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Review
. 2026 Jun:28 Suppl 3:3-15.
doi: 10.1111/dom.70894.

The Duodenal Mucosa Plays a Key Role in Metabolic Regulation: Emerging Physiology and New Opportunities for Cell-Directed and Barrier-Related Interventions for the Treatment of Diabetes and Obesity

David A D'Alessio  1   2 , Jonathan E Campbell  1   2
Affiliations
Review

The Duodenal Mucosa Plays a Key Role in Metabolic Regulation: Emerging Physiology and New Opportunities for Cell-Directed and Barrier-Related Interventions for the Treatment of Diabetes and Obesity

David A D'Alessio et al. Diabetes Obes Metab. 2026 Jun.

Abstract

The duodenum has historically been regarded as a passive digestive conduit for nutrient transit and absorption. However, emerging experimental and clinical evidence supports a revision of this view. In a contemporary model, the proximal small intestine also has roles as a metabolic sensor and endocrine signalling hub that exerts a powerful influence over systemic metabolism. The duodenum contains the highest concentration of enteroendocrine cells in the gastrointestinal tract, secreting a variety of hormones that regulate digestive processes and metabolic networks. In addition, a dense bidirectional vagal network enables rapid communication between duodenal nutrient sensing and central regulation of metabolism. Recent advances have highlighted how the duodenum undergoes a series of maladaptive changes in the setting of obesity and Type 2 diabetes (T2D), including changes in the mucosal layer, accelerated transport of nutrients, chronic low-grade inflammation and impaired barrier integrity. These alterations have raised the hypothesis that duodenal dysfunction may be a major contributor to the pathogenesis of metabolic disease. In support of this, bariatric procedures that exclude the duodenum from nutrient contact, most notably Roux-en-Y gastric bypass, produce rapid and weight-independent improvements in metabolic homeostasis. This mechanistic framework has driven the development of targeted endoscopic and pharmacological strategies, including the duodenal-jejunal bypass liner, duodenal mucosal resurfacing and various pharmacological interventions. A common goal of these interventions is to exploit duodenal biology to restore metabolic homeostasis. This review examines duodenal anatomy and function, the pathological remodelling that takes place in metabolic disease, and provides an overview of the expanding therapeutic landscape that targets this underappreciated organ in the treatment of obesity and T2D.

Keywords: bariatric surgery; barriers; type 2 diabetes; weight management.

Plain language summary

The duodenum—the short segment of intestine just beyond the stomach—has long been viewed as a passive digestive conduit. However, it is now understood to be the most hormonally active region of the gastrointestinal tract, packed with specialised cells that detect nutrients and send signals to the pancreas, liver, brain, and adipose tissue. In people with obesity and type 2 diabetes (T2D), the duodenal lining undergoes damaging changes: it absorbs nutrients more rapidly, produces fewer metabolic hormones, becomes chronically inflamed, and loses its normal barrier function—allowing harmful bacterial products to leak into the circulation. The powerful and rapid metabolic improvements seen after bariatric surgery, which bypasses the duodenum, strongly implicate these changes in the pathogenesis of metabolic disease. This review examines duodenal physiology, its dysfunction in obesity and T2D, and the growing landscape of therapies that target this underappreciated organ. We conducted a narrative review of the literature covering duodenal anatomy, enteroendocrine cell biology, the pathological remodelling that occurs in obesity and T2D, and the mechanisms underlying the metabolic benefits of bariatric surgery. We then reviewed the evidence for interventions that therapeutically target the duodenum, including the duodenal‐jejunal bypass liner (EndoBarrier), duodenal mucosal resurfacing (DMR), and pharmacological agents with duodenal mechanisms of action—metformin, alpha‐glucosidase inhibitors, orlistat, and the investigational drug GLY‐200. Duodenal dysfunction in obesity and T2D encompasses accelerated nutrient absorption, reduced enteroendocrine cell density, chronic mucosal inflammation, and increased gut permeability—changes that collectively impair metabolic regulation and may actively drive disease progression. Interventions that exclude or remodel the duodenal mucosa produce rapid, weight‐independent improvements in glycaemic control, mirroring the effects of gastric bypass surgery. DMR is now approved in Europe for T2D and fatty liver disease, and has received FDA breakthrough device designation. Pharmacological agents including metformin and alpha‐glucosidase inhibitors exert clinically meaningful effects partly through duodenal mechanisms. Across all interventions, shared downstream effects include improved insulin sensitivity, reduced hepatic glucose production, changes in bile acid signalling, and reconfigured postprandial gut hormone secretion. This review provides a unified framework positioning the duodenum as both a site of pathophysiology and a compelling therapeutic target in metabolic disease. By linking the mechanistic lessons of bariatric surgery to emerging endoscopic and pharmacological strategies, it highlights a rapidly expanding therapeutic axis that is largely complementary to existing drug classes. As the pipeline of duodenal‐targeting interventions grows—including devices, ablative procedures, and barrier‐forming drugs—this framework offers clinicians and researchers a coherent basis for understanding and exploiting duodenal biology in the treatment of obesity and T2D.

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References

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