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

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.