30/05/2023
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Research at Kobe
Discovery of a new action of anti-diabetic drugs that ``extract glucose into the stool''
2020/06/03Graduate School of Medicine
research news
A research group led by Professor Wataru Ogawa of the Department of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, and Associate Professor Munenobu Nogami of the Department of Diagnostic Radiology, has found that the most widely used antidiabetic drug in the world is in the stool. It has been clarified in a study on humans that it has the effect of "excreting glucose in the body".
Metformin has been used for more than 60 years and is still the most widely used antidiabetic drug in the world today. Taking metformin lowers the patient's blood sugar level (blood glucose concentration), but the mechanism is not clear, and research into the mechanism of action of metformin is being actively conducted around the world.
This time, through bioimaging research using a new radiological diagnostic device called PET-MRI, it was found that glucose in the blood of patients who took metformin is released (excreted) from the large intestine into the f***s. . This is a new discovery that was not expected at all until now.
The effect of ``excreting glucose in the stool'' discovered this time may explain the various effects of metformin that had not been clarified until now, and this discovery will lead to the development of new antidiabetic drugs. is expected.
The results of this research were published in the American Diabetes Association journal " Diabetes Care " on June 3 (Eastern Standard Time).
point
Metformin is the most commonly used antidiabetic drug in the world, but its mechanism of action was unclear.
In vivo imaging studies on humans revealed that metformin has the effect of "excreting glucose in the stool."
This action may explain the various effects of metformin, and is expected to lead to the development of new antidiabetic drugs.
Research background
Diabetes is a disease in which the blood sugar level (concentration of glucose in the blood) becomes high, and the rise in blood sugar level damages the blood vessels, causing various diseases. The number of diabetes patients in Japan is said to exceed 10 million, and prevention of various complications caused by diabetes is an important medical issue.
Various drugs have been developed to lower blood sugar levels. Among them, metformin is the drug that has been used for the longest time, and more than 60 years have passed since its launch. Metformin is the recommended first-line drug in many countries and is currently the most widely used diabetes drug in the world.
Metformin lowers blood glucose levels in patients, but the mechanism by which metformin lowers blood glucose remains unclear. Understanding the mechanism of action of metformin will lead to the development of better antidiabetic drugs. Therefore, research into the effects of metformin has been actively conducted around the world.
Content of research
Figure 1. Representative FDG-PET MRI images of patients taking and not taking metformin
Areas where FDG (glucose) is concentrated appear black. In the metformin-administered person on the right, the intestine appears black, indicating that FDG (glucose) is concentrated in the intestine.
FDG-PET (fluorodeoxyglucose-positron emission tomography) involves injecting FDG, a substance that closely resembles glucose, into a patient's blood vessels and then measuring where the FDG collects in the body. It is an inspection to check the. FDG moves in the same way as glucose does in the human body, so it can be used to study how glucose moves in the body and which organs use a lot of glucose. 1).
