The duodenum has become recognized as a metabolic signaling center that is involved in regulating insulin action and, therefore, insulin resistance states such as type 2 diabetes. Bariatric surgery and other manipulations of the upper intestine, in particular the duodenum, have shown that limiting nutrient exposure or contact in this key region exerts powerful metabolic effects. Early human clinical trial data suggest that endoscopic hydrothermal duodenal mucosal resurfacing is well tolerated in human subjects and has an acceptable safety profile. This article describes the rationale for this endoscopic approach and its early human use, including safety, tolerability, and early efficacy.
Key points
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The dysmetabolic states of type 2 diabetes and fatty liver disease have a common pathophysiologic foundation in the form of insulin resistance, which drives end-organ disorder in beta cells and the liver respectively.
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Bariatric surgery has uncovered a potent metabolic role of the duodenum that can exert powerful effects on insulin resistance and dysmetabolic states.
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Hydrothermal duodenal mucosal resurfacing (Revita DMR) is an investigational, catheter-based, upper endoscopic procedure designed to modify signaling from the duodenal surface, thereby eliciting beneficial metabolic effects.
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Early clinical experience with hydrothermal DMR suggests that the endoscopic procedure can be safely implemented in humans, with evidence that it elicits improvements in diabetic state with potential to also affect fatty liver disease.
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Further studies are necessary to examine its clinical utility as an important treatment of the metabolic diseases that burden the modern day health care system.
Introduction
The duodenum has become increasingly recognized as a metabolic signaling center that seems to play a role in regulating insulin action and, therefore, insulin resistance states. Insulin resistance is at the core of many dysmetabolic states, and recent advances in pharmacologic development, as well as the recognition that bariatric surgery has a major impact on glucose levels, has heightened interest in the benefits of insulin sensitization as a treatment. Data from studies of bariatric surgery and other manipulations of the upper intestine, in particular the duodenum, show that limiting nutrient exposure or contact in this key region exerts powerful metabolic effects. Duodenal mucosal resurfacing (DMR) targets this specific biology with the assumption that the duodenal surface is in some way mediating an abnormal signal that emanates to endogenous insulin-sensitive tissues. Resurfacing through hydrothermal ablation allows a restoration of a normal mucosal interface that corrects this abnormal signal. This article describes this endoscopic approach, including the rationale for DMR and its early human use, showing its safety, tolerability, and beneficial effects on metabolism.
Introduction
The duodenum has become increasingly recognized as a metabolic signaling center that seems to play a role in regulating insulin action and, therefore, insulin resistance states. Insulin resistance is at the core of many dysmetabolic states, and recent advances in pharmacologic development, as well as the recognition that bariatric surgery has a major impact on glucose levels, has heightened interest in the benefits of insulin sensitization as a treatment. Data from studies of bariatric surgery and other manipulations of the upper intestine, in particular the duodenum, show that limiting nutrient exposure or contact in this key region exerts powerful metabolic effects. Duodenal mucosal resurfacing (DMR) targets this specific biology with the assumption that the duodenal surface is in some way mediating an abnormal signal that emanates to endogenous insulin-sensitive tissues. Resurfacing through hydrothermal ablation allows a restoration of a normal mucosal interface that corrects this abnormal signal. This article describes this endoscopic approach, including the rationale for DMR and its early human use, showing its safety, tolerability, and beneficial effects on metabolism.
Insulin-resistant states: background and current management
Background
Insulin resistance is the underlying cause of several metabolic disorders, including type 2 diabetes and fatty liver disease, which affect a large segment of the general population. Collectively, this pathophysiologic defect drives a massive health economic burden, manifesting with end-stage diabetes complications and premature cardiovascular disease, as well as an increasing recognition that it will also become the primary driver of end-stage liver disease. Through the introduction of the insulin clamp technique in the 1970s, detailed examination of the metabolic state was possible and insulin resistance was made quantifiable. This technique led to a greater understanding of the role of insulin resistance in dysmetabolic states and how insulin-sensitizing interventions exert their effects.
Lifestyle/Behavior Modification
It is recognized that lifestyle modification through healthy exercise and good nutrition can improve the metabolic state. Both lifestyle modification resulting in weight loss and the independent effects of chronic exercise reduce insulin resistance in humans. The current standard of care for treatment of type 2 diabetes promotes lifestyle and behavior modification related to exercise, weight loss, and diet before pharmacologic intervention is considered. At present, lifestyle modification is the only recognized treatment available for fatty liver disease. Two landmark trials, the Diabetes Prevention Program (DPP) trial and, more recently, the Look Action for Health in Diabetes (AHEAD) trial, have shown the metabolic benefit of applying lifestyle modification in prediabetic patients and patients with frank diabetes in a controlled trial setting. However, it is also well recognized that patients struggle to adhere to a lifestyle modification program over time and the real-world impact is transient and/or suboptimal.
