title: New insights concerning the molecular basis for defective glucoregulation in soluble adenylyl cyclase knockout mice.
abstract: 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.
authors: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA; Department of Pharmacology, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA. Electronic address: holzg@upstate.edu.
authors: George G
authors: GG
authors: Holz
authors: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA.
authors: Colin A
authors: CA
authors: Leech
authors: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA.
authors: Oleg G
authors: OG
authors: Chepurny
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout
chemical_list: D007328:Insulin; D000262:Adenylyl Cyclases; D005947:Glucose
keywords: Bicarbonate ion; Glucose; Insulin secretion; Soluble adenylyl cyclase; cAMP