Stumvoll M, Fritsche A, Stefan N, Hardt E, Häring H
Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard Karls Universität, 72076 Tubingen, Germany.
J Clin Endocrinol Metab. 2001 Mar;86(3):1235-9. doi: 10.1210/jcem.86.3.7331.
In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic 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 (3983 +/- 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 significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 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 subjects with IGT, the PI/I ratio in plasma decreased significantly and was not 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 beta-cell dysfunction in IGT.
在糖耐量受损（IGT）的受试者中，胰岛素分泌受损。胰岛素原/胰岛素（PI/I）比值升高表明在此种情况下胰岛素原向胰岛素的加工过程也有所减少。胰岛素分泌颗粒中的PI/I比值理想情况下是通过对胰岛素分泌进行急性刺激后的血浆测量来评估的。在本研究中，我们检验了以下假设：胰岛素分泌的最大刺激会导致胰岛素原转化为胰岛素的途径耗竭。因此，我们测定了11名糖耐量正常（NGT）受试者和11名IGT受试者在葡萄糖（方波高血糖钳夹，10 mmol/L）、胰高血糖素样肽-1（GLP-1；预充式持续输注）以及在持续输注GLP-1期间给予精氨酸刺激下的PI/I比值。在IGT患者中，第一阶段胰岛素水平显著较低（144±20对397±119 pmol/L；P = 0.02），在GLP输注结束时（2142±350对5430±1091 pmol/L；P = 0.002），以及对精氨酸的反应中（3983±375对8663±1430 pmol/L；P = 0.005）。对葡萄糖的反应中，IGT患者的最低PI/I比值显著高于NGT患者（3.4±0.6%对1.4±0.5%；P = 0.02），提示在此种情况下胰岛素原加工存在缺陷。在IGT患者中，GLP-1预充后PI/I比值显著下降（1.7±0.2%；P = 0.02），在GLP-1输注期间给予精氨酸后也下降（1.4±0.2%；P = 0.007），且与NGT患者的值无显著差异（分别为1.3±0.2%和1.3±0.2%；P均=无统计学意义）。总之，在IGT患者胰岛素分泌的最大刺激过程中，血浆中的PI/I比值显著下降，且与正常对照组无异。这有力地反驳了胰岛素原加工缺陷是IGT中β细胞功能障碍主要组成部分的假设。
