Dachicourt N, Bailbé D, Gangnerau M N, Serradas P, Ravel D, Portha B
Lab. Physiopathology of Nutrition, CNRS ESA 7059, Université Paris 7/D. Diderot, France.
Eur J Pharmacol. 1998 Nov 20;361(2-3):243-51. doi: 10.1016/s0014-2999(98)00718-3.
The Goto-Kakisaki rat is a genetic non-overweight model of non-insulin-dependent diabetes mellitus. Adult Goto-Kakisaki rats exhibit a mild basal hyperglycaemia (11 mmol/l) with impaired glucose tolerance, elevated basal plasma insulin level, a failure of insulin release in response to glucose together with a 50% depletion of the total pancreatic beta-cell mass and insulin stores. We have examined the effects of long-term (4 weeks) gliclazide treatment on the severity of diabetes in adult male Goto-Kakisaki rats (10-12 weeks of age). Gliclazide was administered orally (10 mg/kg per day). Gliclazide-treated Goto-Kakisaki rats were evaluated against Wistar and untreated Goto-Kakisaki rats. In the gliclazide-treated Goto-Kakisaki rats, basal plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of treatment, and their basal insulin levels decreased to values similar to those in non-diabetic Wistar rats. Despite their total pancreatic beta-cell remaining unaffected, their pancreatic insulin stores were twice increased, with a similar improvement of the insulin content per individual beta-cell. Furthermore, the glucose-stimulated insulin release as evaluated in vivo during an intravenous glucose tolerance-test was significantly improved (twice increased) in the gliclazide-treated Goto-Kakisaki rats. This was correlated with a modest but significant enhancement of the early phase of insulin release in vitro (isolated perfused pancreas), in response to glucose. However, the overall insulin response in vitro remained clearly defective with no reappearance of the late phase of insulin release. The in vitro response to arginine (which was basically amplified in the Goto-Kakisaki model) or to gliclazide were kept unchanged after the gliclazide treatment. In conclusion, chronic gliclazide does not exert any beta-cytotrophic effect, but improves beta-cell function in the adult Goto-Kakisaki rat as far as it lowers basal insulin release, increases beta-cell insulin stores, and increases the glucose-induced insulin release.
Goto-Kakisaki大鼠是一种遗传性非超重的非胰岛素依赖型糖尿病模型。成年Goto-Kakisaki大鼠表现出轻度基础高血糖（11 mmol/l），糖耐量受损，基础血浆胰岛素水平升高，对葡萄糖刺激的胰岛素释放功能衰竭，同时胰腺β细胞总量和胰岛素储存量减少50%。我们研究了长期（4周）格列齐特治疗对成年雄性Goto-Kakisaki大鼠（10 - 12周龄）糖尿病严重程度的影响。格列齐特通过口服给药（每天10 mg/kg）。将接受格列齐特治疗的Goto-Kakisaki大鼠与Wistar大鼠和未治疗的Goto-Kakisaki大鼠进行对比评估。在接受格列齐特治疗的Goto-Kakisaki大鼠中，基础血浆葡萄糖水平逐渐下降，治疗结束时平均降至8 mmol/l，其基础胰岛素水平降至与非糖尿病Wistar大鼠相似的值。尽管它们的胰腺β细胞总量未受影响，但胰腺胰岛素储存量增加了两倍，单个β细胞的胰岛素含量也有类似改善。此外，在静脉葡萄糖耐量试验中体内评估的葡萄糖刺激的胰岛素释放，在接受格列齐特治疗的Goto-Kakisaki大鼠中显著改善（增加了两倍）。这与体外（离体灌注胰腺）对葡萄糖反应时胰岛素释放早期阶段的适度但显著增强相关。然而，体外总体胰岛素反应仍明显存在缺陷，胰岛素释放后期未再次出现。格列齐特治疗后，对精氨酸（在Goto-Kakisaki模型中其反应基本增强）或格列齐特的体外反应保持不变。总之，慢性格列齐特不发挥任何β细胞营养作用，但在成年Goto-Kakisaki大鼠中改善了β细胞功能，因为它降低了基础胰岛素释放，增加了β细胞胰岛素储存，并增加了葡萄糖诱导的胰岛素释放。
