication and suppression of β‐cell death. Previous studies have established an important role for γ‐aminobutyric acid (GABA) in islet‐cell hormone homeostasis, as well as the maintenance of the β‐cell mass. GABA exerts paracrine actions on α cells in suppressing glucagon secretion, and it has autocrine actions on β cells that increase insulin secretion. Multiple studies have shown that GABA increases the mitotic rate of β cells. In mice, following β‐cell depletion with streptozotocin, GABA therapy can restore the β‐cell mass. Enhanced β‐cell replication appears to depend on growth and survival pathways involving Akt activation. Some studies have also suggested that it induces transdifferentiation of α cells into β cells, but this has been disputed and requires further investigation. In addition to proliferative effects, GABA protects β cells against injury and markedly reduces their apoptosis under a variety of conditions. The antiapoptotic effects depend at least in part on the enhancement of sirtuin‐1 and Klotho activity, which both inhibit activation of the NF‐κB inflammatory pathway. Importantly, in xenotransplanted human islets, GABA therapy stimulates β‐cell replication and insulin secretion. Thus, the intraislet GABAergic system is a target for the amelioration of diabetes therapy, including β‐cell survival and regeneration. GABA (or GABAergic drugs) can be combined with other antidiabetic drugs for greater effect.