β-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion.

Kaihara KA, Dickson LM, Jacobson DA, Tamarina N, Roe MW, Philipson LH, Wicksteed B
Diabetes. 2013 62 (5): 1527-36

PMID: 23349500 · PMCID: PMC3636652 · DOI:10.2337/db12-1013

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.

MeSH Terms (23)

Animals Crosses, Genetic Cyclic AMP Cyclic AMP-Dependent Protein Kinases Enzyme Induction Exenatide Glucose Clamp Technique Hyperglycemia Hypoglycemic Agents Insulin Insulin-Secreting Cells Insulin Secretion Kinetics Mice Mutant Proteins Patch-Clamp Techniques Peptides Phosphorylation Protein Processing, Post-Translational Protein Subunits Second Messenger Systems Up-Regulation Venoms

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