Gumbiner B, Polonsky K S, Beltz W F, Griver K, Wallace P, Brechtel G, Henry R R
Department of Medicine, University of California, San Diego 92037.
J Clin Endocrinol Metab. 1990 Jun;70(6):1594-602. doi: 10.1210/jcem-70-6-1594.
Impairment in pancreatic production of insulin, a cardinal feature of noninsulin dependent diabetes mellitus (NIDDM), was quantified and the kinetics of insulin secretion characterized in six obese individuals with NIDDM before and after weight loss (18.0 +/- 3.0 kg, mean +/- SEM) using a validated mathematical model that employs C-peptide as a marker of the in vivo rate of insulin secretion. The metabolic clearance of C-peptide, assessed by decay analysis after bolus injection of biosynthetic human C-peptide, was not changed by weight loss (0.143 +/- 0.009 L/min.m2 vs. 0.137 +/- 0.010 L/min.m2). Kinetic parameters from each individual's decay curve before and after weight loss were used to derive accurate rates of secretion during the basal (postabsorptive) state, an oral glucose tolerance test and two hyperglycemic clamps. Basal rates of insulin secretion declined 20 +/- 5 pmol/min.m2 (96 +/- 15 to 76 +/- 15 pmol/min.m2, P less than 0.05) concomitant with decreases of 6.9 +/- 0.9 mmol/L in fasting serum glucose (13.7 +/- 1.0 to 6.8 +/- 0.7 mmol/L, P less than 0.05), 60 +/- 14 pmol/L in serum insulin (134 +/- 30 to 74 +/- 15 pmol/L, P less than 0.05), and 0.15 +/- 0.03 pmol/ml in plasma C-peptide (0.67 +/- 0.11 to 0.52 +/- 0.08 pmol/ml, P less than 0.05) concentrations. As expected, weight loss resulted in improved glucose tolerance as measured by the glycemic profiles during the oral glucose tolerance test (P less than 0.05 analysis of variance). The insulin secretory response before weight loss showed a markedly reduced ability to respond appropriately to an increase in the ambient serum glucose. After weight loss, the pancreatic response was more dynamic (P less than 0.05, analysis of variance) and parralleled the moment-to-moment changes in glycemia. Insulin production above basal doubled (11.2 +/- 3.2 to 24.5 +/- 5.8 nmol/6h.m2, P less than 0.05) and peak rates of insulin secretion above basal tripled (55 +/- 16 to 157 +/- 32 pmol/min/m2, P less than 0.05). To assess the beta-cell response to glucose per se and the changes associated with weight reduction, two hyperglycemic clamps were performed at steady state glucose levels in the range characteristic of individuals with severe NIDDM. At a fixed glycemia of 20 mmol/L, average rates of insulin secretion increased almost 2-fold with treatment (161 +/- 41 to 277 +/- 60 pmol/min.m2, P less than 0.05). At an increment of 6 mmol/L glucose above prevailing fasting glucose levels, the average rate of insulin secretion increased 53% (120 +/- 21 to 183 +/- 39 pmol/min.m2, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
胰岛素依赖型糖尿病（NIDDM）的主要特征是胰腺胰岛素分泌受损。本研究对6名肥胖的NIDDM患者在体重减轻前后（平均减轻18.0±3.0kg，均值±标准误）的胰岛素分泌受损情况进行了量化，并利用一个经过验证的数学模型，以C肽作为体内胰岛素分泌速率的标志物，对胰岛素分泌动力学进行了表征。通过推注生物合成人C肽后的衰减分析评估C肽的代谢清除率，结果显示体重减轻并未改变该清除率（分别为0.143±0.009L/min·m²和0.137±0.010L/min·m²）。利用每位患者体重减轻前后衰减曲线的动力学参数，得出基础（吸收后）状态、口服葡萄糖耐量试验和两次高血糖钳夹期间的准确分泌速率。基础胰岛素分泌速率下降了20±5pmol/min·m²（从96±15降至76±15pmol/min·m²，P<0.05），同时空腹血清葡萄糖降低了6.9±0.9mmol/L（从13.7±1.0降至6.8±0.7mmol/L，P<0.05），血清胰岛素降低了60±14pmol/L（从134±30降至74±15pmol/L，P<0.05），血浆C肽降低了0.15±0.03pmol/ml（从0.67±0.11降至0.52±0.08pmol/ml，P<0.05）。正如预期的那样，体重减轻改善了口服葡萄糖耐量试验中的血糖曲线所测量的葡萄糖耐量（方差分析，P<0.05）。体重减轻前，胰岛素分泌对环境血清葡萄糖升高的反应能力明显降低。体重减轻后，胰腺反应更具动态性（方差分析，P<0.05），且与血糖的瞬间变化平行。基础以上的胰岛素分泌量增加了一倍（从11.2±3.2增至24.5±5.8nmol/6h·m²，P<0.05），基础以上的胰岛素分泌峰值速率增加了两倍（从55±16增至157±32pmol/min/m²，P<0.05）。为了评估β细胞对葡萄糖本身的反应以及与体重减轻相关的变化，在严重NIDDM患者特征性的稳态血糖水平下进行了两次高血糖钳夹。在固定血糖水平为20mmol/L时，治疗后胰岛素分泌的平均速率增加了近两倍（从161±41增至277±60pmol/min·m²，P<0.05）。在高于当前空腹血糖水平6mmol/L的葡萄糖增量下，胰岛素分泌的平均速率增加了53%（从120±21增至183±39pmol/min·m²，P<0.05）。（摘要截取自400字）
