1526-P: Alpha Cells Facilitate Neuronally-Stimulated Insulin Secretion at Fasting Glucose

Introduction: Pancreatic islets are richly innervated by parasympathetic neurons and in turn neuronal stimulation can induce insulin secretion even in the fasted state. A prime example of this neuronally-driven insulin secretion is the cephalic phase insulin response, which is the release of insulin in the anticipation of a meal and occurs prior to changes in blood glucose. We recently found IL-1b to be in an important mediator of cephalic phase insulin secretion, however the mechanisms enabling neuronally-mediated insulin release from pancreatic islets in the fasted, low glucose state are still unknown.

Methods: We treated overnight-fasted mice with exogenous glucagon pre-treated with atropine and assessed insulin secretion. Using transgenic mice in which exclusively alpha cells are ablated, we studied the contribution of glucagon in cephalic phase insulin secretion. With isolated islets of wild-type and alpha cell-ablated mice we assessed insulin and glucagon secretion at 3.5mM glucose after co-stimulation with IL-1b and a muscarinic agonist (carbachol). Further, we blocked both glucagon and GLP-1 receptors to investigate which receptor glucagon acts on in our isolated islets setting.

Results: We found that exogenous glucagon can stimulate insulin secretion and this stimulation was absent in atropine-pretreated mice. Further, alpha-cell ablated mice do not exhibit a cephalic phase insulin response. In vitro, co-stimulating islets with the carbachol and IL-1b stimulated insulin secretion at basal glucose, and this was not the case in alpha cell-ablated islets. Lastly, we found that glucagon acts both on the glucagon and GLP-1 receptor to enable carbachol and IL-1b stimulated insulin release.

Conclusion: Alpha cells are essential for cephalic phase insulin secretion and this neuronally-mediated beta-cell response relies on glucagon or GLP-1, thereby positioning alpha cells as an important facilitator of neuronally-stimulated insulin secretion at fasting glucose.