A widely accepted concept has been that metabolites of glucose or factors associated with glucose metabolism, rather than glucose itself, trigger insulin release from the β cells. If this concept is correct, levels of metabolites or cofactors or of both should change within seconds of the glucose pulse. To examine the hypothesis, glucose, glucose-6-P, 6-P-gluconate, fructose-l,6-P2 plus triose-P, 3-P-glycerates plus P-enolpyruvate, ATP, ADP and P-creatine were measured in slices of individual rat islets after intravenous infusion of glucose in vivo or perfusion of the isolated pancreas with glucose in vitro. Tissue samples were obtained by quickfreezing methods as early as fifteen seconds and as late as sixty minutes following the glucose load. Insulin levels in serum and perfusate were measured concomitantly.
Insulin levels in peripheral blood rose within one minute of injection of glucose in vivo. Penetration of glucose, although very rapid, was carrier-mediated. Most of the metabolites and cofactors measured were unchanged during the first five minutes of glucose infusion. After one hour of hyperglycemia there was a marked rise in all metabolites and cofactors except ATP.
In the perfused pancreas, insulin secretion increased within 0.5 minute of the glucose stimulus and the typical biphasic response was observed. The glucose content of islets increased threefold within 0.25 minute and sixfold within 0.5 minute. The levels of all other metabolites measured were virtually unchanged during the early phase of the endocrine response, in spite of the eightfold increment in the glucose of the medium and the almost tenfold rise of insulin release.
The constancy of the islet's metabolite pattern when the islets were exposed to high glucose—particularly during the early transition phase—is remarkable, since glycolytic flux was supposedly increased severalfold.
The fact that the metabolite profile of the islets is so precisely maintained within a narrow range makes it unlikely that any of the metabolites measured might serve as triggers for insulin release. It is more likely that the glucose molecule itself exerts its releasing action by stimulating glucoreceptors located on the cell membrane.