FDG-PETは、通常PET装置とCT(computed tomography、コンピューター断層撮影)装置が一体化した装置を用いてFDG-PETとCTの画像を得て、FDGが体の中のどこに集まっているかを詳しく調べます。最近、PET装置とMRI（magnetic resonance imaging、 核磁気共鳴画像法）装置が一体化したPET-MRIという装置が開発されました。MRIは強力な磁力を利用して体の中を詳しく調べる検査ですが、CTでは解らない構造なども調べることができる点で優れています。PET-MRIは、全国でまだ9台しか設置されてない貴重な検査装置です。
図２．メトホルミンを服用すると「腸の中」にブドウ糖が集まる
左）腸の壁（上）と腸の中（下）へFDGが集まっている様子（集まり方の程度によって色調が変わるカラー画像処理）。
右）腸の中へのブドウ糖の集まり方。小腸の肛門に近い部分（回腸）より肛門側の腸ではメトホルミンを飲んでいるとブドウ糖が多く集まるようになる。
小川教授らはPET-MRIを使って、メトホルミンを飲んでいる糖尿病患者と飲んでいない糖尿病患者の体の中でブドウ糖の動きを調べました。その結果、メトホルミンを飲んでいる患者は、ブドウ糖（FDG）が腸に集まることがわかりました（図1）。さらに、腸の中でどこに集まっているかを知るために、「腸の壁」と「腸の中（便やそのほかの内容物）」に分けて調べたところ、小腸の肛門に近い部分（回腸）から先では、メトホルミンを飲んでいる患者の体内では、「腸の中」にブドウ糖がたくさん集まることが解りました（図2）。一方、「腸の壁」へのブドウ糖の集まり方には、メトホルミンを飲んでいる患者と飲んでいない患者の間で差はありませんでした。
この結果は、メトホルミンを飲むと血液の中のブドウ糖が、腸から便の中へ出てゆくことを示しています。メトホルミンがブドウ糖を便の中へ出させることはもとより、人の体の中で、ブドウ糖が腸から便の中に出てゆくという現象自体、今まで知られていなかった発見です。
最近、SGLT2阻害剤という「尿の中にブドウ糖を出す」作用を持つ糖病治療薬が発売され、その効果に注目が集まっていますが、今回見つかった「便の中へブドウ糖を出す」という作用もメトホルミンが血糖値を下げる効果と関係している可能性があります。
この研究の意義と今後の展開
以前にPET-CTを用いた検討で、メトホルミンを飲むと腸にブドウ糖が集まることは報告されていましたが、十分な根拠のないまま、ブドウ糖は「腸の壁」に集まると信じられていました。今回、PET-MRIという新しい装置を使うことにより、はじめてブドウ糖の集まり方を「腸の壁」と「便の中」に分けて調べることができ、「便の中」に集まることが解りました。
糖尿病治療薬の新薬であるSGLT2阻害剤を飲むと、1日当たり数10グラムのブドウ糖が尿の中に出ていきます。今回の検討では、メトホルミンによって便の中に何グラムのブドウ糖が出てゆくかという量的な評価はできません。今後、新しい撮像法を開発し、量的な評価ができれば、今回の発見の意義が一層明らかになると考えられます。
メトホルミンによる腸内細菌叢の変化(注2)も、血糖を下げる作用と関係していると考えられていますが、メトホルミンがどのようなメカニズムで腸内細菌叢を変化させるかは全く分かっていません。ブドウ糖など栄養素の変化は細菌の増殖に影響を及ぼすため、便にブドウ糖を出すことと腸内細菌叢の変化は関係している可能性があります。
補足説明
（注１）
がんは正常の組織に比べてたくさんのブドウ糖を使うので、FDG-PETは他の検査ではみつかりにくいがんを発見することにも用いられます。
（注２）
人間の腸の中には100兆から1000兆個もの腸内細菌が生息しており、そのような細菌の全体を腸内細菌叢（腸内フローラ）と呼びます。腸内細菌叢の変化は病気の起こり方や薬の効果などに関係することが知られています。
論文情報
タイトル
“ Enhanced Release of Glucose into the Intraluminal Space of the Intestine Associated with Metformin Treatment as Revealed by [18F]Fluorodeoxyglucose PET-MRI ”
DOI: 10.2337/dc20-0093
著者
Yasuko Morita1, Munenobu Nogami2, Kazuhiko Sakaguchi1, Yuko Okada1, Yushi Hirota1, Kenji Sugawara1, Yoshikazu Tamori1,3, Feibi Zeng2, Takamichi Murakami2, and Wataru Ogawa1*
1 Department of Diabetes and Endocrinology, Department of Internal Medicine,
Kobe University Graduate School of Medicine 2 Department of Diagnostic Radiology, Graduate School of Medicine,
Kobe University 3 Department of Health Creation Promotion, Department of Community Medicine and Health Science, Graduate School of Medicine, Kobe University
* Corresponding author
Publication magazine
Diabetes care
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神戸大学大学院医学研究科糖尿病・内分泌内科学部門の小川渉教授、放射線診断学分野の野上宗伸特命准教授らの研究グループは、世界で最も広く使われている糖尿病治療薬が「便の中にブドウ糖を排泄させる」という作用...
