Life Health In the Lab
If Gastric Bypass Benefits Type 2 Diabetes


By Shirley S. Wang
Updated Nov. 2, 2015 9:24 a.m. ET


Several years ago, a team of surgeons at the University of Copenhagen performed gastric-bypass surgery on a severely obese 51-year-old man with Type 2 diabetes, rearranging his digestive tract to bypass his stomach and part of his intestines.

Two days later, because of suspected complications, the patient was fitted with a feeding tube. Nutrients through this tube wouldn’t bypass the stomach or the part of the intestine known as the duodenum. This led to an intriguing observation.

Just weeks after surgery, the doctors noticed the patient’s diabetes had improved dramatically. On days when he was fed by mouth through the rearranged digestive tract, his body behaved more like a healthy person’s and less like a diabetic’s. But on days when he was fed through the tube, he couldn’t control his blood sugar and his diabetes was unchanged. This observation suggested there was something about avoiding the duodenum, or the rearrangement of the gut, that was beneficial to the patient’s diabetes.

The case adds to the evidence indicating certain types of weight-loss surgery help resolve Type 2 diabetes better than intensive diet and exercise alone.

The improvement after surgery often comes before substantial weight-loss has occurred. And it doesn’t always correspond to how much weight someone has lost, prompting researchers to question which factors, other than weight loss, could be responsible for the benefit.
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Some scientists believe the answer could lie with a part of the small intestine called the duodenum. The hormone-rich organ, connecting the stomach to another part of the intestine called the jejunum, has prompted the development of various procedures to bypass or intervene on the duodenum. It was the focus of several presentations at the recent World Congress on Interventional Therapies for Type 2 Diabetes and Diabetes Surgery Summit, in London.

Other scientists, however, believe that getting food through the intestines faster, or that stimulating a part of the lower gastrointestinal tract called the ileum, is the critical factor—or that both factors may contribute.
Dr. David Cummings, an expert on diabetes and weight loss surgery at the University of Washington Medical Center, in Seattle, is an adviser to Fractyl Labs, which developed the duodenal mucosal resurfacing procedure. ENLARGE
Dr. David Cummings, an expert on diabetes and weight loss surgery at the University of Washington Medical Center, in Seattle, is an adviser to Fractyl Labs, which developed the duodenal mucosal resurfacing procedure. Photo: David Cummings

The duodenum produces several hormones that aid in food intake and blood-sugar control, according to Jens Juul Holst, a professor at the University of Copenhagen, who has performed bariatric surgery and conducted research on it. Other work has suggested a gastric bypass changes the type of bacteria in the gut, leading to reduced fat gain. That suggests bypassing the duodenum may improve blood-sugar control, gut bacteria, energy expenditure and body weight, says Dr. Holst.

Operations designed to target the duodenum include a duodenal bypass procedure and the “endoluminal liner,” an implanted flexible tube that lines the duodenum and a very short segment of the jejunum, preventing food from coming into contact with that stretch of the intestine.

Both appear to be effective in decreasing blood glucose levels among patients with Type 2 diabetes, but investigators are still working out safety kinks for these interventions, according to David Cummings, professor of medicine at the University of Washington, Seattle, who has studied bariatric surgery and diabetes extensively and has been involved as a scientific adviser to companies.

Fractyl Labs Inc., in Waltham, Mass., is developing a different investigational treatment for diabetes—a water-filled balloon device that ablates, or burns, the lining of the duodenum. The procedure, called duodenal mucosal resurfacing, could be used as a temporary treatment for diabetes in people who don’t qualify for, or don’t want to have, weight-loss surgery.

The first-in-man trial of the procedure was presented at the recent conference in London. The study of 39 patients found the procedure was well tolerated with few gastrointestinal side effects. The patients generally saw an improvement in glucose control after the procedure, according to Manoel Galvao, the bariatric surgery chair at 9th of July Hospital in San Paolo, Brazil, who conducted the trial with colleagues in Chile.

Currently, Fractyl is running a clinical trial on the procedure at several European sites and one in Brazil. Dr. Cummings, in Seattle, serves on the advisory board for Fractyl; Prof. Holst, in Copenhagen, is performing analysis for the Fractyl study.

On a recent morning at the University College Hospital in London, in a quiet operating room crowded with equipment and people, gastroenterologist Rehan Haidry fiddled with a big joystick controlling the endoscope, a camera that had been fed down the patient’s mouth. He stared at a screen showing the shiny pink interior of the patient’s intestine.

Slowly and carefully, Dr. Haidry and his team, along with personnel from the company who were watching him use the device, injected water and a blue solution into a section of the patient’s duodenum in order to separate the innermost lining, called the mucosa, from the rest of the tissue.

After that, they intended to use a hot-water-filled balloon to burn the lining of 9 centimeters of the duodenum—considered a long length for ablation. Without separating the lining from the rest of the tissue, they might burn the tissue too deeply.

The patient developed a minor difficulty, a small tear in one section of the lining. A kink in the catheter forced the team to take the balloon out and start the final step of ablation again. In the end, Dr. Haidry purposely burned two-thirds of the mucosal that he intended, a result he still considered a success.

Some have their doubts that the duodenal mucosal procedure will work. “I am absolutely not convinced this procedure is going to fly,” says Michel Gagner, clinical professor of surgery at Florida International University, who has worked with several medical device companies, none currently targeting resolution of diabetes.

Dr. Gagner believes the duodenal mucosal procedure trial needs to demonstrate that endocrine cells that have become dysfunctional with diabetes are present in the duodenum, and that their numbers are decreased after the procedure. He also has concerns about whether burning the lining will induce scar tissue that will narrow the intestinal pathway, which could lead to nausea and other side effects.

Dr. Gagner says he has puzzled over evidence that doesn’t seem to fit the theory that bypassing the duodenum is the answer. For instance, why does the gastric “sleeve”—a type of bariatric surgery where the duodenum remains intact—also seem to disproportionately clear up diabetes, although not as well as gastric bypass, according to the data?

Dr. Gagner is studying the role of getting food faster to and stimulating the lower part of the small intestine, the ileum, in resolving diabetes. He recently published a paper in the Annals of Surgical Innovation and Research demonstrating, in pigs, a new procedure connecting the duodenum to the ileum.

Borbala Isidahomen, a 31-year-old London mother of three, would welcome any new procedure that could help her diabetes. She volunteered for the Fractyl clinical trial because “the side effect of diabetes affects my life every day,” she said.

Overweight and diabetic for the past six years, Ms. Isidahomen says she experiences joint and muscle pain that make exercising difficult. She would like bariatric surgery and is in the midst of getting approved for the operation. But when she heard that an ablation procedure could help her blood sugar control in the meantime, she leapt at the chance.

Recovering in a hospital bed two hours after her surgery, Ms. Isidahomen said she felt a bit of soreness in her throat, which is common with endoscopic procedures, but otherwise felt good and was looking forward to going home the next day. “When you’re not being your old self, you’re willing to do anything,” said Ms. Isidahomen.

Write to Shirley S. Wang at shirley.wang@wsj.com
http://www.wsj.com/articles/if-gastric-bypass-benefits-type-2-diabetes-might-other-surgeries-help-too-1446474212

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