Heishi M, Ichihara J, Teramoto R, Itakura Y, Hayashi K, Ishikawa H, Gomi H, Sakai J, Kanaoka M, Taiji M, Kimura T
Dainippon Sumitomo Pharma, 3-1-98, Kasugade-naka, Konohana, Osaka, 554-0022, Japan.
Diabetologia. 2006 Jul;49(7):1647-55. doi: 10.1007/s00125-006-0271-y. Epub 2006 May 23.
AIMS/HYPOTHESIS: Metformin is widely used as a hypoglycaemic reagent for type 2 diabetes. While the reduction of hepatic gluconeogenesis is thought to be a key effect, the detailed molecular mechanism of action of metformin remains to be elucidated. To gain insight into this, we performed a global gene expression profiling study.
We performed DNA microarray analysis to study global gene expression in the livers of obese diabetic db/db mice 2 h after a single administration of metformin (400 mg/kg).
This analysis identified 14 genes that showed at least a 1.5-fold difference in expression following metformin treatment, including a reduction of glucose-6-phosphatase gene expression. The mRNA levels of glucose-6-phosphatase showed one of the best correlations with blood glucose levels among 12,000 genes. Enzymatic activity of glucose-6-phosphatase was also reduced in metformin-treated liver. Moreover, intensive analysis of the expression profile revealed that metformin effected significant alterations in gene expression across at least ten metabolic pathways, including those involved in glycolysis-gluconeogenesis, fatty acid metabolism and amino acid metabolism.
CONCLUSIONS/INTERPRETATION: These results suggest that reduction of glucose-6-phosphatase activity, as well as suppression of mRNA expression levels of this gene, in liver is of prime importance for controlling blood glucose levels in vivo, at least at early time points after metformin treatment. Our results also suggest that metformin not only affects expression of specific genes, but also alters the expression level of multiple genes linked to the metabolic pathways involved in glucose and lipid metabolism in the liver.
目的/假设：二甲双胍作为2型糖尿病的降血糖药物被广泛使用。虽然肝糖异生的减少被认为是一个关键作用，但二甲双胍详细的分子作用机制仍有待阐明。为深入了解这一点，我们进行了一项全基因组表达谱研究。
我们进行了DNA微阵列分析，以研究单次给予二甲双胍（400mg/kg）2小时后肥胖糖尿病db/db小鼠肝脏中的全基因组表达。
该分析鉴定出14个基因，其在二甲双胍治疗后的表达差异至少为1.5倍，包括葡萄糖-6-磷酸酶基因表达的降低。在12000个基因中，葡萄糖-6-磷酸酶的mRNA水平与血糖水平的相关性最佳。在二甲双胍处理的肝脏中，葡萄糖-6-磷酸酶的酶活性也降低。此外，对表达谱的深入分析表明，二甲双胍在至少十条代谢途径中引起了基因表达的显著改变，包括那些参与糖酵解-糖异生、脂肪酸代谢和氨基酸代谢的途径。
结论/解读：这些结果表明，肝脏中葡萄糖-6-磷酸酶活性的降低以及该基因mRNA表达水平的抑制对于体内血糖水平的控制至关重要，至少在二甲双胍治疗后的早期时间点是如此。我们的结果还表明，二甲双胍不仅影响特定基因的表达，还改变了与肝脏中葡萄糖和脂质代谢相关代谢途径相连的多个基因的表达水平。
