Yao Xing-Hai, Chen Li, Nyomba B L Grégoire
Diabetes Research Group, Univ. of Manitoba, 715 McDermot Ave. Rm. 834, Winnipeg, Manitoba, Canada R3E 3P4.
J Appl Physiol (1985). 2006 Feb;100(2):642-8. doi: 10.1152/japplphysiol.01115.2005. Epub 2005 Oct 20.
Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1alpha protein and mRNA; and phosphoenolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and gluconeogenic enzymes, proteins, and mRNAs decreased by 50-70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1alpha protein and mRNA levels were 40-80% higher in EtOH rats than in controls. Similarly, basal phosphoenolpyruvate carboxykinase activity, protein, and mRNA were approximately 1.8-fold greater in EtOH rats than in controls. These parameters decreased by approximately 50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero.
孕期暴露于乙醇的大鼠后代（乙醇大鼠）存在胰岛素抵抗，但它们的糖异生是否增加尚不清楚。为了解决这个问题，我们测定了幼年和成年乙醇大鼠在注射胰岛素前后的血糖以及肝脏糖异生基因、蛋白质和酶活性，并对成年乙醇大鼠进行了丙酮酸激发试验。在幼年大鼠中，两组之间的基础血糖、过氧化物酶体增殖物激活受体共激活因子-1α蛋白和mRNA、磷酸烯醇式丙酮酸羧激酶的酶活性、蛋白质和mRNA相似。注射胰岛素后，乙醇大鼠的这些参数未能降低，但对照大鼠的血糖降低了30%，糖异生酶、蛋白质和mRNA降低了50%-70%。在成年后代中，乙醇大鼠的基础过氧化物酶体增殖物激活受体共激活因子-1α蛋白和mRNA水平比对照组高40%-80%。同样，乙醇大鼠的基础磷酸烯醇式丙酮酸羧激酶活性、蛋白质和mRNA比对照组大约高1.8倍。对照大鼠注射胰岛素后这些参数降低了约50%，但乙醇大鼠中这些参数保持不变。成年大鼠注射胰岛素后，对照大鼠的血糖降低了60%，但乙醇大鼠的血糖没有显著降低。与对照组相比，一部分成年乙醇大鼠存在空腹高血糖，并且对丙酮酸的血糖反应过度。数据表明，产前暴露于乙醇后，成年大鼠后代的糖异生基因表达过度，并且在幼年和成年大鼠中均存在胰岛素抵抗，这解释了糖异生增加的原因。这些改变持续到成年期，可能有助于子宫内暴露于乙醇后2型糖尿病的发病机制。
