Polonsky K S, Given B D, Hirsch L, Shapiro E T, Tillil H, Beebe C, Galloway J A, Frank B H, Karrison T, Van Cauter E
University of Chicago, Pritzker School of Medicine, Illinois 60637.
J Clin Invest. 1988 Feb;81(2):435-41. doi: 10.1172/JCI113338.
The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+
利用先前验证的胰岛素分泌数学模型以及静脉推注生物合成人C肽后通过分析个体衰变曲线得出的C肽速率常数，对14名正常志愿者和15名肥胖受试者的胰岛素分泌及肝脏摄取情况进行了比较。在空腹过夜后，肥胖受试者的胰岛素分泌率显著高于正常受试者（86.7±7.1对50.9±4.8 pmol/m²每分钟，P＜0.001，均值±标准误）；在混合饮食的24小时期间（279.6±24.2对145.8±8.8 nmol/m²每24小时，P＜0.001）；以及在高血糖静脉输注葡萄糖期间（102.2±10.8对57.2±2.8 nmol/m²每180分钟，P＜0.001）。线性回归分析显示胰岛素分泌与体重指数之间存在高度显著的关系。正常受试者和肥胖受试者的基础肝脏胰岛素摄取无显著差异（53.1±3.8对51.6±4.0%）。在正常受试者中，空腹胰岛素与基础肝脏胰岛素摄取无相关性，但在肥胖者中，空腹胰岛素与肝脏胰岛素摄取之间存在显著的负相关（r = -0.63，P＜0.02）。这一发现反映出，在6名空腹胰岛素水平处于正常受试者范围内的肥胖受试者中，其摄取率高于9名空腹胰岛素浓度升高的受试者（61±3对45±6%，P＜0.05）。在高血糖钳夹期间，正常受试者的胰岛素分泌率平均最高增加至基线水平的6.2倍，肥胖受试者增加至5.8倍。在同一时间内，正常受试者外周胰岛素浓度比基线升高14.1倍，肥胖受试者升高16.6倍，表明内源性分泌胰岛素的清除率降低。尽管肥胖受试者胰岛素清除率的下降趋势更大，但两组之间的差异无统计学意义。因此，在基础、空腹条件下以及混合饮食摄入期间，肥胖的高胰岛素血症主要源于胰岛素分泌增加。在基础高胰岛素血症更明显的患者以及胰岛素分泌受到强烈刺激期间，胰岛素清除率的降低可能导致外周胰岛素浓度更大幅度的升高，这是肥胖状态的特征。
