Tsuura Y, Ishida H, Okamoto Y, Kato S, Sakamoto K, Horie M, Ikeda H, Okada Y, Seino Y
Department of Metabolism and Clinical Nutrition, Kyoto University Faculty of Medicine, Japan.
Diabetes. 1993 Oct;42(10):1446-53. doi: 10.2337/diab.42.10.1446.
In the Goto-Kakizaki rat, a new genetic model of NIDDM, insulin response to glucose is selectively impaired. To elucidate the mechanism of this abnormality, we studied the properties of ATP-sensitive K+ channels, the inhibition of which is a key step of insulin secretion induced by fuel substrates, using the patch-clamp technique. The glucose-sensitivity of KATP channels was considerably reduced in GK rats. However, the inhibitory effects of ATP on channel activity and unitary conductance were not significantly different between control and GK rats. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells of GK rats is attributable to insufficient closure of the KATP channels, probably because of deficient ATP production by impaired glucose metabolism. KATP-channel activities in both control and diabetic beta-cells were found to be equally suppressed by glyceraldehyde and 2-ketoisocaproate. These results strongly suggest that the step responsible for the metabolic dysfunction of diabetic beta-cells is located within the glycolytic pathway before glyceraldehyde-3-phosphate or in the glycerol phosphate shuttle.
在NIDDM的新遗传模型——Goto-Kakizaki大鼠中，胰岛素对葡萄糖的反应受到选择性损害。为阐明这种异常的机制，我们使用膜片钳技术研究了ATP敏感性钾通道的特性，该通道的抑制是燃料底物诱导胰岛素分泌的关键步骤。GK大鼠中KATP通道的葡萄糖敏感性显著降低。然而，ATP对通道活性和单位电导的抑制作用在对照大鼠和GK大鼠之间没有显著差异。因此，似乎GK大鼠β细胞中葡萄糖促胰岛素分泌作用受损归因于KATP通道关闭不足，可能是由于葡萄糖代谢受损导致ATP生成不足。发现甘油醛和2-酮异己酸对对照和糖尿病β细胞中的KATP通道活性均有同等程度的抑制作用。这些结果强烈表明，糖尿病β细胞代谢功能障碍的相关步骤位于糖酵解途径中磷酸甘油醛之前或磷酸甘油穿梭途径中。
