Evidence against a rate-limiting role of proinsulin processing for maximalinsulin secretion in subjects with impaired glucose tolerance and beta-cell dysfunction

In subjects with impaired glucose tolerance (IGT) insulin secretion is impa ired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ra tio in the insulin secretory granule is ideally assessed by plasma measurem ents in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretio n results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in II normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hypergly cemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P = 0.002), and in response to arginine (398 3 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significant ly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given du ring GLP-1 (1.4 I 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in sub jects with IGT, the PI/I ratio in plasma decreased significantly and was no t different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the p-cell dysfunction in IGT.