Many people who have Roux-en-Y gastric bypass surgery for obesity experience a striking but welcome side effect. In up to 80 percent of patients who also have type 2 diabetes, the diabetes abates even before they lose weight. A new study helps explain why, and suggests possible ways to combat diabetes (and obesity) without having to actually perform bariatric surgery.
“Our aim is to ‘reverse engineer’ the surgery, to find how it works and apply the mechanisms to new, less invasive treatments,” said study lead author Margaret Stefater, MD, PhD, a fellow in the lab of Nicholas Stylopoulos, MD, in a press release.
The Stylopoulos Lab, in Boston Children’s Hospital’s Division of Endocrinology, previously showed in a seminal 2013 paper that the bypass operation causes the small intestine to ramp up its sugar intake. In rodents, this appeared to account for resolution of their diabetes. Stylopoulos, together with collaborator Anita Courcoulas, MD, MPH of the University of Pittsburgh, then started an NIH-funded observational study of people undergoing Roux-en-Y gastric bypass surgery.
The hungry intestine
Studying biopsy samples from the first 19 of these patients, Stefater and colleagues showed how the operation reprograms intestinal metabolism to fuel the intestine’s increased bioenergetic needs.
The team analyzed samples taken at the time of the surgery and 1, 6 and 12 months after surgery to look for changes in gene expression in intestinal tissue. Starting one month after surgery, they saw dramatic changes in gene expression that were independent of weight loss and persisted over time. Genes affecting pathways related to cellular proliferation, cell cycle regulation and cytoskeletal remodeling were especially more likely to be turned “on.”
“The intestine is a very expensive organ metabolically and needs a lot of energy for its functions,” Stefater explains. “All these remodeling changes may drive increased metabolic demand, essentially making the intestine hungry for substrates like glucose and amino acids.”
The gene expression changes predicted weight loss and improvement in blood glucose levels in the diabetic patients, who showed a concomitant reduction in HbA1c levels as early as one month out. “This study suggests a potential mechanistic role for these processes to explain diabetes remission after bypass surgery and it is the first to show that changes in intestinal gene expression could predict diabetes improvement after this operation,” Stefater says.
She presented the findings earlier this month at the Endocrine Society’s annual meeting in Chicago (ENDO 2018).
Metabolism across species, including pythons
In related work, the Stylopoulos lab is studying Burmese pythons, which make ideal models for studying metabolic factors like glucose management. Because they eat only every 4 to 6 weeks, it is easy to track their physiologic responses and compare them with those observed in mice and humans. “We have performed gene expression analyses in the intestine of all three species and we have come up with a list of common pathways and targets,” says Stylopoulos. “We will now start examining these targets.”