The pancreatic beta-cell recognition of insulin secretagogues. Effects of calcium and sodium on glucose metabolism and insulin release.
The transport and oxidation of glucose, the content of fructose 1,6-diphosphate, and the release of insulin were studied in microdissected pancreatic islets of ob/ob mice incubated in Krebs-Ringer bicarbonate medium. Under control conditions glucose oxidation and insulin release showed a similar dependence on glucose concentration with the steepest slope in the range 5-12mm. The omission of Ca(2+), or the substitution of choline ions for Na(+), or the addition of diazoxide had little if any effect on glucose transport. However, Ca(2+) or Na(+) deficiency as well as diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) or ouabain partially inhibited glucose oxidation. These alterations of medium composition also increased the islet content of fructose 1,6-diphosphate, as did the addition of adrenaline. Phentolamine [2-N-(3-hydroxyphenyl)-p-toluidinomethyl-2-imidazoline] counteracted the effects of adrenaline and Ca(2+) deficiency on islet fructose 1,6-diphosphate. After equilibration in Na(+)-deficient medium, the islets exhibited an increase in basal insulin release whereas the secretory response to glucose was inhibited. The inhibitory effects of Na(+) deficiency on the secretory responses to different concentrations of glucose correlated with those on (14)CO(2) production. When islets were incubated with 17mm-glucose, the sudden replacement of Na(+) by choline ions resulted in a marked but transient stimulation of insulin release that was not accompanied by a demonstrable increase of glucose oxidation. Galactose and 3-O-methylglucose had no effect on glucose oxidation or on insulin release. The results are consistent with a metabolic model of the beta-cell recognition of glucose as insulin secretagogue and with the assumption that Ca(2+) or Na(+) deficiency, or the addition of adrenaline or diazoxide, inhibit insulin release at some step distal to stimulus recognition. In addition the results suggest that these conditions create a partial metabolic block of glycolysis in the beta-cells. Hence the interrelationship between the processes of stimulus recognition and insulin discharge may involve a positive feedback of secretion on glucose metabolism.
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D002794:Choline / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005636:Fructosephosphates / Q000378:metabolism; D005690:Galactose / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007457:Iodine Radioisotopes; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D000432:Methanol; D051379:Mice; D010042:Ouabain / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology*; D013997:Time Factors; D014316:Tritium
D002250:Carbon Radioisotopes; D005636:Fructosephosphates; D007328:Insulin; D007457:Iodine Radioisotopes; D014316:Tritium; D010042:Ouabain; D012964:Sodium; D005947:Glucose; D002794:Choline; D003981:Diazoxide; D002118:Calcium; D005690:Galactose; D000432:Methanol; D004837:Epinephrine; D010646:Phentolamine