Duca Frank A, Côté Clémence D, Rasmussen Brittany A, Zadeh-Tahmasebi Melika, Rutter Guy A, Filippi Beatrice M, Lam Tony K T
Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Nat Med. 2015 May;21(5):506-11. doi: 10.1038/nm.3787. Epub 2015 Apr 6.
Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.
二甲双胍是治疗2型糖尿病的一线治疗选择，尽管其潜在作用机制尚不完全清楚。二甲双胍通过抑制肝糖生成（HGP）来降低血糖水平，最初推测这种作用是由于肝脏中依赖于AMP激活的蛋白激酶（AMPK）的机制。然而，研究对肝脏AMPK在二甲双胍降低高血糖作用中的贡献提出了质疑，并且已经确定了一条介导肠道营养物质和激素诱导的HGP降低的肠-脑-肝轴。因此，二甲双胍可能通过这种器官间的串扰影响HGP。在此，我们表明，在大鼠3天高脂饮食（HFD）诱导的胰岛素抵抗模型中，十二指肠内输注二甲双胍50分钟可激活十二指肠黏膜Ampk并降低HGP。抑制十二指肠Ampk可消除十二指肠内二甲双胍降低HGP的作用，二甲双胍降低HGP需要十二指肠胰高血糖素样肽-1受体（Glp-1r）-蛋白激酶A（Pka）信号传导和神经元介导的肠-脑-肝途径。餐前服用二甲双胍也可降低28天HFD诱导的肥胖和胰岛素抵抗大鼠模型以及烟酰胺（NA）-链脲佐菌素（STZ）-HFD诱导的2型糖尿病大鼠模型的HGP。在非钳夹状态下，抑制十二指肠Ampk可降低糖尿病大鼠模型中单次注射二甲双胍治疗的降糖效果。这些发现表明，在肥胖和糖尿病大鼠模型中，二甲双胍激活了一条以前未被认识的依赖十二指肠Ampk的途径来降低HGP和血浆葡萄糖水平。
