de Souza C J, Russo P, Lozito R, Dunning B E
Metabolic and Cardiovascular Pharmacology, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA.
Diabetes Obes Metab. 2001 Apr;3(2):73-83. doi: 10.1046/j.1463-1326.2001.00114.x.
Abnormal beta-cell function, characterized as the inability of the beta-cell to mount a rapid secretory response to glucose, is a well-established pathology of type 2 diabetes mellitus. These studies were designed to demonstrate the importance of early insulin release on the control of meal-induced glucose excursions by capitalizing on the significant pharmacodynamic differences between several oral insulin secreting agents.
Male Sprague Dawley fitted with indwelling jugular cannulas were used to compare the pharmacodynamic profiles of nateglinide (Nateg), glipizide (Glip) and repaglinide (Repag) through frequent blood samples following the administration of these compounds via oral gavage. In similar animals which were pretrained to consume their daily food intake in two discrete 45-min meals, the effects of compound induced changes in pre-meal, meal and post-meal insulin profiles on glycaemic control were assessed through frequent blood sampling following the administration of these compounds 10 min prior to a 30-min meal.
There were significant pharmacodynamics differences between the three oral agents tested and the time to elicit peak insulin secretory responses increased from Nateg (4 min) to Repag (10 min) to Glip (45 min). During the meal tolerance test, glibenclamide did not increase pre-meal insulin levels and glucose excursions paralleled those in the control. Conversely, the other three agents, at doses that produced hypoglycaemic responses of similar magnitude, all increased early insulin release (Delta AUC(-15 to 3 min) = 0.5 +/- 0.01, 1.6 +/- 0.4, 3.6 +/- 0.0, 1.2 +/- 0.1 and 1.73 +/- 0.4 nmol/min, for control, Nateg at 60 and 120 mg/kg, Glip and Repag, respectively) and curbed glucose excursions during the meal at varying rates and degrees (Delta AUC(0--30 min) = 39 +/- 6, 8 +/- 7, 5 +/- 7, - 1 +/- 8 and - 3 +/- 8 mmol/min for control, Nateg at 60 and 120 mg/kg, Glip and Repag, respectively). However, unlike Nateg, the longer duration of action of Repag and Glip elicited sustained post-meal relative hypoglycaemia.
These data support the impact of early and rapid insulin release in the control of prandial and post-meal glycaemia and demonstrate that a short anticipatory burst of insulin, restricted to the beginning of a meal, provides a clear metabolic advantage and prevents post-meal hypoglycaemic episodes when compared to a greater but reactive insulin exposure that follows a meal-induced increase in glucose excursion.
β细胞功能异常，表现为β细胞无法对葡萄糖产生快速分泌反应，是2型糖尿病公认的病理特征。这些研究旨在利用几种口服胰岛素分泌剂之间显著的药效学差异，证明早期胰岛素释放对控制餐后血糖波动的重要性。
对植入颈静脉插管的雄性斯普拉格-道利大鼠，通过口服灌胃给予这些化合物后频繁采集血样，比较那格列奈（Nateg）、格列吡嗪（Glip）和瑞格列奈（Repag）的药效学特征。在类似的经过预训练在两个45分钟的离散餐中摄入每日食物量的动物中，在30分钟进餐前10分钟给予这些化合物后，通过频繁采血评估化合物诱导的餐前、餐中和餐后胰岛素谱变化对血糖控制的影响。
所测试的三种口服药物之间存在显著的药效学差异，引发胰岛素分泌峰值反应的时间从那格列奈（4分钟）增加到瑞格列奈（10分钟）再到格列吡嗪（45分钟）。在糖耐量试验期间，格列本脲未增加餐前胰岛素水平，血糖波动与对照组相似。相反，其他三种药物在产生相似程度低血糖反应的剂量下，均增加了早期胰岛素释放（对照组、60和120mg/kg那格列奈、格列吡嗪和瑞格列奈的ΔAUC（-15至3分钟）分别为0.5±0.01、1.6±0.4、3.6±0.0、1.2±0.1和1.73±0.4nmol/min），并以不同的速率和程度抑制进餐期间的血糖波动（对照组、60和120mg/kg那格列奈、格列吡嗪和瑞格列奈的ΔAUC（0 - 30分钟）分别为39±6、8±7、5±7、-1±8和-3±8mmol/min）。然而，与那格列奈不同，瑞格列奈和格列吡嗪较长的作用持续时间引发了餐后相对低血糖。
这些数据支持早期和快速胰岛素释放在控制餐后血糖中的作用，并表明与餐后血糖波动增加后更大但反应性的胰岛素暴露相比，仅在进餐开始时出现的短暂预期性胰岛素释放具有明显的代谢优势，并可预防餐后低血糖发作。
