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Disease and treatment

Gastric surgery works: let’s turn it into a pill

The obesity epidemic rages. Every sixth person is extremely obese today. One of the few effective ways of fighting obesity is surgery. Previously it was thought that the people lose weight after surgery because the stomach has less room for food. However, new research shows that people lose weight because of major changes in hormone balance. A new study has charted how the surgery affects the body. The goal is now to recreate this effect by using a pill to avoid surgery.

Gastric bypass surgery is a simple procedure that channels food directly from the upper part of the stomach to the lower part of the intestine, thus eliminating most of the function of the stomach and intestines. This helps most people lose considerable weight and avoid life-threatening diseases such as type 2 diabetes. The reason they lose this weight, however, differs completely from what was expected. Danish researchers have charted the physiological changes resulting from gastric bypass and the more recent gastric sleeve surgery.

“The surgery drastically changes the secretion of hormones. Bypass surgery increases the secretion of the appetite-inhibiting hormones, whereas sleeve surgery reduces the secretion of appetite-stimulating hormones. Our ultimate goal is to mimic these changes without having to do the surgery,” explains co-author Maria Saur Svane, postdoctoral fellow, Hvidovre Hospital, Denmark.

Reducing appetite

Gastric bypass surgery changes the gastrointestinal anatomy so that food flows directly to the remote part of the small intestine and bypasses most of the stomach. A sleeve gastrectomy removes most of the stomach, leaving a narrow passage for food through a small tube.

“These two procedures differ considerably in the rate at which nutrients are absorbed from the food eaten and in the secretion of gut hormones.”

The researchers determined the absorption of nutrients and secretion of gut hormones by combining intravenous stable isotopes of glucose and amino acids combined with giving patients a meal also containing stable isotopes. After the patients ate the food, the researchers then followed the rate at which the isotopes were absorbed and the quantity of hormones secreted by the gut.

“Bypass surgery increases the secretion of the appetite-inhibiting hormones from the remote part of the gut, such as GLP-1 and PYY, whereas sleeve surgery does not substantially increase the secretion of these hormones. Instead, sleeve surgery reduces the secretion of hormones from the gut, such as the appetite-stimulating hormone ghrelin, which is completely suppressed.”

Eliminating diabetes

The most important reason for gastric surgery is major weight loss, but an additional advantage is eliminating diabetes. People undergoing surgery do not eat much during the first couple of days afterwards, which means they start losing fat in the liver. The fat disappears from the liver after only a couple of days.

“This turns out to be vital for the liver regaining its sensitivity to insulin. Insulin can again reduce the glucose production in the liver, and that is one of the essential mechanisms through which diabetes can occur,” explains co-author Jens Juul Holst, Professor, Novo Nordisk Foundation for Basic Metabolic Research, University of Copenhagen.

The second important thing that happens is that, once people start to eat again, the gut is stimulated differently than before surgery. The food enters further down in the small intestine, stimulating many new endocrine cells. This increases the release of hormones that strongly affect insulin secretion at the same time that the amount of glucose from the food increases substantially.

“Together, these two things mean that people produce a lot of insulin. So now they have regained insulin sensitivity and have increased insulin secretion, and this is essential for these people with diabetes. That was their problem. They were insensitive to insulin and they had too little of it, and all of a sudden both these things are repaired after surgery, and this only takes a few days.”

Using nature’s own mechanisms

Although the two surgical procedures, gastric bypass and sleeve gastrectomy, are anatomically very different, their clinical performance in weight loss and diabetes remission seems to be similar. However, the new study shows that the physiological effect of the two procedures differs completely in terms of the rate at which nutrients are absorbed and the rate at which the gut secretes hormones.

”These types of surgery are expensive, they are risky and the patient needs lifelong vitamin replacement and follow-up by doctors. The optimal goal for us is to fully understand the mechanisms behind these favourable effects to mimic these changes without performing the surgery.”

Both gastric bypass and sleeve gastrectomy cause most people to lose considerable weight and eliminate their type 2 diabetes. GLP-1 is one of the hormones whose secretion is especially increased after such surgery. This has already been formulated into a drug. In the future, the researchers hope to combine the different effects of different hormones to provide even more favourable clinical benefits.

“Our ultimate goal is to use these hormonal changes surgery causes to create a new medicine. This means using nature’s own mechanism for reducing food intake and inducing weight loss. Since more than one hormone is involved in causing weight loss after surgery, we hope to combine them and achieve even more synergy.”

“Postprandial Nutrient Handling and Gastrointestinal Hormone Secretion After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy " has been published in Gastroenterology. Researchers from the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen participated in the study.

Jens Juul Holst
Professor
Jens Juul Holst has pioneered the isolation and characterization of GLP-1 and discovery of the potential of GLP-1 for treatment of diabetes and obesity. He is an elected member of the Royal Society of Science and Letters, and has received a number of awards including the Novo Nordisk Award, the Paul Langerhans Award of the German Diabetes Society, the Knud Lundbæk Award, the KFJ-award of Health Science Faculty of the University of Copenhagen, the Bagger-Sørensen Award and the prestigious Claude Bernard Award of the European Association of the Study of Diabetes.
Maria Saur Svane
Læge, PhD-studerende
Aims and objectives Remission of diabetes and appetite regulation after bariatric surgery. Importance of gut hormone. Life Style: Importance of weight loss, exercise and GLP-1 receptor agonist treatment for metabolic health Treatment of hypoglycaemia with "small-doses" of glucagon in patients with type 1 diabetes Research in bone and calcium metabolic diseases. Focus areas Bariatric surgery: 1) intestinal sensing of macro nutrients with focus on the L-cell (GLP-1, PYY secretion)l, 2) mechanism of actions of gastric bypass vs. gastric sleeve surgery, 3) comparison between poor and good responders to gastric bypass surgery. Life style: effect of weight loss, exercise alone and in combination compared with treatment with a GLP-1 receptor agonist on glucose and lipid metabolism, low grade inflammation etc. Treatment of hypoglycaemia: the recovery of hypoglycaemia when using small doses of glucagon after a period of low-carb intake or alcohol intake in insulin pump treated type 1 diabetic patients Bone and calcium metabolic disease: research in osteoporosis, vitamin D and seldom calcium metabolic diseases. Fracture liaison service.