Intestine emerges as new focus of type 2 diabetes treatment in Boston Children’s Hospital study

BOSTON—When considering type 2 diabetes, one often thinks ofthe synonymous terms of glucose, insulin and pancreas—but a team of researchersfrom Boston Children's Hospital would like the medical research community toinsert a new word into that vernacular: intestine.

In a new study published in the journal Science, a team led by Dr. Nicholas Stylopoulos, a researcher inBoston Children's Hospital's Division of Endocrinology, offers evidence thatthe small intestine—which is often regarded as a "passive" organ—has surprisinginvolvement in the body's metabolism. Their paradigm-shifting findings couldhave tremendous impact on the way patients with type 2 diabetes are treated inthe future.

Stylopoulos' lab is actively engaged in the study of weightloss surgery in order to discover new biology and achieve a betterunderstanding of metabolism and weight regulation. Specifically, he and his colleaguesare focused on discovering ways to "reverse engineer" weight loss surgery,especially Roux-en-Y Gastric Bypass (RYGB), which is currently considered themost effective treatment option for severe obesity.

"We focus on bariatric surgery because we believe it is thebest treatment for type 2 diabetes," says Stylopoulos. "Our lab focuses on themechanism of action in wright loss surgery because we believe we canreverse-engineer bariatric surgery. That means we want to know the mechanism bywhich surgery works and apply this mechanism to create new treatments thateliminate the need for invasive surgery."

In recent years, as patients who have obesity and type 2diabetes are increasingly turning to procedures like RYGB, scientists havedocumented the link between weight loss surgery and the reversal of type 2diabetes—although the mechanism of action at play here is not the weight lossthat results from this surgery, as most people may expect. Surprisingly, type 2diabetes is resolved almost immediately after weight loss surgery–even beforeweight loss is achieved.

"Studies about this have been somewhat controversial, butour understanding of weight loss surgery has changed because clinicians havenoticed that patients who depend on insulin injections and other meds actuallydo not require these drugs anymore, even within a week after surgery. This doesnot happen with other weight loss procedures and methods," Stylopoulos notes. "Usually,when you think about the intestine, you don't view it as a glucose-utilizingorgan. The small intestine uses glucose, but not as a main source of fuel. Youdo not expect the intestine to assume such an important role and literallyreprogram metabolism."

Before gastric bypass, intestines typically do not contain aspecific transporter called GLUT-1, which is responsible for removing glucosefrom circulation and utilizing it within the organ. After gastric bypass, theresearchers found that the intestine reprograms itself to contain GLUT-1,taking glucose from circulation and disposing of it, swiftly stabilizing bloodglucose levels in the rest of the body.

"GLUT-1 is a glucose transporter, and its job is to putglucose inside a cell. The intestine expressed Glut only in the fetus. Adultsdon't have it. But all of a sudden, after gastric bypass surgery, thistransporter appears again. That is why we talk about reprogramming," explainsStylopoulos.

To investigate why this happens, Stylopoulos and his teamspent one year studying rats, and observed that after gastric bypass surgery,the small intestine changes the way it processes glucose. Using positronemission tomography (PET) scans, the team observed the intestine using anddisposing of glucose, regulating blood glucose levels in the rest of the bodyand helping to resolve type 2 diabetes.

"We thought, let's look at the whole animal in a study thatwill allow us to look at glucose utilization globally. That is what the PETscan does. It allows you to visualize glucose utilization. You can take apicture one hour later and see cells being used. This is very powerful,"Stylopoulos says.

The team observed that type 2 diabetes was resolved in 100percent of the rats that underwent gastric bypass surgery. Sixty-four percentof type 2 diabetes was resolved by the intestine, and the researchershypothesize that the other 36 percent may be due to weight loss or otherfactors.

These findings pave the way for future investigations of howto create a medical pathway to mimic the intestine's reprogramming without thesurgery, according to Stylopoulos.

"That is the long-term goal, of course," he says. "You canimagine treatment based on ways to increase glucose utilization in theintestine or GLUT-1 transport in the intestine, and a way to force glucose intothe intestine and into cells. In this field, there are a lot of people andcompanies trying to find out more about insulin signaling and how we can provethat, but the fact of the matter is, there are ways of glucose utilization thatare independent of insulin.

Next, Stylopoulos' lab will investigate the same phenomenonin humans, and further probe how GLUT-1 is regulated in the intestine, whichcould potentially be a drugable target.

"Since cells in the intestine have such a short lifespan, wecan easily study and pharmacologically manipulate them to use glucose, withoutlong-term problems," Stylopoulos points out.

The study, "Reprogramming of Intestinal Glucose Metabolismand Glycemic Control

in Rats After Gastric Bypass," was published July 26 in Science. Co-lead authors included Drs.Nima Saeidi, Luca Meoli and Eirini Nestoridi. The research was supported byfunds from Boston Children's Hospital's Department of Medicine and Clinical andTranslational Executive Committee, as well as grants from the U.S. NationalInstitutes of Health.