Objective— To determine if knowledge of characteristics of insulin response to various secretagogues during the preclinical phase of type I diabetes may facilitate the diagnosis of subjects at risk.

Research Design and Methods— A test consisting of sequential intravenous challenge with glucose (0.3 g/kg) and glucagon (1 mg, 10 min after the end of glucose injection) was performed on 171 ICA relatives of type I diabetic patients, 18 ICA+ relatives of type I diabetic patients, and 5 transiently hyperglycemic subjects. Acute response to glucose was expressed as the sum of plasma insulin at 2 and 5 min and response to glucagon as the increase in plasma insulin after 10 min.

Results— Responses below the lower 95% confidence interval in the ICA population (40 and 43 μU/ml for glucose and glucagon, respectively) were considered abnormal. The two values were correlated (r = 0.62). Abnormalities coexisted in 2.3% of the ICA group, 11% of the ICA+ group, and 100% of the transiently hyperglycemic group. All the relatives who subsequently developed diabetes or hyperglycemic subjects who required insulin exhibited combined abnormalities. Some ICA and ICA+ relatives were tested repeatedly over a follow-up period of 1.5–4 yr. Although the intraindividual coefficient of variation for the two responses was high (28 and 30%), values tended to run parallel in both ICA+ and ICA relatives. In 2 patients monitored for 2 and 4 yr before diabetes developed, both responses declined at the same rate. In terms of prediction of diabetes, sensitivity of combined abnormalities was high (100%). But compared with the intravenous glucose tolerance test, improvement of specificity by the double challenge was not statistically significant.

Conclusions— Both insulin responses to glucose and glucagon are related. They depend on the secretory capacity of β-cells and simultaneously become abnormal in the prediabetic phase.

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