β-Cell–Specific Protein Kinase A Activation Enhances the Efficiency of Glucose Control by Increasing Acute-Phase Insulin Secretion
| Autor: | Michael W. Roe, Lorna M. Dickson, Natalia A. Tamarina, David A. Jacobson, Louis H. Philipson, Barton Wicksteed, Kelly Kaihara |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Patch-Clamp Techniques Endocrinology Diabetes and Metabolism medicine.medical_treatment Incretin 030209 endocrinology & metabolism Biology Second Messenger Systems Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Insulin-Secreting Cells Internal medicine Insulin Secretion Cyclic AMP Internal Medicine medicine Animals Hypoglycemic Agents Insulin Phosphorylation Protein kinase A Crosses Genetic Original Research 030304 developmental biology 0303 health sciences Venoms Glucose clamp technique Cyclic AMP-Dependent Protein Kinases Up-Regulation Insulin oscillation Kinetics Protein Subunits Endocrinology Enzyme Induction Hyperglycemia Second messenger system Glucose Clamp Technique Commentary Exenatide Mutant Proteins Peptides Protein Processing Post-Translational Signal Transduction Hormone |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute-phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic β-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute-phase insulin secretion alone. Acute-phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute-phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute-phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute-phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute-phase insulin secretion are mediated by the phosphorylation of proteins involved in β-cell exocytosis. Thus, β-cell PKA activity transduces the cAMP signal to dramatically increase acute-phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose. |
| Databáze: | OpenAIRE |
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