基于文献和前期成果提出"糖尿病状态下肝CYP3A等CYP450酶的诱导不但改变药物体内代谢，影响其疗效和毒性，也引起内源性底物代谢紊乱。同时这种肝CYP3A酶诱导反过来又加重糖尿病病情"推论，设计试验验证该推论。以II型糖尿病大鼠为模型研究肝CYP3A等CYP450酶诱导；这种诱导对瑞格列奈、那格列奈、睾丸酮和视黄醇等代谢影响；药物治疗过程中代谢动力学及疗效；糖尿病状态下引起肝CYP3A酶诱导机制。通过合用CYP3A诱导剂或抑制剂研究CYP3A酶活性与糖尿病关系，分析糖尿病状态下肝CYP3A酶诱导是否反过来加重糖尿病病情及机制。用ob/ob小鼠和基因敲除小鼠验证上述结果。用软脂酸诱导肝细胞胰岛素抵抗，研究CYP3A酶诱导与肝细胞胰岛素抵抗的关系及机制，用基因沉默和转染进一步验证上述结果。其成果对于阐明肝CYP3A等CYP450酶诱导在糖尿病病情发展中作用，合理用药和不良反应预测有重要意义。

Based on both reports by literatures and our previous results, a new hypothesis was raised as follows. The induction of hepatic CYP3As etc CYP450s under diabetic condition not only alters drug metabolism, therapeutic effect and toxicological activity, but also leads to metabolism disturbance of some endogenous substrates including testosterone and retinol. In turn, the inducted hepatic CYP3As further worsens the diabetes. A series of experiments were designed to verify above hypothesis. II diabetic rats were included in the studies. Induction of CYP450s including CYP3As under diabetic rats and effects of the induced hepatic CYP450s on pharmacokinetics of nateglinide, repaglinide，testosterone and retinol were investigated. The pharmacokinetics and pharmacodynamics of therapeutic drugs were also measured during drug therapy. Mechanisms inducing CYP3As were also documented both in vivo and in vitro. Relationship between activity of hepatic CYP3A and diabetes by co-administration of CYP3A inhibitors as well as CYP3A inducer was studied to investigate whether the induced hepatic CYP3As worsens diabetes and its mechanisms. The above results were further verified using results from ob/ob mice and cyp3a11 knockout (cyp3a11-/-) mice. Hepatic cells charactering insulin residence induced by palmitic acid were also used to investigate relationship between hepatic CYP3A induction and insulin residence. The mechanisms leading to above results were also studied. The results may highlight roles of hepatic CYP3A induction in diabetic development, as well as give gudainces for drug and prediction of drug adverse effects in diabetic patients.