Molecular physiological and biological studies on the mechanismof impaired glucose-induced insulin secretion in diabetes mellitus

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In order to elucidate the molecular mechanism of impairment of glucose-induced insulin secretion in type 2 diabetes mellitus, we examined the altered expression of SNARE proteins (syntaxin 1A and SNAP-25), which are known to play an important role on exocytolic process of insulin secretary granules as sensor molecules for the intracellular CaィイD12+ィエD1 elevation and metabolic signals derived from glucose, in diabetic GK (Goto-Kakizaki) rats. Immunoblot analysis revealed that protein levels of syntaxin 1A and SNAP-25 in GK rat islets decreased to 〜60% of the levels in control rat islets. Restoration of these proteins to normal levels in GK rats was achieved via the recombinant adenovirus-mediated gene transduction system. Glucose-stimulated insulin release from Adex 1CA syntaxin 1A and Adex 1CA SNAP-25-infected GK rat islets increased up to those from normal rat islets. The decreased expression of SNARE proteins is at least in part the defect responsible for impaired insulin secretion. For the screening of the agents, which can augment the CaィイD12+ィエD1 sensitivity of exocytotic mechanism of insulin secretory granules, pimobendan and JTT-608 were examined. Both of them increased the glucose-induced insulin secretion dose-dependently. Using electrically permeabilized rat pancreatic islets, they augmented the sensitivity for intracellular CaィイD12+ィエD1 elevation to trigger the exocytosis. It is revealed that pimobendan can exhibit its effect by in part activating CaィイD12+ィエD1/calmodulin dependent protein kinase II, and that JTT-608 can do it by inhibiting phosphodiesterase activity to increase intracellular cAMP levels. Accordingly, these agents would become novel therapeutic means for the treatment of impaired insulin secretion in type 2 diabetes mellitus.