Excessive Secretion of Insulin Precursors Characterizes and Predicts Gestational Diabetes

Using assays that specifically measure insulin, intact proinsulin, and 32,33 split proinsulin, we examined the β-cell secretory response to an oral glucose tolerance test (OGTT) in 64 women with gestational diabetes mellitus (GDM) and 154 pregnant normoglycemic control subjects of comparable age and body mass index. Women with GDM were characterized by a lower 30-min insulin increment (40.8 [34.9–47.6] vs. 58.6 [53.6–64] pmol insulin/mmol glucose, P < 0.001; geometric mean [95% confidence interval]) and a higher plasma insulin level at 120 min (702 [610–808] vs. 444 [400–492] pmol/l, P < 0.001). 32,33 split proinsulin levels were elevated in GDM patients in both fasting (9.1 [7.3–11.4] vs. 6.7 [6.0–7.5] pmol/l, P < 0.02) and 120-min (75.2 [62.9–90.0] vs. 52.2 [46.7–58.3] pmol/l, P < 0.001) samples, respectively. Intact proinsulin levels were significantly elevated at 120 min in the women with GDM (21.3 [18.1–25.1] vs. 14.8 [13.4–16.3] pmol/l, P < 0.001). Thus, the qualitative abnormalities of insulin secretion in GDM patients (low 30-min insulin increment, high 120-min plasma insulin, and elevated 32,33 split proinsulin) are similar to those seen in nonpregnant subjects with impaired glucose tolerance. To determine whether measures of proinsulinlike molecules (PLMs) might assist in the prediction of GDM, women who had a 1-h glucose level of >7.7 mmol/1 after a 50-g glucose challenge at 28–32 weeks’ gestation had insulin and PLMs measured in the 1-h sample. The percentage of total insulin-like molecules accounted for by proinsulin-like molecules (%PLM) was significantly raised in those women in whom a subsequent OGTT showed GDM versus those in whom a later OGTT was normal (13.9 [11.5–16.7] vs. 10.3 [9.6–11.2]% P = 0.003). In a logistic regression analysis, %PLM at screening was more strongly associated with later GDM than age, obesity, the degree of hyperglycemia at screening, or any individual insulin or PLM variable at the screening test. Incorporation of a measure of %PLM in the routine 50-g screening test has the potential for improving the predictive power of screening tests for GDM.