Why bypass surgery helps in diabetes

To manage obesity, various different surgical procedures can be performed on the stomach, including so-called bypass surgery in which, as well as reducing the size of the stomach, a bypass is created to send food directly into the distal gut (which, before the operation, is far from the stomach).

In obese patients who also suffer from diabetes, spectacular improvement in the diabetes is routinely observed following this type of operation although the mechanism underlying this phenomenon was not understood. Now, experiments conducted in mice by scientists from Université Claude Bernard - Lyon 1, Inserm, CNRS, INRA and the Hôpital Bichat in Paris, have elucidated the mechanism in question. The bypass stimulates glucose synthesis in the gut, an effect that is sustained between meals. Detection of this glucose induces the sending of a signal to the brain which leads to enhanced responsiveness to insulin. These findings - which are reported in the September issue of the journal Cell Metabolism - could point to novel therapeutic approaches in both obesity and diabetes.

In obese patients, the main objective of gastric surgery is to reduce the size of the stomach and this is most commonly achieved by implanting a gastric ring. When the patient also suffers from diabetes, the latter condition tends to improve once he or she has lost some weight. Bypass surgery however has a specific effect in that dramatic improvement is obtained almost immediately-as of discharge of the patient from hospital-a phenomenon which has been hitherto poorly understood. In this form of surgery, as well as reducing the size of the stomach, a bypass is created to send food directly into the distal intestine (which, before the operation, is far from the stomach). The proximal intestine (which is physiologically located immediately after the stomach) is left in place but it no longer receives any food.

Fabrizio Andréelli and his team (Inserm Unit 695, Hôpital Bichat, Paris) have developed models of "ring" and "bypass" surgery in mice in order to elucidate the specific effects of the two techniques.

It was already known that, in the gut (specifically in the wall of the portal vein - the portal vein collects blood coming from the gut), there is a nerve-based system capable of detecting glucose and sending this information to the brain. In 2005, Gilles Mithieux (Inserm Unit 855, Université Lyon 1, INRA–USC 2028) showed that when de novo glucose synthesis is triggered in the intestine (in a process called neoglucogenesis), this signalling system is activated. The sending of the message results in attenuation of feelings of hunger and also has a beneficial effect on blood glucose regulation.

Now, the teams of Fabrizio Andréelli and Gilles Mithieux, in collaboration with those of Christophe Magnan (CNRS UMR 7059, Paris 7) and Bernard Thorens (Lausanne), have tested the hypothesis that intestinal neoglucogenesis is involved in the observed, specific effects of gastric bypass surgery. They fed mice a diet rich in lipids and carbohydrates (sugar) to mimic metabolic conditions in diabetic obesity.

The scientists observed strong expression of genes involved in glucose synthesis throughout the guts of the "bypass" mice but not "ring" mice. They also observed that, between meals, glucose was still being released into the portal vein after the ingested food had been absorbed. Enough glucose was being released to trigger the portal vein signalling system, thereby leading to a reduction in the amount of food eaten and dramatic improvement in the ability of insulin to bring the blood glucose concentration down.

These findings shed light on why gastric bypass surgery induces such rapid improvement in diabetes, a phenomenon which was hitherto unexplained. According to the authors, "These results could point to new therapeutic strategies - surgery or drugs - relevant not only to obesity but also to diabetes".

http://www.cellmetabolism.org/