PKA Enhances the Acute Insulin Response Leading to the Restoration of Glucose Control.

ABSTRACT

Diabetes arises from insufficient insulin secretion and failure of the ß-cell mass to persist and expand. These deficits can be treated with ligands to Gs-coupled G-protein-coupled receptors that raise ß-cell cAMP. Here we studied the therapeutic potential of ß-cell cAMP-dependent protein kinase (PKA) activity in restoring glucose control using ß-caPKA mice. PKA activity enhanced the acute insulin response (AIR) to glucose, which is a primary determinant of the efficacy of glucose clearance. Enhanced AIR improved peripheral insulin action, leading to more rapid muscle glucose uptake. In the setting of pre-established glucose intolerance caused by diet-induced insulin resistance or streptozotocin-mediated ß-cell mass depletion, PKA activation enhanced ß-cell secretory function to restore glucose control, primarily through augmentation of the AIR. Enhanced AIR and improved glucose control were maintained through 16 weeks of a high-fat diet and aging to 1 year. Importantly, improved glucose tolerance did not increase the risk for hypoglycemia, nor did it rely upon hyperinsulinemia or ß-cell hyperplasia, although PKA activity was protective for ß-cell mass. These data highlight that improving ß-cell function through the activation of PKA has a large and underappreciated capacity to restore glucose control with minimal risk for adverse side effects.