Researchers have uncovered new clues to the mystery of how the gut’s nervous system affects glucose metabolism in the rest of the body. Their findings could lead to new treatments for type 2 diabetes.
Type 2 diabetes causes the body’s cells to become less sensitive to signals from insulin, the hormone responsible for regulating levels of glucose in the blood.
This low sensitivity is called insulin resistance, and it keeps the cells from absorbing the extra glucose that enters the bloodstream after a meal.
Over time, high concentrations of glucose in the blood damage tissues all over the body, causing complications such as heart disease, vision loss, and kidney disease.
The Centers for Disease Control and Prevention (CDC) estimate that more than 30 million people in the United States have type 2 diabetes.
Changes to the diet, exercise, and other aspects of life can improve symptoms and even reverse the condition in some people. Drugs are also available to treat type 2 diabetes, but they can cause side effects such as nausea and diarrhea.
Another drawback to some antidiabetic drugs is that they have to be injected.
Discovering oral treatments that are not only effective but also free of side effects is therefore a priority for diabetes researchers.
Now, a group of scientists, many affiliated with the French National Institute of Health and Medical Research, or INSERM, in Toulouse, believe that they are a step closer to developing such a treatment. They have published their findings in the journal Gut.
This latest research builds on previous work suggesting that fat, or lipid, molecules produced by “friendly” gut bacteria can improve blood glucose metabolism.
These lipids are thought to influence the gut-brain axis — the vital two-way communication between the brain and the gut’s highly developed nervous system, also known as the enteric nervous system or “second brain.”
In type 2 diabetes, communication between the gut and brain appears to break down. As a result, after a meal, the brain fails to send signals to the liver, muscles, and fat tissue telling them to absorb more glucose from the bloodstream. This, in turn, leads to insulin resistance.
Normally the duodenum, the first part of the small intestine, signals to the brain, which involves a relaxation of the smooth muscles in its lining. In individuals with type 2 diabetes, however, these muscles are permanently contracted, or hypercontractile, so the signal is never sent.
The researchers believe that friendly gut bacteria are the key to reversing hypercontractility and restoring healthy glucose metabolism.
Nutrients that feed friendly bacteria are called prebiotics. In particular, carbohydrates called fructooligosaccharides (FOS) are known to promote the growth of bacteria that improve glucose metabolism through the production of various lipids.
However, the identity of these lipids has remained unknown until now.
To find out more, the researchers fed mice a special diet supplemented with FOS. Then, they compared the contents of their colons with those of mice that did not receive supplementary FOS.
The team discovered that the only lipid with significantly increased levels in the colons of the FOS mice was a lipid called 12-HETE.
When they fed 12-HETE to diabetic mice, the lipid not only reduced duodenal hypercontraction but also improved the mice’s blood glucose levels.
To explore whether these results applied to humans, the scientists analyzed biopsies from the duodenums of people with type 2 diabetes who had received antidiabetic treatments and those of healthy volunteers who had not.
They found that there was 38% less 12-HETE in the duodenums of the people with diabetes, compared with the healthy volunteers. The researchers acknowledge that this finding was not statistically significant, but also point to the small numbers of volunteers in their study.
Finally, they showed that 12-HETE reduces muscle contraction in the duodenum by boosting the signal from a nerve receptor called the mu-opioid receptor. This restored communication between the gut and the brain.
This study is one of the latest to reveal intimate relationships between the bacteria in the human gut, known collectively as the microbiota, and our health.
The scientists are optimistic that their work will inspire new treatments, which could either boost production of 12-HETE in the gut or involve taking the lipid orally, as a supplement.
In their paper, the researchers conclude:
“Using a combination of nutritional and pharmacological approaches, we have identified a new mode of communication between gut microbes and the host. In addition, we have identified novel targets and their mechanisms of action in rodents, and possibly in humans. The identification of specific targets […] to treat [type 2 diabetes] and its comorbidities represent a groundbreaking solution to develop medications without side effects.”