图解：二甲双胍是如何在肠道里发挥作用的?∣答题赢奖

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上一期我们的题目是——

以下哪项研究是降糖领域历时最长的前瞻性研究：

UKPDS

VADT

CANVAS

PROactive

正确答案是A。

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这一期我们的话题是——

二甲双胍与肠道

二甲双胍发挥抗高血糖疗效的很重要的一部分机制在于其在肠内的作用，包括促进GLP-1分泌、增加肠壁内葡萄糖的无氧代谢，以及对肠道微生物组的潜在影响。

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胍胍说亮点 来自默博士 00:00 01:15

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有助于提高二甲双胍整体疗效的胃肠道作用机制概览

我们先用一张图来为您阐述二甲双胍在肠道内的作用。

DPP4：二肽基肽酶 - 4；FXR：法尼醇X受体；FDG：氟脱氧葡萄糖；GLP - 1：胰高血糖素样肽-1；OCT：有机阳离子转运蛋白；PMAT：血浆膜单胺转运蛋白；SERT：5 - 羟色胺转运蛋白。

二甲双胍的吸收

口服二甲双胍大部分在小肠上部进行吸收。这就解释了为什么二甲双胍的生物利用度相对较低（40% - 60%），以及口服给药后吸收持续时间相对较短的问题。

缓释二甲双胍片的开发利用了这种现象。例如，当前临床使用的缓释二甲双胍片可在服用后立刻吸收水分并膨胀，导致它比速释片在胃内的保留时间更长。这样可以延长吸收期，也会减少二甲双胍的胃肠道副作用。

The absorption of orally administered metformin occurs mostly within the upper small intestine. This accounts for the relatively low bioavailability of metformin, and its relatively short duration of absorption after oral dosing.

The development of prolonged-release metformin tablets exploits this phenomenon. For example, such a tablet in current clinical use was designed to absorb water and swell immediately after ingestion, causing it to be retained for longer within the stomach than the immediate-release version. This prolongs the absorption phase, with fewer of the gastrointestinal side-effects characteristic of metformin.

肠道：二甲双胍发挥抗高血糖作用的重要靶点

二甲双胍增加肠内葡萄糖利用

在小鼠的空肠内给予二甲双胍可以增加局部净葡萄糖利用率，导致乳酸产生增加。同样，二甲双胍口服给药后在受试者肠壁内的积累，也与葡萄糖无氧代谢生成乳酸增加相关。肠内葡萄糖无氧代谢成乳酸的过程产生的能量相对较少，乳酸盐在其它组织中可以转换回葡萄糖从而增加葡萄糖转换率，这一过程可能作为 “无效循环”，导致二甲双胍治疗期间通常不会出现体重增加。

Intra-jejunal metformin administration to mice increased the net local glucose disposal rate, with an associated increase in lactate production. Similarly, the accumulation of orally administered metformin within the intestinal wall of human subjects is associated with increased anaerobic glucose metabolism to lactate. The relatively low energy yield of anaerobic glucose metabolism to lactate in the intestine, and the conversion of lactate back to glucose in other tissues increases glucose turnover and may serve as a ‘futile cycle’ that contributes to a lack of weight gain typically noted with metformin therapy.

二甲双胍增加肠道净葡萄糖利用率的过程，我们可以用下面这张图表示。

二甲双胍增强肠促胰岛素肽活性

给予GLP – 1类似物或使用DPP4抑制剂保护内源性GLP – 1，对2型糖尿病患者具有多种有益的疗效，这些药物在疾病管理中的应用已经成熟。已经证明，二甲双胍治疗在糖尿病和非糖尿病人群中均可增加循环中未被降解和/或总GLP – 1的水平。相反，撤除二甲双胍导致循环GLP - 1 水平明显降低，一旦再开始二甲双胍治疗，循环GLP - 1 水平将重返基线值，并且血糖也将重返二甲双胍治疗时的水平。

