S. Raptis

DYNAMICS OF INSULIN SECRETION: COMPARISON OF VARIOUS IN VITRO PREPARATIONS *

SUMMARY All preparations examined displayed qualitatively rather than quantitatively different patterns of response to tolbutamide as compared to HB 419. The rapidly occurring but short-lasting enhancement of the insulin secretion brought about by tolbutamide contrasted to the delayed but more persisting stimulation provoked by HB 419. Tolbutamide interferred with the glucose-induced insulin secretion, resulting in an inhibition of the release after withdrawal of the drug. HB 419, on the other hand, did not inhibit but rather potentiated the effect of glucose, except when the sugar was present in the highest concentrations. Furthermore, when the insulin secretion was stimulated by repeated pulses of sulfonylurea, a refractory state occurred more rapidly when tolbutamide was used, as compared to HB 419. In the presence of low glucose concentrations (60 mg%), neither drug stimulated the insulin release more than did pulses of high glucose concentration (200 mg%). The observed synergism between glucose and HB 419 is in accordance with the great blood-sugar-lowering capacity and the high plasma insulin levels induced by the new compound, when given together with glucose to normal human subjects ( Raptis et al., 1969 ). Also, elderly diabetic subjects, unresponsive to tolbutamide, not only showed increased concentrations of insulin in plasma and moderate hypoglycemia after treatment with HB 419 alone, but also displayed a clear rise of immunoreactive insulin and lower blood sugar values when given a combination of HB and oral glucose ( Raptis et al., 1969 ; Chandalia et al., 1969 ). This response might not be due to the greater molar efficiency of the new compound as compared to tolbutamide but to some specific interaction with the glucose metabolism and/or energy production in the β-cell. It should be mentioned that intestinal hormones like glucagon (Melani et al., 1966, 1967 ; Simpson et al., 1966 ) and secretin ( Raptis et al., 1968, 1969 ; Deckert, 1968 ) have similar effects in diabetic subjects which are unresponsive to glucose alone.