The early phase of insulin release in the first five minutes after intravenous administration of glucose, glucagon, and glucose-plus-glucagon was investigated systematically in various clinical conditions.

In normal subjects there is an immediate release of insulin after glucose, glucagon, and glucose-plus-glucagon infusions. The latter combination produced the highest insulin levels.

Of a group of nonobese subjects with diabetic heritage, some had impaired early release of insulin, but0 their mean response did not differ significantly from the normal group.

Investigation of nonobese potential diabetics (offspring of two diabetic parents) revealed that as a group average they had decreased insulin levels during the early phase of insulin release, even though intravenous glucose tolerance was normal. Four of ten subjects had a normal response.

Nonobese, noninsulin-dependent diabetics had no insulin response to infused glucose, but when glucagon was added to glucose a significant and rapid insulin discharge was observed. However, the magnitude of this response was about half that seen in normal subjects after glucose-plusglucagon.

Finally, the early phase of insulin release was studied in obese nondiabetic subjects who demonstrated an exaggerated insulin release to each stimulus. Again, glucose-plusglucagon was the most potent stimulator of insulin release.

It is postulated that impairment in the early phase of insulin release may be the first detectable abnormality of insulin secretion in diabetes mellitus and that glucagon has the capability of restoring this toward normal.

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