Abdel-Halim S M, Guenifi A, Khan A, Larsson O, Berggren P O, Ostenson C G, Efendić S
Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Diabetes. 1996 Jul;45(7):934-40. doi: 10.2337/diab.45.7.934.
The GK rat is a spontaneous model of NIDDM. The insulin response to 16.7 mmol/l glucose was markedly impaired in both isolated perfused pancreas and isolated islets from GK rats compared with control Wistar rats. Depolarization with 30 mmol/l KCl in the presence of 3.3 mmol/l glucose and 250 micromol/l diazoxide induced similar insulin responses in perfused pancreases of GK and control rats. In contrast, the glucose-stimulated insulin release was also severely impaired in GK pancreases in the depolarized state. Forskolin (1 micromol/l) markedly enhanced insulin release at 3.3 mmol/l glucose in GK but not control pancreases (54 +/- 15 vs. 3 +/- 1 pmol/10 min, P < 0.001). Dibutyryl cAMP (1 mmol/l) exerted effects similar to forskolin on insulin release in the perfused pancreas. In depolarized pancreases of GK but not control rats, forskolin also induced a marked insulin response at 3.3 mmol/l glucose (163 +/- 48 vs. 16 +/- 1 pmol/20 min, P < 0.03). Similarly, in studies on isolated islets from GK rats cultured in 5.5 or 16.7 mmol/l glucose for 48 h, forskolin (5 pmol/l) restored insulin release in response to 16.7 mmol/l glucose but had no effect on islet glucose utilization at 3.3 or 16.7 mmol/l glucose. Forskolin markedly stimulated insulin release at 3.3 mmol/l glucose in GK but not control rat islets cultured for 48 h in 5.5 mmol/l glucose, whereas 20 mmol/l arginine had an almost identical effect in both islet varieties. However, in islets cultured in 16.7 mmol/l glucose, forskolin stimulated insulin release similarly both in control and GK islets at 3.3 mmol/l glucose. In conclusion, this study suggests that the insulinotropic effects of glucose are coupled to a direct regulation of the exocytotic machinery in the pancreatic beta-cell. This pathway is markedly impaired in GK rats, contributing to defective insulin response to glucose. In this model, cAMP generation restores the insulin response to 16.7 mmol/l glucose and exerts a marked insulin release even at 3.3 mmol/l glucose.
GK大鼠是2型糖尿病的自发模型。与对照Wistar大鼠相比，GK大鼠的离体灌注胰腺和离体胰岛对16.7 mmol/l葡萄糖的胰岛素反应均明显受损。在3.3 mmol/l葡萄糖和250 μmol/l二氮嗪存在的情况下，用30 mmol/l氯化钾进行去极化处理，在GK大鼠和对照大鼠的灌注胰腺中诱导出相似的胰岛素反应。相比之下，在去极化状态下，GK胰腺中葡萄糖刺激的胰岛素释放也严重受损。福斯高林（1 μmol/l）在3.3 mmol/l葡萄糖时显著增强了GK胰腺而非对照胰腺的胰岛素释放（54±15对3±1 pmol/10分钟，P<0.001）。二丁酰环磷腺苷（1 mmol/l）对灌注胰腺中胰岛素释放的作用与福斯高林相似。在GK大鼠而非对照大鼠的去极化胰腺中，福斯高林在3.3 mmol/l葡萄糖时也诱导出显著的胰岛素反应（163±48对16±1 pmol/20分钟，P<0.03）。同样，在对在5.5或16.7 mmol/l葡萄糖中培养48小时的GK大鼠离体胰岛的研究中，福斯高林（5 pmol/l）恢复了对16.7 mmol/l葡萄糖的胰岛素释放，但对3.3或16.7 mmol/l葡萄糖时的胰岛葡萄糖利用没有影响。在5.5 mmol/l葡萄糖中培养48小时的GK大鼠而非对照大鼠胰岛中，福斯高林在3.3 mmol/l葡萄糖时显著刺激胰岛素释放，而20 mmol/l精氨酸在两种胰岛类型中具有几乎相同的作用。然而，在16.7 mmol/l葡萄糖中培养的胰岛中，福斯高林在3.3 mmol/l葡萄糖时对对照和GK胰岛的胰岛素释放刺激作用相似。总之，本研究表明，葡萄糖的促胰岛素作用与胰腺β细胞中胞吐机制的直接调节相关。该途径在GK大鼠中明显受损，导致对葡萄糖的胰岛素反应缺陷。在该模型中，环磷腺苷的生成恢复了对16.7 mmol/l葡萄糖的胰岛素反应，甚至在3.3 mmol/l葡萄糖时也能显著促进胰岛素释放。
