Sugiyama Y, Shimura Y, Ikeda H
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Endocrinol Jpn. 1989 Feb;36(1):65-73. doi: 10.1507/endocrj1954.36.65.
The present studies were designed to clarify the contribution of the liver to the development of hyperglycemia in Wistar fatty rats. The hepatic activities of insulin-inducible enzymes involved in glycolysis (glucokinase; GK and pyruvate kinase) and lipogenesis (glucose-6-phosphate dehydrogenase), were higher in fatty rats than in lean rats at 4 and 8 weeks of age because of the higher insulin levels in the former. Thereafter, the GK activities of fatty rats decreased slightly in spite of severe hyperinsulinemia, and did not differ from those of lean rats. In addition, fatty rats had higher levels of insulin-suppressible gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and fructose-1, 6-diphosphatase. These findings indicate that the hepatic enzymes of fatty rats are resistant to insulin. This postulation was supported by the fact that the hepatic enzyme activities of fatty rats showed a lower response to changes in plasma insulin levels produced by fasting and refeeding. The G6Pase/GK ratio, which indicates net glucose handling in the liver, increased in fatty rats and decreased in lean rats with advancing age, suggesting that hepatic glucose production in fatty rats becomes dominant with advancing age. The changes in hepatic glycolytic intermediates supported this suggestion; the glycolytic steps both from glucose to glucose-6-phosphate and from phospho-enolpyruvate to pyruvate in fatty rats were accelerated at 5 weeks of age, but suppressed at 12 weeks of age. These results indicate that insulin resistance in the hepatic enzyme regulation may contribute to the development of hyperglycemia in Wistar fatty rats.
本研究旨在阐明肝脏在Wistar肥胖大鼠高血糖发展过程中的作用。参与糖酵解（葡萄糖激酶；GK和丙酮酸激酶）和脂肪生成（葡萄糖-6-磷酸脱氢酶）的胰岛素诱导酶的肝脏活性，在4周龄和8周龄时，肥胖大鼠高于瘦大鼠，这是因为前者胰岛素水平较高。此后，尽管存在严重的高胰岛素血症，肥胖大鼠的GK活性仍略有下降，且与瘦大鼠的GK活性无差异。此外，肥胖大鼠中胰岛素可抑制的糖异生酶、葡萄糖-6-磷酸酶（G6Pase）和果糖-1,6-二磷酸酶的水平较高。这些发现表明肥胖大鼠的肝脏酶对胰岛素具有抗性。这一假设得到了以下事实的支持：肥胖大鼠的肝脏酶活性对禁食和再喂食引起的血浆胰岛素水平变化反应较低。G6Pase/GK比值表明肝脏中的葡萄糖净处理情况，随着年龄的增长，肥胖大鼠的该比值升高，瘦大鼠的该比值降低，这表明随着年龄的增长，肥胖大鼠的肝脏葡萄糖生成占主导地位。肝脏糖酵解中间产物的变化支持了这一观点；肥胖大鼠中从葡萄糖到葡萄糖-6-磷酸以及从磷酸烯醇丙酮酸到丙酮酸的糖酵解步骤在5周龄时加速，但在12周龄时受到抑制。这些结果表明肝脏酶调节中的胰岛素抵抗可能导致Wistar肥胖大鼠高血糖的发展。
