Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adenosine analogue formycin A is phosphorylated to its triphosphate ester in a sequence of reactions catalyzed by adenosine kinase and adenylate kinase. Formycin A triphosphate is an ATP analogue that is currently used to probe for ATP binding sites. Considering the key role ascribed to ATP in the coupling of metabolic to cationic events in the process of glucose-stimulated insulin release, we investigated whether formycin A displays insulinotropic action in rat pancreatic islets. Formycin A (10 microM to 1.0 mM) caused a concentration-related increase of insulin release evoked by 8.3 mM D-glucose and prevented the fall in insulin output otherwise observed over two successive incubations of 90 min each. Formycin A (1.0 mM) also augmented insulin secretion at low (5.6 mM) and high (16.7 mM) concentrations of D-glucose. At the low hexose concentration, the secretory response to formycin A was comparable to that evoked by either glibenclamide or glipizide. At higher concentrations of D-glucose, however, formycin A was more potent than the hypoglycemic sulfonylureas in enhancing insulin output. These findings support the role of ATP in glucose-stimulated insulin release and, therefore, suggest that ATP mimetics represent a new class of insulinotropic agents that have potential utility in the treatment of non-insulin-dependent diabetes mellitus.
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PMID:Insulinotropic action of formycin A. 785 78

By closing ATP-sensitive K+ (K+-ATP) channels, glucose promotes depolarization-dependent Ca2+ entry and cytoplasmic free Ca2+ concentration ([Ca2+]i) rise in beta-cells. Ca2+-dependent exocytosis of insulin granules is then potentiated by a K+-ATP channel-independent action of glucose. The underlying mechanisms of this second pathway are still unclear. They were studied by incubating normal mouse islets in the presence of diazoxide to open K+-ATP channels and 30 mmol/l K+ to restore Ca2+ entry. The effect of glucose did not require priming of beta-cells by preincubation in the presence of high glucose and could not be attributed to interaction of the sugar with a "glucoreceptor." There is no evidence that protein kinases A and C are involved in the K+-ATP channel-independent pathway, because inhibitors of the kinases did not alter the effect of glucose. In 3 mmol/l glucose, fatty acids did not influence K+-induced insulin secretion, even in the presence of bromopalmitate, an inhibitor of fatty acid oxidation. Bromopalmitate alone had no effect, but it decreased the potentiation that the fatty acids produce in 20 mmol/l glucose. It is thus unlikely that long-chain acyl CoAs mediate the effect of glucose. The action of glucose was not associated with an increase in arachidonic acid release from the islets and was not mimicked by exogenous arachidonic acid. Phospholipase A2 inhibitors antagonized the effect of glucose, but their action was not reversed by arachidonic acid or palmitate and was associated with a fall in islet ATP. No evidence could be found for the intervention of NO, cGMP, Mg, phosphate, phosphatidylinositol 3-kinase, or pertussis toxin-sensitive G-proteins. Formycin A, an adenosine analog that is converted to formycin A-triphosphate in islets, increased insulin secretion in the absence and presence of glucose. In conclusion, the present and our previous results strongly suggest that among all known potential second messengers, adenine nucleotides are the best candidates as regulators of insulin secretion through the K+-ATP channel-independent pathway.
Diabetes 1998 Nov
PMID:The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose: in search of the underlying mechanism. 979 40