| First Author | Kaihara KA | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 5 | Pages | 1688-97 |
| PubMed ID | 25475437 | Mgi Jnum | J:249507 |
| Mgi Id | MGI:5922527 | Doi | 10.2337/db14-1051 |
| Citation | Kaihara KA, et al. (2015) PKA Enhances the Acute Insulin Response Leading to the Restoration of Glucose Control. Diabetes 64(5):1688-97 |
| abstractText | Diabetes arises from insufficient insulin secretion and failure of the beta-cell mass to persist and expand. These deficits can be treated with ligands to Gs-coupled G-protein-coupled receptors that raise beta-cell cAMP. Here we studied the therapeutic potential of beta-cell cAMP-dependent protein kinase (PKA) activity in restoring glucose control using beta-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 beta-cell mass depletion, PKA activation enhanced beta-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 beta-cell hyperplasia, although PKA activity was protective for beta-cell mass. These data highlight that improving beta-cell function through the activation of PKA has a large and underappreciated capacity to restore glucose control with minimal risk for adverse side effects. |
