FIG. 1. Metabolic hypothesis of glucose-stimulated insulin release from
ß-cells. In mammalian ß-cells, the rate of glucose phosphorylation,
catalyzed via glucokinase, is the bottleneck for further metabolic flux.
Because of the kinetic properties of GK, this rate is proportional to the
extracellular glucose concentration. It is unknown if other hexokinases and
G6P dephosphorylation can influence this rate-limiting step. Mitochondrial
uptake and metabolism of pyruvate—both carboxylation and
decarboxylation—allows production of various messengers for exocytosis,
such as the ATP/ADP ratio and the efflux of mitochondrial metabolic
intermediates. Glucose signaling pathways are amplified via production of
cAMP, which is stimulated by activated GLP-1Rs, GIP, and glucagon (not shown).
This effect is further modulated by the phospholipase C pathway (not shown)
and the signaling induced by insulin receptors (not shown) and
leptin-receptors (Ob-R). Recent data indicate that part of the effect of cAMP
on exocytosis in ß-cells is mediated via a protein kinase
A—independent pathway involving the GDP/GTP-exchanging protein
cAMP-GEFII (117). 
V,
membrane depolarization.