在DPP4 抑制剂治疗同时加入二甲双胍也会增加2型糖尿病患者的循环GLP - 1 水平。肠内二甲双胍作用导致的GLP - 1受体激活增强可以改变肠道GLP - 1系统和代谢动态平衡的中枢调控之间的相互影响（'肠 – 脑轴'）。

The administration of analogues of GLP-1, or preservation of endogenous GLP-1 using DPP4 inhibitors, exerts multiple beneficial therapeutic effects in type 2 diabetes and these agents are established firmly within the management of the disease. Treatment with metformin has been shown to increase circulating levels of intact and/or total GLP-1 in people with and without diabetes. Conversely, withdrawal of metformin was associated with a clear reduction in circulating GLP-1 levels, which returned to their baseline value once metformin had been restarted and blood glucose had returned to its previous level while taking metformin.

Adding metformin to a DPP4 inhibitor also increased circulating GLP-1 levels in people with type 2 diabetes. Increased activation of GLP-1 receptors as a consequence of the action of metformin within the gut may alter the interplay between the enteric GLP-1 system and the central control of metabolic homeostasis (the “gut-brain axis”).

二甲双胍减少胆汁酸吸收

二甲双胍治疗可以减少回肠内胆汁酸的吸收，从而增加更远端肠道内胆汁酸的量。这个作用可能会进一步增加二甲双胍诱导的GLP - 1分泌，或通过渗透效应促进二甲双胍相关性腹泻的发生。

Treatment with metformin reduces the uptake of bile acids within the ileum, increasing the quantity of bile acids present in the more distal intestine. Such an effect may augment metformin-induced secretion of GLP-1, or contribute to metformin-associated diarrhoea, via an osmotic effect.

二甲双胍和微生物组

越来越多来源于动物和人类的研究提示，二甲双胍的部分疗效可能来自对肠道细菌的作用。糖尿病本身和随后的二甲双胍治疗似乎都会影响肠内微生物组的组成，有利于产生短链脂肪酸（例如，丁酸盐）的细菌，而不利于机会性致病菌的生长。但是，目前来自人类的数据相对有限。

A growing evidence base from studies in animals and humans suggests that part of the efficacy of metformin may arise from actions on intestinal bacteria. Both diabetes per se and subsequent treatment with metformin appear to influence the composition of the gut microbiome, favouring bacteria that produce short-chain fatty acids (such as butyrate), and opposing the growth of opportunistic pathogens. However, data from humans are relatively limited at this time.

总结

综上，在二甲双胍发挥降血糖作用的过程中，肠道是其增加葡萄糖利用的重要部位。最近的研究突出了小肠L细胞分泌GLP – 1增多对二甲双胍整体治疗作用的重要性。在肠道其它部位，二甲双胍引起的肠壁中葡萄糖无氧代谢增强已经被认为具有显著的临床抗高血糖作用。而二甲双胍相关性肠道微生物组改变的重要意义，仍需进一步研究予以阐明。

Overall, the gut is a quantitatively important site of increased glucose utilization during the blood glucose-lowering effect of metformin. Recent research has highlighted the importance of elevation of GLP-1 secretion from the L cells of the small intestine to the overall therapeutic profile of metformin. Elsewhere in the gut, anaerobic glucose metabolism in the gut wall has been under appreciated as a clinically significant anti-hyperglycaemic action of metformin. Elucidation of the importance of metformin-associated alterations in gut microbiome will require further study.

下期预告

二甲双胍与肾脏

参与答题赢大奖

格华止缓释片减少胃肠道反应的机制：

a. 增加胃部停留时间

b.增加肠道停留时间

c. 缓慢释放药物成分

d. a c e. b c

本章执笔专家

CliffordJ Bailey

英国伯明翰 阿斯顿大学

生命与健康科学学院

参考文献

1 .Ian W Campbell, Harry CS Howlett, Rury RHolman, Clifford J Bailey (2017). Metformin, 60 years of clinical experience. Wiley.

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