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

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 5; pp. 1688 - 1697
• Main Authors: Kaihara, Kelly A, Dickson, Lorna M, Ellenbroek, Johanne H, Orr, Caitlin M D, Layden, Brian T, Wicksteed, Barton
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.05.2015
• Subjects: Aging; Animals; Blood Glucose - physiology; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Diabetes; Diabetes Mellitus, Experimental; Genotype; Glucose; Glucose - metabolism; Insulin; Insulin - pharmacology; Insulin Resistance; Insulin-Secreting Cells - physiology; Islet Studies; Mice; Mice, Transgenic; Muscle, Skeletal - metabolism; Proteins; Rodents
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db14-1051

Diabetes arises from insufficient insulin secretion and failure of the β-cell mass to persist and expand. These deficits can be treated with ligands to Gs-coupled G-protein-coupled receptors that raise β-cell cAMP. Here we studied the therapeutic potential of β-cell cAMP-dependent protein kinase (PKA) activity in restoring glucose control using β-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 β-cell mass depletion, PKA activation enhanced β-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 β-cell hyperplasia, although PKA activity was protective for β-cell mass. These data highlight that improving β-cell function through the activation of PKA has a large and underappreciated capacity to restore glucose control with minimal risk for adverse side effects.