Project Summary/Abstract 31 million Americans suffer from Type 2 Diabetes Mellitus (T2DM) with numbers growing in the elderly and children. An additional 84.1 million prediabetic Americans risk becoming diabetic. Current pharmaceutical therapies have poor patient compliance and, along with bariatric surgical approaches, are expensive and have negative side-effects. We have developed Targeted Dual Neuromodulation Therapy (TDN Therapy), an innovative approach to blood glucose reduction. The closed loop TDN system (implantable pulse generator (IPG), continuous blood glucose monitor (CGM) and bipolar nerve leads) senses elevated blood glucose levels and reduces those levels by blocking conduction of the hepatic branch of the vagus nerve with High Frequency Alternating Current (HFAC) while concurrently stimulating the celiac branch with Low Frequency Alternating Current (LFAC). We hypothesize that esophageal and, or gastric High-definition Endoscopic Ultrasound (EUS) will allow precise vagus branch identification and laparoscopic TDN nerve lead placement with reduced off target physiological effects. In Preliminary studies, EUS imaging of nerves within the celiac plexus and ganglion was successfully confirmed with a spyglass fiberoptic probe. These nerves were then manipulated with biopsy forceps under EUS guidance and stimulated to modify gastric physiological effects. This NIH-SBIR Phase I study will successfully demonstrate feasibility in swine as follows: Specific Aim 1: Identify celiac and hepatic branches of the vagus nerve using endoscopic ultrasound and or transillumination on endoscopy with feasibility confirmed by successful EUS guided imaging of the vagus celiac and hepatic branches with further confirmation by fiberoptic probe. Aim 2: Use laparoscopy with endoluminal EUS and endoscopy to place electrodes on the hepatic and celiac branching points of the vagus nerve in a consistent manner with feasibility demonstrated by confirmation of electrode placement by tracing the branches to the pancreas and liver during laparoscopy and necropsy. Aim 3: Minimize off target effects during stimulation of the hepatic and celiac branches with feasibility demonstrated by determination of the lowest current amplitudes to minimize off target effects while staying in a therapeutic current amplitude range. Evaluated off target effects will include non-GI effects of heart rate, blood pressure, & the GI related off target effects of pyloric contraction & relaxation, lower esophageal sphincter pressure, gastric & small intestinal contraction in the stomach. Liver effects will be assessed by hepatic hormones, & portal & hepatic venous pressures. Pancreas effects will be evaluated by assaying insulin, glucagon & GLP-1, amylase & lipase. Future Phase II efforts will incorporate EUS in TDN Therapy animal implants for future FDA submissions.