title: PKA Enhances the Acute Insulin Response Leading to the Restoration of Glucose Control.
abstract: 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.
authors.affiliation: Kovler Diabetes Center, The University of Chicago, Chicago, IL Committee for Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Kaihara
authors.affiliation: Kovler Diabetes Center, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Dickson
authors.affiliation: Kovler Diabetes Center, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.
authors.forename: Johanne H
authors.initials: JH
authors.lastname: Ellenbroek
authors.affiliation: Kovler Diabetes Center, The University of Chicago, Chicago, IL Committee for Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.
authors.forename: Caitlin M D
authors.initials: CM
authors.lastname: Orr
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Layden
authors.affiliation: Kovler Diabetes Center, The University of Chicago, Chicago, IL Committee for Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL wicksteed@uchicago.edu.
authors.forename: Barton
authors.initials: B
authors.lastname: Wicksteed
mesh_terms: D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose