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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 of the synonymous terms of glucose, insulin and pancreas—but a team of researchers from Boston Children's Hospital would like the medical research community to insert 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 in Boston Children's Hospital's Division of Endocrinology, offers evidence that the small intestine—which is often regarded as a "passive" organ—has surprising involvement in the body's metabolism. Their paradigm-shifting findings could have tremendous impact on the way patients with type 2 diabetes are treated in the future.
Stylopoulos' lab is actively engaged in the study of weight loss surgery in order to discover new biology and achieve a better understanding of metabolism and weight regulation. Specifically, he and his colleagues are focused on discovering ways to "reverse engineer" weight loss surgery, especially Roux-en-Y Gastric Bypass (RYGB), which is currently considered the most effective treatment option for severe obesity.
"We focus on bariatric surgery because we believe it is the best treatment for type 2 diabetes," says Stylopoulos. "Our lab focuses on the mechanism of action in wright loss surgery because we believe we can reverse-engineer bariatric surgery. That means we want to know the mechanism by which surgery works and apply this mechanism to create new treatments that eliminate the need for invasive surgery."
In recent years, as patients who have obesity and type 2 diabetes are increasingly turning to procedures like RYGB, scientists have documented the link between weight loss surgery and the reversal of type 2 diabetes— although the mechanism of action at play here is not the weight loss that results from this surgery, as most people may expect. Surprisingly, type 2 diabetes is resolved almost immediately after weight loss surgery–even before weight loss is achieved.
"Studies about this have been somewhat controversial, but our understanding of weight loss surgery has changed because clinicians have noticed that patients who depend on insulin injections and other meds actually do not require these drugs anymore, even within a week after surgery. This does not 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-utilizing organ. The small intestine uses glucose, but not as a main source of fuel. You do not expect the intestine to assume such an important role and literally reprogram metabolism."
Before gastric bypass, intestines typically do not contain a specific transporter called GLUT-1, which is responsible for removing glucose from circulation and utilizing it within the organ. After gastric bypass, the researchers found that the intestine reprograms itself to contain GLUT-1, taking glucose from circulation and disposing of it, swiftly stabilizing blood glucose levels in the rest of the body.
"GLUT-1 is a glucose transporter, and its job is to put glucose inside a cell. The intestine expressed Glut only in the fetus. Adults don't have it. But all of a sudden, after gastric bypass surgery, this transporter appears again. That is why we talk about reprogramming," explains Stylopoulos.
To investigate why this happens, Stylopoulos and his team spent one year studying rats, and observed that after gastric bypass surgery, the small intestine changes the way it processes glucose. Using positron emission tomography (PET) scans, the team observed the intestine using and disposing of glucose, regulating blood glucose levels in the rest of the body and helping to resolve type 2 diabetes.
"We thought, let's look at the whole animal in a study that will allow us to look at glucose utilization globally. That is what the PET scan does. It allows you to visualize glucose utilization. You can take a picture one hour later and see cells being used. This is very powerful," Stylopoulos says.
The team observed that type 2 diabetes was resolved in 100 percent of the rats that underwent gastric bypass surgery. Sixty-four percent of type 2 diabetes was resolved by the intestine, and the researchers hypothesize that the other 36 percent may be due to weight loss or other factors.
These findings pave the way for future investigations of how to create a medical pathway to mimic the intestine's reprogramming without the surgery, according to Stylopoulos.
"That is the long-term goal, of course," he says. "You can imagine treatment based on ways to increase glucose utilization in the intestine or GLUT-1 transport in the intestine, and a way to force glucose into the intestine and into cells. In this field, there are a lot of people and companies trying to find out more about insulin signaling and how we can prove that, but the fact of the matter is, there are ways of glucose utilization that are independent of insulin.
Next, Stylopoulos' lab will investigate the same phenomenon in humans, and further probe how GLUT-1 is regulated in the intestine, which could potentially be a drugable target.
"Since cells in the intestine have such a short lifespan, we can easily study and pharmacologically manipulate them to use glucose, without long-term problems," Stylopoulos points out.
The study, "Reprogramming of Intestinal Glucose Metabolism and 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 by funds from Boston Children's Hospital's Department of Medicine and Clinical and Translational Executive Committee, as well as grants from the U.S. National Institutes of Health.