PKA Enhances the Acute Insulin Response Leading to the Restoration of Glucose Control
| Autor: | Lorna M. Dickson, Barton Wicksteed, Kelly Kaihara, Johanne H. Ellenbroek, Brian T. Layden, Caitlin M.D. Orr |
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| Rok vydání: | 2014 |
| Předmět: |
Blood Glucose
Aging medicine.medical_specialty Genotype Endocrinology Diabetes and Metabolism Glucose uptake medicine.medical_treatment Mice Transgenic 030209 endocrinology & metabolism Biology Hypoglycemia Diabetes Mellitus Experimental Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Insulin-Secreting Cells Diabetes mellitus Internal medicine Internal Medicine medicine Hyperinsulinemia Animals Insulin Muscle Skeletal Receptor Protein kinase A 030304 developmental biology 0303 health sciences medicine.disease Cyclic AMP-Dependent Protein Kinases 3. Good health Glucose Endocrinology Islet Studies Insulin Resistance |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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