Bruttomesso D, Pianta A, Mari A, Valerio A, Marescotti M C, Avogaro A, Tiengo A, Del Prato S
Cattedra di Malattie del Metabolismo, University of Padova, National Research Council, Italy.
Diabetes. 1999 Jan;48(1):99-105. doi: 10.2337/diabetes.48.1.99.
The loss of first-phase insulin secretion is a characteristic feature of type 2 diabetic patients. The fast-acting insulin analog lispro provides a therapeutic tool for assessing the metabolic outcome of restoration of an early rise in plasma insulin levels after the ingestion of an oral glucose load. We studied eight type 2 diabetic patients on two different occasions when they received an oral glucose load (50 g) preceded by either human regular insulin or insulin analog lispro (both 0.075 U/kg lean body mass). Tritiated glucose was infused throughout the studies, and the oral glucose was labeled with [13C6]glucose for monitoring systemic and oral glucose kinetics, respectively. Basal plasma glucose (8.2 +/- 0.9 vs. 7.5 +/- 0.8 mmol/l), insulin (224 +/- 21 vs. 203 +/- 21 pmol/l), and endogenous glucose production (10.4 +/- 1.0 vs. 11.1 +/- 1.1 micromol x kg(-1) x min(-1)) were similar on both occasions. In spite of comparable incremental areas under the curve, the time course of plasma insulin concentration was much different. After injection of regular insulin, plasma insulin peaked at 120 min (368 +/- 42 pmol/l), while with lispro, the peak occurred at 60 min (481 +/- 42 pmol/l). Plasma insulin concentration during the last 3 h of the study, however, was lower with lispro compared with regular insulin. The incremental area under the curve of plasma C-peptide was lower with lispro (0.05 +/- 0.01 vs. 0.13 +/- 0.04 micromol/300 min; P < 0.01). After the ingestion of the oral glucose load, plasma glucose concentration increased by 78% at 80-100 min with regular insulin and by 62% with lispro (P < 0.05) and remained lower for the ensuing 3 h. The incremental area under the curve was 46% lower with lispro (715 +/- 109 vs. 389 +/- 109 pmol/300 min; P < 0.01). There was no difference in the two studies in the rate of appearance of the ingested glucose and in the overall rate of glucose disposal. During the initial 90 min, however, the rate of endogenous glucose production was suppressed in a prompter and more profound manner when lispro was administered (1.39 +/- 0.10 vs. 5.00 +/- 1.22 micromol x kg(-1) x min(-1); P < 0.05), while there was no difference in the late prandial phase. These results show that an early rise in plasma insulin levels after the ingestion of a glucose load is associated with a significant improvement in glucose tolerance due to a prompter, though short-lived, suppression of endogenous glucose production. This amelioration in plasma glucose profile prevents late hyperglycemia and hyperinsulinemia. Therefore, restoration of a more physiologic profile of prandial plasma insulin profile represents a rational approach for treatment of type 2 diabetic patients.
第一阶段胰岛素分泌缺失是2型糖尿病患者的一个特征性表现。速效胰岛素类似物赖脯胰岛素为评估口服葡萄糖负荷后血浆胰岛素水平早期升高恢复的代谢结果提供了一种治疗工具。我们对8例2型糖尿病患者进行了两次不同的研究，在口服葡萄糖负荷（50g）前分别给予人常规胰岛素或胰岛素类似物赖脯胰岛素（均为0.075U/kg瘦体重）。在整个研究过程中持续输注氚标记葡萄糖，口服葡萄糖用[13C6]葡萄糖标记，分别用于监测全身和口服葡萄糖动力学。两次研究时的基础血浆葡萄糖（8.2±0.9 vs. 7.5±0.8mmol/L）、胰岛素（224±21 vs. 203±21pmol/L）和内源性葡萄糖生成（10.4±1.0 vs. 11.1±1.1μmol·kg-1·min-1）相似。尽管曲线下增量面积相当，但血浆胰岛素浓度的时间进程差异很大。注射常规胰岛素后，血浆胰岛素在120分钟时达到峰值（368±42pmol/L），而使用赖脯胰岛素时，峰值出现在60分钟（481±42pmol/L）。然而，在研究的最后3小时内，赖脯胰岛素组的血浆胰岛素浓度低于常规胰岛素组。血浆C肽曲线下增量面积赖脯胰岛素组较低（0.05±0.01 vs. 0.13±0.04μmol/300分钟；P<0.01）。口服葡萄糖负荷后，常规胰岛素组在80 - 100分钟时血浆葡萄糖浓度升高78%，赖脯胰岛素组升高62%（P<0.05），并在随后3小时内保持较低水平。曲线下增量面积赖脯胰岛素组低46%（715±109 vs. 389±109pmol/300分钟；P<0.01）。两项研究中摄入葡萄糖的出现率和葡萄糖处置总体率没有差异。然而，在最初90分钟内，给予赖脯胰岛素时内源性葡萄糖生成率受到更快且更显著的抑制（1.39±0.10 vs. 5.00±1.22μmol·kg-1·min-1；P<0.05），而在餐后晚期没有差异。这些结果表明，口服葡萄糖负荷后血浆胰岛素水平的早期升高与葡萄糖耐量的显著改善相关，这是由于内源性葡萄糖生成受到更快（尽管短暂）的抑制。血浆葡萄糖谱的这种改善可预防晚期高血糖和高胰岛素血症。因此，恢复更符合生理的餐时血浆胰岛素谱是治疗2型糖尿病患者的合理方法。
