de Souza C J, Gagen K, Chen W, Dragonas N
Metabolic and Cardiovascular Pharmacology, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA.
Diabetes Obes Metab. 2001 Apr;3(2):85-95. doi: 10.1046/j.1463-1326.2001.00115.x.
Islet dysfunction, characterized by the loss of an acute insulin secretory response (AIR) to glucose is a well-established pathology of type 2 diabetes mellitus. Using oral insulin secreting agents with very different pharmacodynamic profiles, the present study was undertaken to test the hypothesis that, within the setting of an underlying insulin resistance, changes in the insulin response profile can differentially affect glycaemic control.
The mildly insulin resistant high-fat fed Sprague Dawley (HF) rat and the very insulin resistant Zucker fatty (fa/fa) rat, chronically fitted with indwelling jugular cannula were subjected to an oral glucose load. Compounds were administered 5 min before the oral glucose load. Nateglinide (Nateg) was administered to elicit only an early insulin secretory response and glipizide (Glip) to elicit a later but greater insulin secretory response. Acetaminophen was used as a marker to assess for potential effects of these compounds on gastric emptying rates.
Nateg rapidly increased early insulin release (from -5 to 0) while the effects on total insulin release were similar to those in the controls and glucose excursions were eliminated in both diabetic models with no evidence of sustained hypoglycaemia. Conversely, Glip did not affect early insulin release but increased total insulin release (- 15 to 120 min), but only after the oral glucose load. Glip partially curbed glucose excursions in the mildly insulin resistant HF rodent and was totally ineffective in the very insulin resistant Zucker rat. The differential effects could not be attributed to effects on gastric emptying rates.
These data support the importance of early insulin release in type 2 diabetes mellitus and indicate that, independent of the level of insulin resistance, stimulating insulin release early and briefly provides for more effective and tighter glycaemic control than increasing insulin exposure to a greater magnitude later.
胰岛功能障碍，其特征为对葡萄糖的急性胰岛素分泌反应（AIR）丧失，是2型糖尿病公认的病理表现。本研究使用具有截然不同药效学特征的口服胰岛素分泌剂，以检验以下假设：在存在基础胰岛素抵抗的情况下，胰岛素反应曲线的变化可对血糖控制产生不同影响。
给长期植入颈静脉插管的轻度胰岛素抵抗的高脂喂养斯普拉格-道利（HF）大鼠和胰岛素抵抗严重的 Zucker 脂肪（fa/fa）大鼠口服葡萄糖负荷。在口服葡萄糖负荷前5分钟给予化合物。给予那格列奈（Nateg）仅引发早期胰岛素分泌反应，给予格列吡嗪（Glip）引发后期但更强的胰岛素分泌反应。对乙酰氨基酚用作标志物，以评估这些化合物对胃排空率的潜在影响。
Nateg迅速增加早期胰岛素释放（从-5到0），而对总胰岛素释放的影响与对照组相似，并且在两种糖尿病模型中均消除了血糖波动，且无持续低血糖的证据。相反，Glip不影响早期胰岛素释放，但增加总胰岛素释放（-15至120分钟），但仅在口服葡萄糖负荷后。Glip部分抑制了轻度胰岛素抵抗的HF啮齿动物的血糖波动，而在胰岛素抵抗严重的Zucker大鼠中则完全无效。这种差异效应不能归因于对胃排空率的影响。
这些数据支持早期胰岛素释放在2型糖尿病中的重要性，并表明，与胰岛素抵抗水平无关，早期短暂刺激胰岛素释放比后期更大程度地增加胰岛素暴露能提供更有效、更严格的血糖控制。
