SUN-598 Rescue Of Diabetic Gastroparesis Through Neuronal Modulation And Its Monitoring Via Breath Volatile Organic Compounds In Mouse Models

Abstract Disclosure: E. Kim: None. S. Hwang: None. S. Lee: None. H. Chung: None. O. Kwon: None. Backgrounds & Aims: Diabetic gastroparesis (DG) is a prevalent autonomic neuropathy in patients with diabetes mellitus (DM), leading to a poor quality of life and adverse outcomes. Currently, there are no therapies that can sufficiently alleviate DG. Considering a recently reported case involving a Nav1.8 mutation and gastroparesis, we investigated whether the stimulation of Nav1.8-expressing neurons effectively enhances gastric emptying. We also aimed to identify breath volatile organic compounds (VOCs) for the noninvasive diagnosis and monitoring of DG. Methods: Nav1.8-Cre mice were crossed with Cre-dependent hM3Dq mice (DqNav1.8) for chemogenic activation through Clozapine-N-oxide (CNO). DM was induced via streptozotocin injection. Gastric emptying rates were assessed by (1) orally administering acetaminophen (AAP) followed by checking its blood plasma levels using liquid chromatography with tandem mass spectrometry and (2) scintigraphy after intragastric gavage of fluorescence probes. Breath VOCs were sampled into bags, concentrated, and analyzed using thermal desorption-gas chromatography-mass spectrometry. Discriminative analyses were performed to identify VOC patterns associated with the presence of DG and to monitor its symptoms after the activation of Nav1.8-expressing neurons. Results: Eight weeks after the induction of DM, the plasma levels of AAP were significantly decreased in DM mice compared to non-diabetic (ND) mice, implying decreased gastric motility. Also, the expression of c-Kit was reduced in DM mice compared to ND mice, suggesting the loss of interstitial cells of Cajal, the pathological findings of gastroparesis. Following CNO injection, the DM-DqNav1.8 group exhibited a higher concentration of AAP in plasma and a faster gastric emptying image by scintigraphy than the DM-Dq- group (without Nav1.8-Cre). In the DM-DqNav1.8 group, one VOC increased, and five VOCs decreased compared to the DM-Dq- group, suggesting that they can serve as potential biomarkers for symptom progression of DG mice. The receiver operating characteristic (ROC) curve exhibited an area under the curve exceeding 0.8, indicating robust predictive performance of the VOC-based model in characterizing gastric emptying effects. ROC curve analyses identified two VOCs in exhaled breath as a potential diagnostic panel of biomarkers for alleviated gastric emptying. Conclusions: Stimulation of Nav1.8-expressing neurons can rescue gastric motility in DG. Breath VOC analysis may enable monitoring of gastric emptying, with several expiratory VOCs serving as potential biomarkers. Given that breath sampling is non-invasive, breath analysis holds promise as a supplementary diagnostic tool. Although there is a translational gap between experimental mice and humans, clinical protocols could be adapted to apply this approach to DG monitoring in humans. Presentation: Sunday, July 13, 2025