The riddle of formycin A insulinotropic action.
Formycin A augments insulin release evoked by glucose (5.6 mm or more), this effect not being rapidly reversible. The mechanism responsible for the insulinotropic action of formycin A was investigated in isolated pancreatic islets. It could not be ascribed to facilitation of glucose metabolism. On the contrary, formycin A inhibited glucose oxidation, lowered ATP content, and impaired glucose-stimulated protein biosynthesis. The insulinotropic action of formycin A was apparently attributable to its conversion to formycin A 5'-triphosphate, both this process and the secretory response to formycin A being abolished by the inhibitor of adenosine kinase 5-iodotubercidin. In agreement with the latter view, adenosine receptor antagonists such as 8-cyclopentyl-1, 3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine failed to suppress and, instead, augmented the insulinotropic action of formycin A. Unexpectedly, however, formycin A failed to decrease 86Rb efflux, this coinciding with a low efficiency of formycin A 5'-triphosphate to inhibit KATP-channel activity in excised membranes and with the fact that formycin A increased gliben-clamide-stimulated insulin release. The secretory response to formycin A represented a Ca2+-dependent process suppressed in the absence of extracellular Ca2+ or presence of verapamil and associated with an increased net uptake of 45Ca. Nevertheless, the view that formycin A exerts any major effect upon intracellular Ca2+ redistribution, protein kinase C activity, or cyclic AMP net production also met with objections such as the minor secretory effect of formycin A in islets exposed to a high concentration of K+ in the presence of a diazoxide analog, the resistance of formycin A insulinotropic action to bisindolylmaleimide, the poor increase of cyclic AMP content in formycin A-stimulated islets, and the pronounced enhancement by forskolin or theophylline of insulin release from islets exposed to formycin A. It is concluded, therefore, that the mechanism of action of formycin A in the pancreatic beta-cell remains to be elucidated.
Malaisse
W J
WJ
Laboratorie of Experimental Medicine, Brussels Free University, Brussels, Belgium.
Lebrun
P
P
Pirotte
B
B
Van Poelje
P D
PD
Viñambres
C
C
Villanueva-Peñacarrillo
M L
ML
Valverde
I
I
Gäbel
J
J
Rorsman
P
P
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D005573:Formycins / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012265:Ribonucleotides / Q000378:metabolism; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D005573:Formycins; D007328:Insulin; D012265:Ribonucleotides; D014970:Xanthines; C032552:formycin triphosphate; C034214:5-iodotubercidin; C034550:formycin; C051360:1,3-dipropyl-8-cyclopentylxanthine; D014700:Verapamil; D005947:Glucose; D000241:Adenosine; D014372:Tubercidin; D003981:Diazoxide; D005905:Glyburide; D002118:Calcium