Antidiabetic drug turns sugar into stool

Researchers from Kobe University have discovered that metformin, the most widely prescribed antidiabetic drug globally, promotes the excretion of blood sugar from the large intestine into the stool — a mechanism that had never before been realised. Their findings have been published in the journal Diabetes Care.

Diabetes is characterised by the elevation of blood sugar concentration, which damages the blood vessels and in turn leads to various diseases. The good news is that a number of drugs that reduce blood sugar concentration are available for the more than 400 million people who suffer from diabetes around the world.

Metformin, recommended as a first-line drug in many countries, is the most frequently prescribed medication for diabetes, having been in use for more than 60 years. Administration of metformin lowers blood sugar levels, but the mechanism behind this effect was previously not understood. Elucidation of this mechanism would contribute to the development of new and better diabetes drugs; metformin’s mode of action has thus been actively researched over the world.

One such method of research has involved the use of FDG-PET (fluorodeoxyglucose-positron emission tomography) — an imaging test to study where and how much FDG (a substance similar to sugar) is accumulated in the body after the administration of this substance through the vessels. Because FDG behaves in a similar way to sugar in the human body, FDG-PET can reveal organs or tissues that consume or accumulate large amounts of sugar.

FDG-PET is generally conducted with a device that integrates both PET and CT (computed tomography) imaging, allowing for the examination of locations where FDG has accumulated. A more recent device development involves the integration of PET and MRI (magnetic resonance imaging), using a strong magnetic field to examine bodily structures that cannot be analysed by CT. Only nine PET-MRI devices have been installed in Japan, one of which was taken advantage by the Kobe research team.

The team used PET-MRI to investigate the movement of sugar in the bodies of diabetic patients, both those who were taking metformin and those who were not. The team found that sugar (ie, FDG) is heavily accumulated in the intestine of patients taking metformin. To understand exactly where in the intestine sugar accumulates, the team subsequently investigated the ‘wall of the intestine’ and the ‘inside of the intestine’ (stool and other contents) separately.

They found that, in patients taking metformin, more sugar was accumulated in the areas inside the intestine that are distal to the ileum (the anal side part of the small intestine). On the other hand, there was no difference in sugar accumulation in the wall of the intestine between patients who were taking and not taking metformin.

These results indicate that, when a patient takes metformin, sugar in the blood is released from the intestine into the stool. It was previously not known that sugar could be excreted from the intestine into the stool, nor that metformin promoted this activity.

Representative FDG-PET MRI images of patients taking and not taking metformin; the areas where FDG (sugar) is accumulated appear black. In patients taking metformin (right), the intestine appears black, which indicates that FDG (sugar) is accumulated in the intestine.

Previous studies using PET-CT had shown that FDG accumulated in the intestines of patients taking metformin, but PET-CT could not separately show the wall and the inside the intestine. In the current study, PET-MRI allowed the research team to investigate the accumulation in the wall and the inside of the intestine (stool) separately, revealing that metformin-induced accumulation of sugar occurred exclusively inside the intestine.

Interestingly, metformin appears to share characteristics with another antidiabetic drug, known as an SGLT2 inhibitor, which lowers blood sugar concentrations by excreting sugar in the urine. Taking a SGLT2 inhibitor results in the excretion of tens of grams of sugar per day; the Kobe researchers were unable to quantitatively evaluate how many grams of sugar were excreted in stool. The significance of the discovery will, however, be further confirmed by using a new imaging method that will enable the excreted sugar in the stool to be quantified.

Top image credit: ©stock.adobe.com/au/adragan

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