圖解：二甲雙胍是如何在腸道裡發揮作用的?∣答題赢獎

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上一期我們的題目是——

以下哪項研究是降糖領域曆時最長的前瞻性研究：

UKPDS

VADT

CANVAS

PROactive

正确答案是A。

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這一期我們的話題是——

二甲雙胍與腸道

二甲雙胍發揮抗高血糖療效的很重要的一部分機制在于其在腸内的作用，包括促進GLP-1分泌、增加腸壁内葡萄糖的無氧代謝，以及對腸道微生物組的潛在影響。

先聽為快

胍胍說亮點 來自默博士 00:00 01:15

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有助于提高二甲雙胍整體療效的胃腸道作用機制概覽

我們先用一張圖來為您闡述二甲雙胍在腸道内的作用。

DPP4：二肽基肽酶 - 4；FXR：法尼醇X受體；FDG：氟脫氧葡萄糖；GLP - 1：胰高血糖素樣肽-1；OCT：有機陽離子轉運蛋白；PMAT：血漿膜單胺轉運蛋白；SERT：5 - 羟色胺轉運蛋白。

二甲雙胍的吸收

口服二甲雙胍大部分在小腸上部進行吸收。這就解釋了為什麼二甲雙胍的生物利用度相對較低（40% - 60%），以及口服給藥後吸收持續時間相對較短的問題。

緩釋二甲雙胍片的開發利用了這種現象。例如，當前臨床使用的緩釋二甲雙胍片可在服用後立刻吸收水分并膨脹，導緻它比速釋片在胃内的保留時間更長。這樣可以延長吸收期，也會減少二甲雙胍的胃腸道副作用。

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.

腸道：二甲雙胍發揮抗高血糖作用的重要靶點

二甲雙胍增加腸内葡萄糖利用

在小鼠的空腸内給予二甲雙胍可以增加局部淨葡萄糖利用率，導緻乳酸産生增加。同樣，二甲雙胍口服給藥後在受試者腸壁内的積累，也與葡萄糖無氧代謝生成乳酸增加相關。腸内葡萄糖無氧代謝成乳酸的過程産生的能量相對較少，乳酸鹽在其它組織中可以轉換回葡萄糖從而增加葡萄糖轉換率，這一過程可能作為 “無效循環”，導緻二甲雙胍治療期間通常不會出現體重增加。

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.

二甲雙胍增加腸道淨葡萄糖利用率的過程，我們可以用下面這張圖表示。

二甲雙胍增強腸促胰島素肽活性

給予GLP – 1類似物或使用DPP4抑制劑保護内源性GLP – 1，對2型糖尿病患者具有多種有益的療效，這些藥物在疾病管理中的應用已經成熟。已經證明，二甲雙胍治療在糖尿病和非糖尿病人群中均可增加循環中未被降解和/或總GLP – 1的水平。相反，撤除二甲雙胍導緻循環GLP - 1 水平明顯降低，一旦再開始二甲雙胍治療，循環GLP - 1 水平将重返基線值，并且血糖也将重返二甲雙胍治療時的水平。

在DPP4 抑制劑治療同時加入二甲雙胍也會增加2型糖尿病患者的循環GLP - 1 水平。腸内二甲雙胍作用導緻的GLP - 1受體激活增強可以改變腸道GLP - 1系統和代謝動态平衡的中樞調控之間的相互影響（'腸 – 腦軸'）。

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”).

二甲雙胍減少膽汁酸吸收

二甲雙胍治療可以減少回腸内膽汁酸的吸收，從而增加更遠端腸道内膽汁酸的量。這個作用可能會進一步增加二甲雙胍誘導的GLP - 1分泌，或通過滲透效應促進二甲雙胍相關性腹瀉的發生。

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.

二甲雙胍和微生物組

越來越多來源于動物和人類的研究提示，二甲雙胍的部分療效可能來自對腸道細菌的作用。糖尿病本身和随後的二甲雙胍治療似乎都會影響腸内微生物組的組成，有利于産生短鍊脂肪酸（例如，丁酸鹽）的細菌，而不利于機會性緻病菌的生長。但是，目前來自人類的數據相對有限。

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.

總結

綜上，在二甲雙胍發揮降血糖作用的過程中，腸道是其增加葡萄糖利用的重要部位。最近的研究突出了小腸L細胞分泌GLP – 1增多對二甲雙胍整體治療作用的重要性。在腸道其它部位，二甲雙胍引起的腸壁中葡萄糖無氧代謝增強已經被認為具有顯著的臨床抗高血糖作用。而二甲雙胍相關性腸道微生物組改變的重要意義，仍需進一步研究予以闡明。

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.

下期預告

二甲雙胍與腎髒

參與答題赢大獎

格華止緩釋片減少胃腸道反應的機制：

a. 增加胃部停留時間

b.增加腸道停留時間

c. 緩慢釋放藥物成分

d. a c e. b c

本章執筆專家

CliffordJ Bailey

英國伯明翰 阿斯頓大學

生命與健康科學學院

參考文獻

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

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