The dual function of glucose in islets of Langerhans.

It is widely accepted that metabolites of glucose rather than glucose itself trigger insulin release from p-cells. If so, level changes of such metabolites ought to occur in P-cells within seconds of a glucose pulse. To examine this hypothesis, glucose, glucose-6-P, fructose-diP plus triose-P, 6-P-gluconate, ATP, and P-creatine were measured in individual rat islets after intravenous infusion for 1 to 60 min of glucose, mannoheptulose, and xylitol, or combinations of these compounds. Insulin levels in serum were determined concomitantly. Some of the animals were fasted for 5 or 6 days prior to glucose infusion. Individual islets were dissected from freeze-dried sections sampled with quick freezing methods. The sensitivity and specificity needed for analysis of metabolites and cofactors were gained by using enzymatic fluorometric procedures combined with an oil well method and enzymatic cycling of pyridine nucleotides. Serum insulin was determined immunochemically. Insulin levels in peripheral blood rose within 1 min of injection of glucose. Mannoheptulose as well as fasting blocked this glucose effect. Penetration of glucose, although very rapid, was carrier mediated, since under special conditions mannoheptulose and also xylitol caused exit countertransport of glucose from the P-cells. This shows that mannoheptulose has effects on glucose metabolism of islets that are independent of its ability to inhibit phosphorylation. Most of the metabolites and cofactors measured were unchanged during the first 5 min of glucose infusion. Fructose-dip plus triose-P rose within 1 min in fed animals, but also increased when insulin release was blocked in various ways. After 1 hour of hyperglycemia there was a marked rise in all metabolites and cofactors save ATP. The metabolic changes induced by glucose infusion in severely fasted animals, indicate that islet cell metabolism was stimulated, although insulin release was blocked. These results and reports by other investigators suggest that glucose itself rather than its metabolites triggers insulin secretion.