Duodenal myoelectrical hyperactivity drives diabetic remission in rat models of type 2 diabetes

While Roux-en-Y gastric bypass (RYGB) effectively treats diabetes, its underlying mechanisms remain unclear, highlighting the need to develop less-invasive alternatives. Emerging evidence suggests duodenal involvement in metabolic homeostasis and type 2 diabetes pathophysiology, yet the role of duodenal myoelectrical activity in diabetes and RYGB is poorly understood. This study aims to characterise duodenal myoelectrical changes in diabetes and RYGB, and evaluate their therapeutic potential.

Duodenal myoelectrical activity was recorded in male Sprague Dawley rats and high-fat diet/streptozocin (HFD/STZ)-induced diabetic rats, with or without RYGB. An antro-duodenum electrical stimulation (ADES) system was developed to mimic RYGB-associated myoelectrical hyperactivity. Its effects were examined by reducing stimulating power or chemically ablating duodenal myoelectrical activity with benzalkonium chloride, alongside pancreatic morphometric analyses. ADES was further validated in male Zucker diabetic fatty (ZDF) rats.

RYGB induced duodenal myoelectrical hyperactivity in HFD/STZ rats, characterised by shortened migrating myoelectric complex cycles, a nearly doubled phase III duration, and a 50.9% increase in fed-state spike frequency. By replicating these specific patterns, ADES achieved glucose-lowering effects comparable with those of RYGB, decreasing fasting glucose levels, reducing the OGTT AUC by approximately 40%, and enhancing insulin secretion by 71.7% at the 30 min time point. These glycaemic improvements were attenuated by either reducing the stimulating power or through benzalkonium chloride-mediated ablation of myoelectrical activity. Furthermore, ADES promoted pancreatic beta cell recovery, increasing beta cell mass by 1.5-fold through a 65.3% enhancement in proliferation and a 39.0% reduction in apoptosis. It also preserved beta cell identity, as evidenced by upregulated expression and promoted nuclear localisation of the key transcription factors pancreatic and duodenal homeobox factor-1 (PDX1) and MAF bZIP transcription factor A (MAFA). In ZDF rats, ADES similarly improved glucose homeostasis, significantly lowering 120 min OGTT glucose, and ameliorated hyperinsulinaemia, reducing plasma insulin levels by 35.1%.

ADES mimics RYGB-induced duodenal hyperactivity, offering comparable glucose-lowering effects. Targeting duodenal myoelectrical activity may provide a minimally invasive alternative to RYGB for diabetes treatment.