Inhibition of protein kinase A-induced glucagon synthesis and secretion by glucose

The control of glucagon biosynthesis and secretion in the pancreatic islet was examined in response to protein kinase A stimulation at various glucose concentrations. Forskolin plus 3-isobutyl 1-methylxanthine (IBMX) stimulated both glucagon synthesis and secretion at a glucose concentration equivalent to hypoglycemia (0.5 g/L, P<.001), but not at higher glucose concentrations (1.0, 2.0, and 4.0 g/L, P>.05). Destruction of B cells with streptozotocin or inhibition of glycolysis with mannoheptulose did not reverse the inhibitory action of high glucose (4.0 g/L) on the response of glucagon to forskolin plus IBMX. In contrast, citrate but not EGTA treatment permitted forskolin plus IBMX to stimulate glucagon synthesis and secretion (P<.05 and P<.001, respectively) in the presence of high glucose. We conclude that citrate can block the inhibitory action of glucose on the response of A cells to the protein kinase A pathway, possibly through its effects on an intracellular metabolic pathway.