Pharmacologic Treatment
Targeted treatment of insulin resistance was made available through the introduction of the thiazolidinedione (TZD) insulin-sensitizing class of agents for the treatment of type 2 diabetes. The long-used biguanide, metformin, was also shown to have insulin-sensitizing properties at that time. More recently, the glucagon-like peptide 1 receptor (GLP-1R) agonist and sodium/glucose cotransporter 2 (SGLT2) inhibitor classes have also been shown to have weak insulin-sensitizing properties, which may or may not have a weight-independent component.
It was through the use of these pharmacologic agents in the clinic that a wider array of their effects was observed beyond improved glycemic control: reductions in blood pressure, lowering of hepatic transaminase levels, altered lipid metabolism, and restoration of ovulation in previously anovulatory women with features of the insulin-resistant condition polycystic ovarian syndrome (PCOS; also termed metabolic reproductive syndrome). These effects allowed a broader view of insulin action and insulin-sensitive end-organs (ie, liver, skeletal muscle, adipose tissue, ovary) and how they are each affected by insulin resistance. Metformin, the TZDs and GLP-1r agonists have each shown positive attributes in one or more insulin-sensitive end-organ systems beyond their ability to improve glycemia. More specifically, both TZDs and GLP-1r agonists have been explored in fatty liver disease, and metformin, TZDs, and GLP-1r agonists have shown positive effects in patients with PCOS.
However, although pharmacologic intervention has brought a broad array of benefits through insulin sensitization, a major drawback of these agents has been the ability of patients to adhere to regular daily dosing, which is related in part to these agents’ unattractive side effects, including gastrointestinal intolerance (metformin and GLP1r agonists), edema (TZDs) and heart failure (TZDs). In the case of GLP-1r agonists, route of administration (ie, injection) may also pose a barrier.
Bariatric Surgery
Over the last 20 years, bariatric surgery involving bypass of the upper intestine has become established as a highly impactful intervention that elicits beneficial metabolic effects. It has been shown to result in dramatic improvements in the glycemic state and so-called disease remission in some patients with type 2 diabetes. It has also been shown to halt or reverse disease progression of nonalcoholic steatohepatitis (NASH), and to correct anovulation in PCOS. The groundswell of interest in surgery and its metabolic effects has resulted in the recent authoring of a consensus statement, embraced by multiple professional organizations, recommending that bariatric (now termed metabolic) surgeries be included in the treatment algorithm for patients with type 2 diabetes. It is notable that much of the metabolic benefit is observed acutely, within days of the procedure, preceding by weeks and months the substantial weight loss that is also seen with bariatric surgery. This effect is noted particularly after Roux en Y gastric bypass, suggesting that avoiding the contact of food with the duodenum and proximal jejunum may quickly elicit beneficial metabolic effects. More recently, detailed accounts of metabolic changes by various investigators have shown that there is a clear and measurable insulin-sensitizing effect within the first 2 weeks postsurgery that is sustained over time (a year or more). The insulin-sensitizing response seems to be an important contributor to the observed metabolic effect, and it is hard to consider either short-term caloric restriction as a consequence of the surgery or a surgery-mediated incretin effect to be a major confounder of this observation. As further evidence of the substantial regulatory role this gut-borne signal apparently plays in diabetic rats and humans with type 2 diabetes, reintroduction of nutrients to the bypassed section of duodenum rapidly elicits a return to hyperglycemia and restores insulin resistance.
The duodenal-jejunal bypass sleeve (or EndoBarrier GI liner [GI Dynamics, Inc, Boston, MA]) gives further credence to the mechanism observed with bariatric surgery. The sleeve is anchored in the duodenal bulb and prevents contact of food with the mucosal surface of the duodenum and proximal jejunum. The implanted sleeve device is placed for up to 12 months in situ and it has been shown to induce some weight loss in obese patients and to improve glucose homeostasis in patients with type 2 diabetes.
Bariatric surgery is likely to remain a key component of the type 2 diabetes treatment algorithm and, as more data accumulate, it may establish a therapeutic role in fatty liver disease and other dysmetabolic states, and even more so as technological and surgical techniques advance. However, bariatric surgery is unlikely to become a major solution at a population level, because it is not an easily scalable intervention and surgery remains a disincentive for many patients.
Metabolic role of the duodenum
An increasing body of evidence suggests that the duodenum is a key metabolic signaling center and the mucosal surface may manifest with some form of maladaptation when exposed to unhealthy nutrients through fat and sugar ingestion. These changes imply a role of the duodenum in the development of insulin resistance and the pathogenesis of related metabolic diseases.
