Inositol hexakisphosphate and sulfonylureas regulate beta-cell protein phosphatases |
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Authors: | Lehtihet Mikael Honkanen Richard E Sjöholm Ake |
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Institution: | Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, SE-118 83 Stockholm, Sweden. |
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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. |
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Keywords: | Polyphosphoinositides Islet Insulin secretion Diabetes Sulfonylurea Protein phosphatase Okadaic acid Signal transduction Exocytosis |
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