鉴于糖尿病下调肝视黄醇脱氢酶(ADHs/RDHs)和上调视黄醛脱氢酶(RALDHs)活性与表达，导致肝视黄醛浓度降低和视黄酸浓度升高事实，在文献和前期基础上用诱导性和自发性糖尿病鼠，以肝为靶器官，结合基因敲除动物，研究1)糖尿病下调肝ADHs/RDHs和上调RALDHs活性和表达机制及其对视黄醛和视黄酸浓度失衡贡献；2)肝视黄醛和视黄酸浓度失衡与PEPCK等肝糖代谢和SREBP-1c等脂肪代谢相关蛋白表达关系；3)视黄醛和视黄酸对肝细胞糖和脂肪代谢及相关蛋白表达影响，用RALDH1基因沉默和转染验证。验证“糖尿病下调肝ADHs/RDHs和上调RALDHs活性，导致视黄醛和视黄酸浓度失衡，损伤肝糖代谢和脂肪代谢，加重肝胰岛素抵抗和糖尿病”推论。其成果对于阐明糖尿病引起肝视黄醛与视黄酸浓度失衡机制及其在肝胰岛素抵抗和糖尿病中作用，维生素A类药物合理使用和RALDH1作为药物潜在靶点有重要意义。

Our previous report showed that diabetes downregualted hepatic retinol dehydrogenase (ADHs/RDHs) but upregulated retinaldehyde dehydrogenase (RALDHs) activities and expressions, leading to significant decreases in concentration of hepatic retinaldehyde and significant increases in concentration of hepatic retinoic acid in rats. Here, we used both the induced diabetic animals and spontaneously diabetic animals: 1) to investigate the real mechanisms that diabetes decreased hepatic ADHs/RDHs and increased RALDHs activities and expressions, as well as their contribution to unbalance levels of hepatic retinaldehyde and retinoic acid in liver; 2) to study effects of alterations in levels of hepatic retinoic acid and retinaldehyde on glucose metabolism and lipid metabolism, as well as expressions of corresponding targeted proteins and mRNAs such as PEPCK and SREBP-1c in diabetic animals. The results would be further verified using RALDH1a1-/- mice. 3) to document effects of retinaldehyde and retinoic acid on hepatic glucose metabolism and lipid metabolism and expression of the corresponding proteins and which insulin signaling pathways were involved in glucose metabolism and lipid metabolism mediated by retinaldehyde and retinoic acid in primary rat/human hepatocytes and HepG2 cells, which would be further verified using gene silencing and transfection of RALDH1. Above results would support the our hypothesis, i.e “Diabetes downregualted ADHs/RDHs but upregulated RALDHs activities and expressions, leading to unbalance of hepatic retinaldehyde and retinoic acid, which impaired hepatic glucose metabolism and lipid metabolism, in turn, aggravated hepatic insulin residence and diabetes”. The findings would highlight roles of unbalance levels of hepatic retinal and retinoic acid in liver insulin resistance and diabetes, as well as give gudainces for clinical medication of retinoids and therapeutic target of RALDH1.