06 Feb 2019 --- The way that bariatric surgery helps people with obesity and diabetes is related to changes in the way the gut senses food and nutrients after the operation, University of Cambridge research has found. The study discovered that following surgery, altered patterns of digestion and absorption lower in the gut trigger production of higher levels of gut hormones, especially glucagon-like peptide 1 (GLP-1), which in turn causes higher insulin production. The researchers note that future medications for groups of people struggling with hypoglycemic episodes following weight loss surgery could be developed off of these findings. In the even further future, potential drugs that mimic the effects of bariatric surgery could be on the cards, but more research is warranted.
“For people who have gastric bypass surgery to treat obesity and also suffer from diabetes, after surgery body weight is reduced and diabetes melts away quickly,” says senior author Fiona Gribble of the Cambridge University Metabolic Research Laboratories at the Wellcome Trust – MRC Institute of Metabolic Science. “But in lean patients with gastric cancer, they start off having normal glucose control and after the operation, they end up having frequent hypoglycemic episodes because their sugar levels dip.”
The team wanted to learn more about the mechanism explaining these opposite results regarding glucose management.
Researchers have long known that bariatric surgery changes how the food you eat is digested and absorbed in the gut. They also knew that hormone-producing cells in the gut, such as GLP-1 and peptide-YY (PYY), are elevated afterward. But they did not know the precise connection between these facts.
For this study, the team decided to focus on GLP-1 as it is a major hormone involved in diabetes treatment. At least a half dozen GLP-1-based medications are available for managing Type 2 diabetes. “Our theory was that the high GLP-1 levels produced after surgery are quite important for improving your blood glucose after surgery,” says Gribble.
The team studied five individuals receiving bariatric surgery for a hereditary form of gastric cancer. Participants received Exendin-9, a compound that blocks the action of GLP-1, at the same time as taking glucose orally. They found that concentrations of insulin, the hormone responsible for lowering blood glucose levels, did not increase as dramatically when these individuals were given Exendin-9 and did not suffer hypoglycemic episodes. “We found that blocking the GLP-1 hormone with the Exendin-9 blocked its effect on the pancreatic beta cells that produce the insulin,” says Gribble.
Gribble tells NutritionInsight that the pronounced role of GLP-1 surprised the team. “Insulin concentrations are usually very high after a glucose drink in this group, but when we blocked GLP-1 action, the plasma insulin looked like that of our healthy control group,” she says.
“Most digestion does not happen until the bile and the pancreatic enzymes coming down from one side join the food coming down the other side, which occurs lower in the gut,” explains Gribble. This is important because most GLP-1 is released lower down the gut. “If you digest and absorb your nutrients a bit lower down, you consequently stimulate the release of much more GLP-1.”
Using new RNA sequencing and mass spectrometry-based measurements, developed for this research, the team mapped the location of various hormonal peptides in the gut in humans and mice before and after surgery.
They found that the cells producing the GLP-1 hormone and other gut hormones are not affected by the surgery. “This means that the reason for higher GLP-1 secretion is not because the surgery changes the hormone production by the gut, but it is because nutrient digestion and absorption happens in a different place in the gut and that causes higher levels of GLP-1 and PYY,” says Gribble.
Looking forward, the team hopes to learn the precise mechanism responsible for the rapid weight loss in bariatric surgery.
“If you can work that out and make a therapy that mimics that, it is what everyone wants: an injectable or oral medication that could mimic the surgery and cause weight loss in people without the surgery,” she says.
However, Gribble tells NutritionInsight that this is difficult: “One of our approaches is to try to stimulate the endocrine cells in different regions of the gut pharmacologically and to see whether we can mimic the effects of bariatric surgery. We did find a small effect of GLP-1 blockade on hunger in the gastric cancer group, but we could not determine whether this effect of GLP-1 was large enough to contribute to weight loss. There are other hormones like PYY that are also elevated after bariatric surgery, that might contribute to the weight loss.”
For those suffering from hypoglycemia after gastric cancer surgery, development of a compound that blocks GLP-1 on a more permanent basis may help improve quality of life for patients who currently make significant adaptations to their eating behavior to avoid hypoglycemic episodes.
“There are drugs under development that should provide a sustained block of GLP-1 action. A major use of these drugs will be in the growing population of people who had bariatric surgery for obesity several years ago and now have symptoms similar to the cancer surgery group because they have lost so much weight. Drugs should be in clinical trials in the next few years,” notes Gribble.
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