Evidence from Animal Models
In animal studies, researchers have described both morphologic and functional changes in the duodenum following unhealthy nutrient exposure. Adachi and colleagues reported morphologic changes in the small intestines of 3 types of diabetic rats and observed intestinal hyperplasia in all of the models. These researchers also showed that markers of proliferation were increased in diabetic strains compared with controls. In the Wistar rat, Gniuli and colleagues found that a high-fat diet stimulates duodenal proliferation of endocrine cells differentiating toward K cells and oversecreting gastric inhibitory polypeptide (GIP). Bailey and colleagues showed in obese hyperglycemic (ob/ob) mice that a high-fat diet stimulates the production and secretion of intestinal immunoreactive GIP, a mediator of insulin secretion, and increases the density of GIP-secreting intestinal K cells compared with a stock diet. Ponter and colleagues have similarly shown alterations in plasma and small intestinal GIP in response to a high-fat diet in pigs.
Lee and colleagues observed impaired glucose sensing in the enteroendocrine and enterochromaffin cells in a diabetic rodent model, with evidence of impaired downstream neural signaling in the gut.
Salinari and colleagues tested the effects of proteins extracted from the duodenum-jejunum conditioned-medium of db/db (diabetic) or Swiss (nondiabetic) mice, or from the jejunum of insulin-resistant human subjects captured during abdominal surgery. The mouse proteins were tested in several experimental settings, including in vivo in Swiss mice during an intraperitoneal caloric challenge, and in Swiss mice soleus muscle in vitro, whereas human-extracted proteins were studied on human myotubes ex vivo. Overall, these proteins were found to cause insulin resistance in cultured muscle cells, whether of murine or human origin, providing strong evidence that a factor isolated from the duodenal or jejunal tissue may affect insulin sensitivity.
Evidence from Humans
In concert with animal findings, studies in humans also reveal abnormal mucosal hypertrophy, hyperplasia of enteroendocrine cells, and increases in enteroendocrine cell and enterocyte numbers in the upper GI tracts of diabetic patients compared with nondiabetic controls.
Theodorakis and colleagues specifically noted an increase in L and L/K cells in the duodenal mucosa of type 2 diabetic patients compared with nondiabetic controls, whereas Verdam and colleagues showed increases in small intestinal enterocyte mass and increases in enterocyte loss related to chronic hyperglycemia in severely obese subjects. Salinari and colleagues conducted an intricate study of the upper GI tract in obese subjects with and without type 2 diabetes by infusing nutrients at 3 different starting points in the small bowel (duodenum, proximal jejunum, and mid-jejunum) through a balloon catheter. They showed that bypass of the duodenum, with delivery of nutrients to the jejunum instead, resulted in an approximate 50% increase in insulin sensitivity in both groups. This finding offers direct evidence of the apparent insulin-resisting signal that seems to emanate from the region of the duodenum and how it is attenuated when nutrient delivery to the region is prevented.
Duodenal mucosal resurfacing: method for correcting duodenal metabolic signaling
Rationale for Targeting Duodenal Mucosa
Collectively, the observations described earlier support an approach that targets the duodenum mucosal surface for the treatment of metabolic disease without the need for placing a permanent implant. To this end, a novel endoscopic catheter system (Revita DMR system [Fractyl Laboratories, Inc, Lexington, MA]) was designed to deliver a hydrothermal exchange at the mucosal surface, resulting in superficial tissue ablation. Currently under investigation in the United States, the Revita DMR system holds a CE (Conformité Européene) mark in Europe.
As background, ablation is a common treatment modality for a wide variety of medical conditions ( Table 1 ). Intervention involves the physical removal of superficial abnormal tissue and the regrowth and restoration of normal tissue through a stem cell–mediated healing response. The most anatomically analogous approach to DMR is endoscopic ablative therapy through either radiofrequency (Barrx, Covidien, Sunnyvale, CA) or argon plasma coagulation for Barrett’s esophagus, a precancerous condition and complication of gastroesophageal reflux disease, in which the normal squamous epithelium of the distal esophagus transforms to a columnar-lined intestinal metaplasia. This treatment modality has become well established and its efficacy and safety are well described. Ablation is followed by restoration of the squamous epithelium.
| Ablation Method | Examples of Clinical Use |
|---|---|
| Radiofrequency | Barrett’s esophagus Atrial fibrillation Liver tumors |
| Laser | Benign prostatic hyperplasia Dermatologic conditions |
| Cryoablation | Atrial fibrillation Actinic keratosis Warts |
| Chemical | Cardiac arrhythmias Telangiectasias Facial rejuvenation |
| Mechanical | Dermatologic conditions |
| Hydrothermal | Heavy uterine bleeding Type 2 diabetes (investigational [United States], approved [European Union]) NAFLD/NASH (investigational) |
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