Should we slow down gut contractions to control diabetes? ⋅ Inserm, Science for Health

Glucose would control the contractions of the gut involved in digestion and even its own absorption via mechanisms involving the enteric nervous system. By describing these processes and studying how they malfunction in diabetic mice, researchers from Toulouse have just identified a modulation pathway that could be used to better control this metabolic disease.

In a normal situation, food intake is followed by an increase in the contraction of the intestines. Information is transmitted to the brain from the nervous system that controls the digestive system—the enteric nervous system. At the central level, certain mediators, such as nitric oxide (NO) produced by the hypothalamus, then act to control and then normalize glycemia, ie the amount of sugar available in the blood. At the same time, the gut neurons also produce NO, which is involved in this regulation. But in diabetic mice and humans, after a meal, intestinal hypermotor function is exacerbated and intestinal absorption of glucose is abnormally high. The control of glycemia then eludes the classic mechanisms linked to the action of NO: the glucose remains in the blood in high quantities and the peripheral tissues that use it as a source of energy are less able to absorb it. A vicious circle sets in, damaging the body’s glycemic balance.

The gut-brain axis, which enables the digestive system and central nervesystem Interaction plays an obvious role in the development and maintenance of diabetes, but all mechanisms have yet to be precisely determined. Claude Knauf* and his team are working to describe exactly how this axis intervenes in the regulation of blood sugar, in normal or pathological situations. For several years they have developed and validated a new concept that enterosyns: “These are Molecules that can alter the function of the gut-brain axis by interacting with the enteric nervous systemsays the researcher. These are hormones neurotransmittersfrom nutrientbacteria or metabolites Bacteria capable of controlling the contractions of the intestines, thus modulating the messages sent to the brain. The goal of our laboratory is therefore to identify among these molecules those that would be able to do so slow gut motility to improve diabetes control. »

Alignment with the GLUT2 signaling pathway

Her work led her to study the influence of glucose itself: what effect does it have on gut motility, exactly, and through what mechanisms? Through experiments performed in vitro and in mice, the researchers showed that glucose stimulates intestinal contractions during a meal by interacting with two intestinal glucose transporters: SGLT-1 and GLUT2. When the meal is unusually rich, the expression of the genes that code for these two transporters increases and therefore, logically, increases blood sugar. In diabetics, this mechanism is so amplified that it leads to a plateau beyond which glucose has no additional effect on gut motility.

At the same time, the team described a direct link between the concentration of glucose in the blood and the reduction in the release of NO by the enteric nervous system under the action of GLUT2. Then, using a GLUT2 inhibitor, phloretin, she observed that the mechanism was reversible: thanks to this inhibitor it is possible to reduce the effect of glucose on intestinal contractions, both in normal mice and in diabetic animals. . For Claude Knauf ” Targeting this transporter could therefore be particularly relevant to better control glucose absorption in type 2 diabetics: this strategy could lead to the restoration of a functioning gut-brain axis “.

Before considering such an approach more concretely, the researcher now wants to examine the effects of the mechanisms described here at the cerebral level. ” We have already identified the action of several enterosyns such as apelin, galanin or certain prebiotics like oligofructose on cerebral NO levels and improvement in diabetic status. We now want to find enterosyns that are able to interact with the GLUT2-triggered signaling pathway. Such molecules would also present many alternatives or complementary approaches to those currently offered to people suffering from type 2 diabetes. concludes the scientist.

note :
* Unit 1220 Inserm/INRAE/Toulouse III – Paul Sabatier University/National Veterinary School, Digestive Health Research Institute, Physiopathology of the Gut-Brain-Axis Team