Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Czech Republic.
Sci Rep. 2019 Apr 16;9(1):6156. doi: 10.1038/s41598-019-42531-0.
Metformin is currently the most prescribed drug for treatment of type 2 diabetes mellitus in humans. It has been well established that long-term treatment with metformin improves glucose tolerance in mice by inhibiting hepatic gluconeogenesis. Interestingly, a single dose of orally administered metformin acutely lowers blood glucose levels, however, little is known about the mechanism involved in this effect. Glucose tolerance, as assessed by the glucose tolerance test, was improved in response to prior oral metformin administration when compared to vehicle-treated mice, irrespective of whether the animals were fed either the standard or high-fat diet. Blood glucose-lowering effects of acutely administered metformin were also observed in mice lacking functional AMP-activated protein kinase, and were independent of glucagon-like-peptide-1 or N-methyl-D-aspartate receptors signaling. [F]-FDG/PET revealed a slower intestinal transit of labeled glucose after metformin as compared to vehicle administration. Finally, metformin in a dose-dependent but indirect manner decreased glucose transport from the intestinal lumen into the blood, which was observed ex vivo as well as in vivo. Our results support the view that the inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin.
二甲双胍目前是治疗人类 2 型糖尿病最常用的药物。已有研究证实，长期使用二甲双胍可以通过抑制肝糖异生来改善小鼠的葡萄糖耐量。有趣的是，单次口服给予二甲双胍可急性降低血糖水平，但对于这种作用的机制知之甚少。与给予载体的小鼠相比，无论动物是喂食标准饮食还是高脂肪饮食，预先口服给予二甲双胍均可改善葡萄糖耐量试验评估的葡萄糖耐量。在缺乏功能性 AMP 激活蛋白激酶的小鼠中也观察到急性给予二甲双胍的降血糖作用，并且与胰高血糖素样肽-1 或 N-甲基-D-天冬氨酸受体信号无关。[F]-FDG/PET 显示，与给予载体相比，给予二甲双胍后标记葡萄糖在肠道中的转运速度较慢。最后，二甲双胍以剂量依赖但间接的方式降低了从肠腔向血液中的葡萄糖转运，这在离体和体内实验中均观察到。我们的结果支持这样一种观点，即抑制肠道上皮细胞的葡萄糖转运是口服给予二甲双胍早期降低血糖水平的原因。
