Plasma levels of proinsulin and its conversion intermediates are elevated in NIDDM patients. Recent studies have suggested that proinsulin levels are also increased relative to insulin levels in subjects who subsequently develop NIDDM. This may be due to insulin resistance or a defect in proinsulin processing or insulin secretion. If insulin resistance is the trigger, the proinsulinto-insulin ratio would be higher in insulin-resistant subjects than in insulin-sensitive subjects. We examined the association of fasting proinsulin, 32,33 split proinsulin, and the proinsulin-to-insulin ratio with insulin sensitivity (SI), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model in 138 normoglycemic subjects ages 53–61 years. We also investigated the relation of proinsulins and the proinsulin-to-insulin ratio to acute insulin response (AIR). Fasting specific insulin (r = −0.64), intact proinsulin (r = −0.43), and 32,33 split proinsulin (r = −0.54) concentrations were inversely correlated and the proinsulin-to-insulin ratio positively (r = 0.31) correlated with SI (P < 0.001). Fasting specific insulin (r = 0.64), intact proinsulin (r = 0.35), and 32,33 split proinsulin (r = 0.45) concentrations were positively correlated and proinsulin-to-insulin ratio (r = −0.40) inversely correlated with AIR (P < 0.001). The proinsulin-to-insulin ratio increased by increasing levels of SI (quartiles of 5, from low to high: 0.048, 0.078, 0.078, 0.068; P = 0.012) and decreased by increasing SI (quartiles of SI from low to high: 0.088, 0.068, 0.058, 0.058; P = 0.005). These associations were independent of age, sex, BMI, and waist-to-hip ratio. Furthermore, the relation between the proinsulin-to-insulin ratio and AIR was independent of SI In conclusion, in normoglycemic subjects, insulin resistance (low SI was associated with a low rather than a high proinsulin-to-insulin ratio. Subjects who maintained normoglycemia with a low AIR had an increased proinsulin-to-insulin ratio compared with those who needed high to maintain normoglycemia. These results suggest that, in subjects with normal glucose tolerance, insulin resistance does not induce increased proinsulin relative to insulin secretion, but rather is associated with enhanced processing of proinsulin.

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