제 2형 당뇨병 비약물 치료를 위한 십이지장 점막 재생술 전임상 평가

Abstract

Introduction: Type 2 Diabetes Mellitus (T2DM) have become a major global health concern due to growing adoption of western dietary habits and an increasing aging population. Despite the growing demand for effective treatments, Type 2 diabetes remission using pharmacological methods alone remains challenging. The duodenum has been presented as a key organ for treatment of metabolic disorders including T2DM and obesity. Therefore, it is imperative that innovative non-pharmacological treatments related to the duodenum continue to be developed. Duodenal mucosal regeneration (DMR), which targets thickened mucosa to ablate and regenerate healthy tissue, has recently been implemented. However, current DMR procedures are complex and pose risks of irreversible damage, highlighting the need for developing safer and more effective methods. The aim of this study is to evaluate the therapeutic effects of advanced DMR application using T2DM animal model including rodent and pig. We also assess the efficacy of DMR using application with light emitting diodes (LED)/Organic light emitting diode (OLED) by quantitatively analyzing molecular biological results and gut microbiome changes between the treatment and control groups.

Methods & Materials: In this preclinical trial, we utilized Goto-Kakizaki (GK) rat models of T2DM to conduct DMR using endoscopic application with LED/OLED. The study evaluated the safety and efficacy of an endoscopic application equipped with a dual-wavelength (630/850nm) point light source LED module and a catheter with a single-wavelength (650nm) surface light source OLED module. Additionally, scaled-up DMR application which is attachable to endoscopic to assess the potential for clinical application, the safety and efficacy of an expanded endoscopic attachment device with a dual-wavelength LED module were evaluated using T2DM mini pig model. Oral glucose tolerance tests (OGTT) were conducted in GK rats and diabetic mini pigs after fasting overnight to assess blood glucose levels at multiple intervals post-DMR. Biochemical and hormonal analyses were performed on plasma samples to measure liver enzyme activities and hormone concentrations, including insulin, glucagon-like peptide 1, and gastric inhibitory polypeptide. Histological examinations of the duodenum, liver, and pancreas included Hematoxylin and eosin, Masson trichrome, and multiplex immunohistochemistry staining, followed by digital analysis to evaluate tissue alterations and islet cell morphology. Additionally, microbiome analysis was performed on fecal samples to assess alterations in bacterial composition following DMR.

Results: The promising therapeutic outcomes of DMR using LED and OLED catheters highlight the potential of these technologies in treating T2DM and related complications. Our research evaluated the efficacy of DMR with red or infrared LED light in a T2DM animal model, showing significant improvements in serum glucose levels, insulin sensitivity with preserved pancreatic islet and hepatic parameters in GK rats. Similarly, DMR with an OLED catheter resulted in notable reductions in blood glucose levels and improved insulin sensitivity, indicated by lower homeostasis model assessment-insulin resistance levels. Additionally, DMR with LED/OLED light significantly decreased liver fibrosis and altered the gut microbiome. These findings suggest that DMR using LED/OLED catheters directly impacts the duodenal mucosa, leading to consistent metabolic improvements and reduced liver fibrosis, further supporting its potential in enhancing metabolic outcomes.

Conclusion: In conclusion, the endoscopic DMR using LED/OLED applications presents a noninvasive approach to improve glycemic control, reduce insulin resistance, preserve pancreatic islet regeneration, and modulate the gut microbiome. The findings not only suggest that DMR could serve as an effective treatment modality for metabolic disorders, including T2DM but also help validate the efficacy and safety of this DMR application. Further clinical trial using the endoscopic attachable DMR application based on dual wavelength are necessary to support the potential of this novel non-pharmacological treatment.