H. Yajima et al., CAMP enhances insulin secretion by an action on the ATP-sensitive K+ channel-independent pathway of glucose signaling in rat pancreatic islets, DIABETES, 48(5), 1999, pp. 1006-1012
Cyclic AMP potentiates glucose-stimulated insulin release by actions predom
inantly at a site, or sites, distal to the elevation of the cytosolic free
Ca2+ concentration ([Ca2+](i)). Glucose also acts at a site, or sites, dist
al to the elevation of [Ca2+](i) via the ATP-sensitive K+ channel (K-ATP(+)
channel)-independent signaling pathway. Accordingly, using rat pancreatic
islets, me studied the location of the action of cAMP and its interaction w
ith the glucose pathway. Forskolin, an activator of adenylyl cyclase, raise
d intracellular cAMP levels and enhanced KCl-induced (Ca2+-stimulated) insu
lin release in the presence, but not in the absence, of glucose. Thus, cAMP
has no direct effect on Ca2+-stimulated insulin release. The interaction b
etween cAMP and glucose occurs at a step distal to the elevation of [Ca2+](
i) because forskolin enhancement of KCl-induced insulin release, in the pre
sence of glucose, was demonstrated in the islets treated with diazoxide, a
K-ATP(+) channel opener. The enhancement of insulin release was not associa
ted with any increase in [Ca2+](i). Furthermore, the interaction between cA
MP and glucose was unequivocally observed even under stringent Ca2+-free co
nditions, indicating the Ca2+-independent action of cAMP. This action of cA
MP is physiologically relevant, because not only forskolin but also glucago
n-like peptide 1, glucose-dependent insulinotropic polypeptide, and pituita
ry adenylyl cyclase activating polypeptide exerted similar actions. In conc
lusion, the cAMP/protein kinase A pathway has no direct effect on Ca2+-stim
ulated insulin exocytosis. Rather, it strongly potentiates insulin release
by increasing the effectiveness of the K-ATP(+) channel-independent action
of glucose.