Yen T T, Gill A M, Powell J G, Sampson B M
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Int J Obes Relat Metab Disord. 1992 Nov;16(11):923-33.
Hypercorticism has been observed in numerous obese and diabetic animal models. Adrenalectomy reduces adiposity, hyperglycemia, hyperinsulinemia, and insulin resistance in these animals. The effects of adrenalectomy can be reversed by glucocorticoid replacement. Male and female viable yellow mice share all phenotypic expressions caused by the viable yellow mutation except that males are hyperglycemic and most females are either normoglycemic or only mildly hyperglycemic. The mechanisms that protect female viable yellow mice from hyperglycemia are not known. Implantation of dexamethasone pellets induced hyperglycemia in female viable yellow mice but had no effect on blood glucose of male viable yellow mice and male and female normal mice. The duration of dexamethasone-induced hyperglycemia correlated to the time endogenous plasma corticosterone levels were suppressed. Plasma insulin levels rose in normal mice but only transiently in viable yellow mice. Ciglitazone prevented and reversed dexamethasone-induced hyperglycemia in female viable yellow mice. Since female viable yellow mice, similar to male viable yellow mice, are obese, hyperinsulinemic and insulin resistant, and since dexamethasone is known to cause insulin resistance, these data suggest that dexamethasone increased insulin resistance to a degree that the protective mechanism was overwhelmed and hyperglycemia was induced. Ciglitazone, a compound known to improve insulin sensitivity, may prevent and reverse dexamethasone-induced hyperglycemia by ameliorating the additional insulin resistance caused by dexamethasone. On a molecular level, since dexamethasone suppresses glucose transport, an insulin-sensitive process in many tissues, whereas ciglitazone and other thiazolidinediones facilitate glucose transport, it is possible that ciglitazone prevents and reverses dexamethasone-induced hyperglycemia by regulating the glucose transport systems in insulin-sensitive tissues.
在众多肥胖和糖尿病动物模型中均观察到了皮质醇增多症。肾上腺切除术可减轻这些动物的肥胖、高血糖、高胰岛素血症和胰岛素抵抗。肾上腺切除术的效果可通过糖皮质激素替代得以逆转。雄性和雌性活力黄色小鼠具有由活力黄色突变引起的所有表型表现，只是雄性小鼠存在高血糖，而大多数雌性小鼠血糖正常或仅轻度高血糖。保护雌性活力黄色小鼠不发生高血糖的机制尚不清楚。植入地塞米松微丸可诱导雌性活力黄色小鼠发生高血糖，但对雄性活力黄色小鼠以及雄性和雌性正常小鼠的血糖没有影响。地塞米松诱导的高血糖持续时间与内源性血浆皮质酮水平被抑制的时间相关。正常小鼠的血浆胰岛素水平升高，但活力黄色小鼠仅短暂升高。吡格列酮可预防并逆转雌性活力黄色小鼠由地塞米松诱导的高血糖。由于雌性活力黄色小鼠与雄性活力黄色小鼠一样，存在肥胖、高胰岛素血症和胰岛素抵抗，且已知地塞米松会导致胰岛素抵抗，因此这些数据表明，地塞米松增加胰岛素抵抗的程度超过了保护机制的承受能力，从而诱导了高血糖。吡格列酮是一种已知可改善胰岛素敏感性的化合物，它可能通过改善地塞米松引起的额外胰岛素抵抗来预防并逆转地塞米松诱导的高血糖。在分子水平上，由于地塞米松会抑制葡萄糖转运，这是许多组织中一种对胰岛素敏感的过程，而吡格列酮和其他噻唑烷二酮类药物则促进葡萄糖转运，因此吡格列酮有可能通过调节胰岛素敏感组织中的葡萄糖转运系统来预防并逆转地塞米松诱导的高血糖。
