title: Inositol hexakisphosphate and sulfonylureas regulate beta-cell protein phosphatases.
abstract: In human type 2 diabetes, loss of glucose-stimulated insulin exocytosis from the pancreatic beta-cell is an early pathogenetic event. Mechanisms controlling insulin exocytosis are, however, not fully understood. We show here that inositol hexakisphosphate (InsP(6)), whose concentration transiently increases upon glucose stimulation, dose-dependently and differentially inhibits enzyme activities of ser/thr protein phosphatases in physiologically relevant concentrations. None of the hypoglycemic sulfonylureas tested affected protein phosphatase-1 or -2A activity at clinically relevant concentrations in these cells. Thus, an increase in cellular phosphorylation state, through inhibition of protein dephosphorylation by InsP(6), may be a novel regulatory mechanism linking glucose-stimulated polyphosphoinositide formation to insulin exocytosis in insulin-secreting cells.
authors.affiliation: Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, SE-118 83 Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Lehtihet
authors.forename: Richard E
authors.initials: RE
authors.lastname: Honkanen
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008387:Marine Toxins; D009132:Muscles / Q000378:metabolism; D019319:Okadaic Acid / Q000378:metabolism; D010080:Oxazoles / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D010833:Phytic Acid / Q000378:metabolism*; D054645:Protein Phosphatase 1; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction; D013453:Sulfonylurea Compounds / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D008387:Marine Toxins; D010080:Oxazoles; D013453:Sulfonylurea Compounds; D019319:Okadaic Acid; C059041:calyculin A; D010833:Phytic Acid; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D005947:Glucose