Insulinogenic reserve was tested with arginine, glucagon, and epinephrine in eight unstable and four stable diabetics and in five normal subjects. All subjects were fasted and resting during the tests. Blood glucose regulatory stability was measured during near-normal (ambulatory-fed) conditions in the same subjects. Evaluation of insulinogenic reserve was based on changes in plasma immunoreactive insulin (IRI) concentration. The validity of assessing changes in IRI concentration in the presence of insulin-binding antibodies was supported with simultaneous measurements of indirect indications of the biologic effects of insulin. The changes, from base-line values, in IRI concentrations were consistent with and appropriate for the changes in blood glucose and serum free fatty acid and ketone body concentrations. No significant blood glucose fluctuations occurred under unstimulated fasting-resting conditions in any subject (saline test), in contrast to the distinct differences between groups in the amplitude of glycemic excursions during ambulatory-fed conditions. Blood glucose and ketone body concentrations increased steadily during the saline test in unstable diabetics in contrast to stable diabetics and normals. A correlation was evident between insulin secretory ability under resting-fasting conditions and blood glucose regulatory stability during ambulatory-fed conditions. Unstable diabetics had no demonstrable insulinogenic reserve, except for one maturity-onset diabetic with biochemical and clinical characteristics of unstable diabetes. Stable diabetics had demonstrable insulinogenic reserve but less than that of normals.