Recently published findings indicate that a knockout (KO) of soluble adenylyl 
cyclase (sAC, also known as AC-10) gene expression in mice leads to defective 
glucoregulation that is characterized by reduced pancreatic insulin secretion 
and reduced intraperitoneal glucose tolerance. Summarized here are current 
concepts regarding the molecular basis for this phenotype, with special emphasis 
on the potential role of sAC as a determinant of glucose-stimulated insulin 
secretion. Highlighted is new evidence that in pancreatic beta cells, oxidative 
glucose metabolism stimulates mitochondrial CO₂production that in turn generates 
bicarbonate ion (HCO(3)(-)). Since HCO(3)(-) binds to and directly stimulates 
the activity of sAC, we propose that glucose-stimulated cAMP production in beta 
cells is mediated not simply by transmembrane adenylyl cyclases (TMACs), but 
also by sAC. Based on evidence that sAC is expressed in mitochondria, there 
exists the possibility that beta-cell glucose metabolism is linked to 
mitochondrial cAMP production with consequent facilitation of oxidative 
phosphorylation. Since sAC is also expressed in the cytoplasm, sAC catalyzed 
cAMP production may activate cAMP sensors such as PKA and Epac2 to control ion 
channel function, intracellular Ca²⁺ handling, and Ca²⁺-dependent exocytosis. 
Thus, we propose that the existence of sAC in beta cells provides a new and 
unexpected explanation for previously reported actions of glucose metabolism to 
stimulate cAMP production. It seems possible that alterations of sAC activity 
might be of importance when evaluating new strategies for the treatment of type 
2 diabetes (T2DM), or when evaluating why glucose metabolism fails to stimulate 
insulin secretion in patients diagnosed with T2DM. This article is part of a 
Special Issue entitled: The role of soluble adenylyl cyclase in health and 
disease.