Normal Proinsulin Responses to Glucose in Mild Type II Subjects With Subnormal Insulin Response

IPI, 32–33 SPI, and insulin were measured by specific assays and related to plasma glucose and BMI in diet-treated type II diabetic subjects (FPG 7.3 ± 1.8 mM) and nondiabetic control subjects, both fasting and during a 12-mM hyperglycemic clamp. In both groups, BMI correlated with fasting plasma insulin (r_s = 0.76, P < 0.001 and 0.50, P < 0.01, respectively) and IPI (r_s = 0.49, P = 0.03 and r^s = 0.69, P < 0.001, respectively). Accounting for obesity, fasting plasma insulin was subnormal in diabetic subjects (58% of control group, 1 SD range, 49–68%), but did not correlate with FPG. In contrast, fasting plasma IPI correlated with FPG in the diabetic patients (r_s = 0.47, P < 0.05). In all subjects, 64% of the variance in plasma IPI was explained by BMI and FPG. Fasting 32–33 SPI was similar in the two groups. In response to a hyperglycemic clamp, the diabetic subjects had subnormal insulin concentrations (geometric means 71 and 214 pM, P < 0.001), but normal IPI concentrations (11.6 and 14.2 pM, respectively). Reduction of 32–33 SPI concentrations in diabetic subjects was intermediate (7.3 and 13.2 pM, P < 0.05). In diabetic subjects both fasting and clamp responses were subnormal for insulin but apparently normal for IPI. The major defect in pancreatic function is an impaired insulin response to glucose, and this, rather than an increase in proinsulin secretion, gives rise to the relative increase in proinsulin.