Defects inβ-Cell Function and Insulin Sensitivity in Normoglycemic Streptozocin-Treated Baboons: A Model of Preclinical Insulin-Dependent Diabetes*

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Abstract
During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic .beta.-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in .beta.-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo .beta.-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozotocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozotocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 .+-. 0.2% .+-. SE) to 1.2 .+-. 0.1%/min (P < 0.01), the acute insulin response to arginine (AIRarg) fell from 67.7 .+-. 19.4 .mu.U/mL (485.8 .+-. 139.2 pmol/L) to 32.8 .+-. 7.2 .mu.U/mL (235.3 .+-. 51.7 pmol/L; P < 0.05), and the acute insulin response to glucose (AIRgluc) fell from 881 .+-. 243 .mu.U/mL .cntdot. 10 min (6321 .+-. 1744 pmol/L .cntdot. 10 min) to 334 .+-. 82 .mu.U/mL .cntdot. 10 min (2396 .+-. 588 pmol/L .cntdot. 10 min; P < 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIRarg (expressed as the slope of potentiation). This was reduced by 94% from 1.8 .+-. 0.5 to 0.1 .+-. 0.1 (P < 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozotocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of .beta.-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 .+-. 4.3 mg/dL (4.7 .+-. 0.2 mmol/L), Kg was 1.8 .+-. 0.3%/min, fasting plasma insulin was 35.9 .+-. 8.5 .mu.U/mL (257.6 .+-. 6.10 pmol/L), AIRarg was 67.0 .+-. 15.4 .mu.U/mL (480.7 .+-. 110.5 pmol/L), and AIRgluc was 615.3 .+-. 265.3 .mu.U/mL .cntdot. 10 min (4413 .+-. 1901 pmol/L .cntdot. 10 min), and tissue insulin sensitivity was 2.7 .+-. 0.4 .times. 104 min/.mu.U .cntdot. mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3. After further streptozocin administration, diabetes was produced, with a fasting plasma glucose level of 182 .+-. 19 mg/dL (10.1 .+-. 1.1 mmol/L) and a Kg of 0.7 .+-. 0.1%/min; this was associated with a small AIRarg [17 .+-. 6 .mu.U/mL (122 .+-. 43 pmol/L] but no detectable AIRgluc or slope of glucose potentiation. These results indicate that after relatively slight .beta.-cell injury, in which fasting plasma glucose and Kg remain within the normal range, there is significant reduction in insulin secretion and insulin sensitivity. Some of these changes represent the response to acute injury from which there is subsequent recovery. The most sensitive in vivo measurement of .beta.-cell function in this situation was the slope of glucose potentiation of AIRarg, which was markedly reduced and remained low. These findings are very similar to those in nondiabetic first degree relatives of type I diabetic patients and suggest that the impairment in insulin secretion and insulin sensitivity in these human subjects could be the result of .beta.-cell damage.

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