It’s generally taken for granted that insulin resistance and Type 2 diabetes are best addressed through diet and exercise. Medications, including insulin, don’t really address the root cause of the condition, but they can help manage the symptoms. But what if a doctor could fix insulin resistance and T2D with an endoscopic procedure so quick and easy that patients could go back to work the very next day?
That’s the dream of a Massachusetts biotech firm named Fractyl, which has developed a new procedure that it calls duodenal mucosal resurfacing.
When it comes to the causes of and solutions to insulin resistance and diabetes, we usually concentrate on the pancreas or the liver. Fractyl’s new technique focuses on the duodenum, the first segment of the small intestine, which also plays an important role in keeping the body metabolically healthy. A modern Western diet, high in fat and sugar, causes dysfunction to duodenum’s hormonal signaling by causing the organ’s lining to grow and thicken. The new technique works by removing layers of this overgrown lining, stimulating healthy regrowth and restoring regular hormonal function. The procedure takes just a few hours, and could be performed at an outpatient endoscopy clinic.
The most recent study of duodenal mucosal resurfacing evaluated its effect on adults with Type 2 diabetes that were treated with insulin. The results were impressive: a year after the procedure, participants experienced both weight loss and a reduction in liver fat, and a majority had stopped using insulin entirely.
I spoke to Dr. Harith Rajagopalan, the CEO and co-founder of Fractyl, about the technique: what inspired his innovation, why it works, and what might come next.
The story starts about a decade ago, when Dr. Rajagopalan began to consider some unexpected results that had been observed following bariatric surgery for weight loss.
Bariatric surgery works by essentially re-routing the digestive system, purposefully limiting either the amount of food that patients can eat or the nutrients they can absorb from their food (or both). The surgery is extremely effective at combatting Type 2 diabetes, but because it’s so expensive and intense it’s often seen as a last resort. While the primary benefit of bariatric surgery is weight loss, the improvements to diabetes are not due merely to caloric restriction; the surgery also creates instantaneous metabolic improvements that are unrelated to weight loss. Dr. Rajagopalan explained how surprising this is:
“When you bypass the duodenum, which is the first part of the small intestine, you get an immediate improvement in blood sugar and insulin resistance in patients with Type 2 diabetes. There’s nothing that I learned in medical school or that’s in the textbooks that could explain this. It defied explanation.
“A lot of times in medicine you make advances by really surprising clinical observations that defy explanation.
“The eureka moment came when I uncovered a paper from a group of doctors in Denmark who showed when they re-fed the duodenum after bypass surgery, the patient’s blood sugars worsened again immediately. Now I had evidence that the duodenum was like an on/off switch for insulin resistance and high blood sugars.
“It taught me that it’s not actually the food that we’re consuming, it’s actually where the food is hitting the gut that’s causing the disease.”
Further investigation of the duodenum “led to the discovery that the duodenal mucosa is somehow pathologically changed by modern diets that are high in fat and sugar.”
And this part of the intestine, by interacting with the pancreas and the liver and fat cells, has a much larger effect on metabolic health and blood sugar than previously suspected.
“What we discovered is that the gut is the body’s largest hormone-producing endocrine organ, and the lining of the different parts of the gut release different hormones in fasting and after meals in order to help keep blood sugar within a pretty tight range.”
This healthy process is rendered dysfunctional by a poor diet.
“When you eat a high-fat and high-sugar diet, the hormones coming out of the duodenum start to change because of an overgrowth of the mucosa, or the lining of the duodenum, which drives the body towards an insulin-resistant state.”
The hormones secreted by the duodenum seem to have an especially important effect on insulin resistance in the liver, a major component of Type 2 diabetes that helps drive hyperinsulinemia and, eventually, Beta cell burnout.
Dr. Rajagopalan told me that the modern Western diet’s negative effect on the intestinal lining is “a well-described phenomenon known as mucosal adaptation.” Unnatural amounts of sugar and fat cause the duodenum to work so hard that digestion becomes something like a weight-lifting session, leading to a built-up lining in much the same way that bench pressing leads to bigger muscles. “The lining of the gut gets thicker and thicker and thicker.”
Duodenal mucosal resurfacing aims to repair the thickened gut lining through the process of ablation:
“It’s a very precise delivery of heat energy through a catheter, to cause the targeted destruction of the overgrown lining of the intestine. And what that does is it allows the lining to grow back anew, but grow back in a normal thickness.
“The reason we thought that this would work is because people do this all the time in other parts of the body.” In laser skin resurfacing, for example, “the skin grows back and it looks younger and it stays that way for years. We’re applying the same principle of ablation-induced rejuvenation to the gut, as opposed to the skin.”
I asked Dr. Rajagopalan to give me the details on the procedure itself:
“It’s a routine upper endoscopic procedure. An endoscopic camera is introduced into your mouth, past your stomach, and into the duodenum. Our catheter is introduced alongside that endoscope.
“The patients experience 45-60 minutes of sedation in the endoscopy suite, followed by 90 minutes or so in the recovery room, and then they go home the same day. They could go back to work the very next day. We’re really talking about a few hours.”
The procedure would be performed at an endoscopy clinic, not a hospital. While the endoscope insertion can lead to some discomfort, Dr. Rajagopalan says that the ablation itself is painless—there are no sensory nerve fibers in the duodenum’s lining. “Most patients don’t experience any symptoms at all.”
The primary result is immediate glycemic improvements, with reductions in both fasting and post-prandial blood sugars. In the most recent study HbA1c declined, from 7.4% to 6.7%. 75% of participants had stopped using insulin after 6 months; after 12 months, 56% were still off it. The study population also exhibited significantly reductions in liver fat, a significant marker of improved metabolic health.
Remarkably, patients in studies that received duodenal mucosal resurfacing have also lost a surprising amount of weight, and so far they have kept it off. This is an exciting finding because study participants are not actually instructed to change their diet or exercise habits. It’s not clear yet why they’ve lost weight, but Dr. Rajagopalan noted that bariatric surgery patients are often observed to change their food preferences, and speculated that something similar may be happening to patients with a rejuvenated duodenal lining. It does seem plausible that an overnight improvement in insulin resistance could also interrupt the vicious cycle that drives hunger and is theorized to compel people with Type 2 diabetes to overeat.
Fractyl will need to plan much more study of the technique to understand its true potential. How durable are the improvements? Would patients benefit from subsequent ablations? Should it be used in conjunction with other blood sugar lowering therapies? Would the procedure be similar effective for patients that have not yet needed insulin therapy? Does it have uses for gestational diabetes, or Type 1 diabetes, or pre-diabetes?
The next big step for the company is a much larger study, this one using many more participants and a placebo or control group. This study, held in the United States, will begin enrolling soon. Readers with Type 2 diabetes that may be interested in participating are encouraged to put themselves on the Fractyl mailing list. There’s a box to click: “Contact me about Revita clinical trials.”
Dr. Rajagopalan hopes that, given good results, the next study will be a “game-changer” for Type 2 diabetes therapy. At the very least, it could lead to FDA approval for the procedure in the United States. (The procedure has already received approval in Europe, but the COVID-19 pandemic has interrupted the rollout for the time being.)
For now, Dr. Rajagopalan dreams that duodenal mucosal resurfacing might someday be successful and widespread enough to “totally change the trajectory of Type 2 diabetes.”
“It enables you to imagine a brand-new paradigm of care in Type 2 diabetes around eliminating the need for insulin therapy, and truly pointing the direction towards reversing this disease, as opposed to escalating therapies.”
