β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation.

Although it is well-established how nutrients, growth factors, and hormones impact functional β-cell mass (BCM), the influence of the central nervous system in this regard, and especially in the context of islet immune modulation, has been understudied. Here we investigated the expression and activity of pancreatic islet α7 nicotinic acetylcholine receptor (α7nAChR) in islet anti-inflammatory and prosurvival signaling. Systemic administration of α7nAChR agonists in mice improved glucose tolerance and curtailed streptozotocin-induced hyperglycemia by retaining BCM, in part through maintaining Pdx1 and MafA expression and reducing apoptosis. α7nAChR activation of mouse islets ex vivo led to reduced inflammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling. Because the vagus nerve conveys anti-inflammatory signals to immune cells of the spleen and other nonneural tissues in the viscera by activating α7nAChR agonists, our study suggests a novel role for β-cell α7nAChR that functions to maintain β-cell survival and mass homeostasis through modulating islet cytokine and phosphatidylinositol 3-kinase-dependent signaling pathways. Exploiting these pathways may have therapeutic potential for the treatment of autoimmune diabetes.