ELEVATED ISLET AMYLOID PANCREATIC-POLYPEPTIDE AND PROINSULIN IN LEAN GESTATIONAL DIABETES

Recent research indicates that islet amyloid pancreatic polypeptide (I APP) might have a regulatory effect on beta-cell insulin processing an d secretion. To study such interaction in more detail, IAPP secretion and kinetics and the serum concentrations of proinsulin were assessed both before and after delivery in lean pregnant women with gestational diabetes mellitus (GDM patients) in comparison to those with normal g lucose tolerance (NGT) and to nonpregnant healthy lean (control) and o bese insulin-resistant women during oral glucose tolerance tests. Kine tic analysis of IAPP was performed with mathematical modeling, providi ng indirect estimates of its secretion and fractional clearance. Total insulin secretion per 180 min was elevated by 30% in GDM patients (35 +/- 3 pmol/l) versus control subjects (27 +/- 1 pmol/l) (P < 0.05), b ut increased even more (190-250%) in obese insulin-resistant women, co mpared with all other groups (68 +/- 7 pmol/l, P < 0.0005). Pregnancy induced a more marked fourfold increase in apparent total IAPP secreti on rate (TIR) (GDM patients, 172 +/- 31 pmol . l(-1) . 3 h(-1); NGT su bjects, 166 +/- 31 pmol . l(-1) . 3 h(-1); control subjects, 40 +/- 1 pmol . l(-1) . 3 h(-1)) and a twofold rise in its fractional clearance versus control subjects (P < 0.01), whereas in GDM patients a 30% inc rease of IAPP secretion and a decreased clearance was found, compared with obese insulin-resistant women (TIR, 112 +/- 14 pmol . l(-1) . 3 h (-1)). The increase in IAPP secretion in both pregnant groups was much higher than that of the insulin groups, resulting in a marked change of the IAPP-insulin cosecretion factor when compared with lean or obes e nonpregnant women (P < 0.0005). Associated serum proinsulin and the postprandial (total divided by 180 min) proinsulin-to-insulin ratio we re greater in GDM patients versus NGT and control subjects (0.11 +/- 0 .01 vs. 0.07 +/- 0.01 and 0.08 +/- 0.01 pmol/l, P < 0.05), while the f asting proinsulin-to-insulin ratio was only increased in GDM patients versus control subjects (0.22 +/- 0.03 vs. 0.13 +/- 0.01 pmol/l, P < 0 .05). After delivery, total IAPP secretion (52.4 +/- 1.5 pmol/l) was c ompletely normalized in the GDM group, as were the clearance rate and the IAPP-insulin cosecretion factor. Similarly, serum proinsulin conce ntrations returned to normal, whereas proinsulin-to-insulin ratios rem ained elevated. In conclusion, IAPP hypersecretion is characteristic f or pregnancy and might partially decrease hyperinsulinemia in pregnanc y by inhibiting insulin secretion. Increased proinsulin concentrations and a raised proinsulin-to-insulin ratio, which did not abate followi ng delivery, are specific to GDM and might thus serve as its marker an d potentially even identify subjects at high risk for the development of NIDDM.