Project Summary/Abstract 31 million Americans suffer from Type 2 Diabetes Mellitus (T2DM) with numbers growing in the elderly and children. Also, 84.1 million prediabetic Americans risk becoming diabetic. Current pharmaceutical therapies are expensive and have negative side-effects with poor patient compliance. Bariatric surgery provides a high initial complete, or partial T2DM remission. However, these procedures are complex, prone to potentially harmful side-effects, treatment durability is questionable and typically indicated only for morbidly obese patients unresponsive to pharmaceutical therapy. We propose Diabetes Targeted Dual Neuromodulation Therapy (TDN Therapy), an innovative approach to blood glucose reduction. TDN implantable pulse generators (IPGs) block conduction of the hepatic branch of the Vagus nerve w/ High Frequency Alternating Current (HFAC) while stimulating the celiac branch. This SBIR Phase I study will successfully demonstrate feasibility of TDN Therapy for treatment of T2DM by validation of our hypothesis that decreased TDN HFAC signal amplitude will maintain glycemic control. Specific Aim 1: We have demonstrated that a TDN HFAC amplitude of 8 mA increases glycemic control in alloxan treated swine. However, the minimum current amplitude for effective TDN is unknown. A safe and efficient commercialized TDN device depends heavily on an optimal HFAC current amplitude. We propose testing HFAC TDN amplitudes below 8 mA in alloxan treated swine during oral glucose tolerance tests (OGTTs). Feasibility: Demonstrated by determining if lower HFAC amplitudes than 8 mA can maintain TDN efficacy. Aim 2: Low HFA current amplitudes are advantageous to decrease off-target effects as well as increase device efficacy. Feasibility: Demonstrated by preservation of euglycemia with downward HFAC titration. Aim 3: Autonomic function changes precede T2DM development and are resolved following effective treatment. Heart rate variability (HRV) is a surrogate for vagal tone. Lower HRV precedes cardiovascular T2DM co-morbidities and has been observed in diabetic swine. Feasibility: Demonstrated by increasing HRV with TDN during Aim 1 and Aim 2 experiments. Aim 4: Patients report esophageal sensations and heart burn when receiving monopolar HFAC delivered to the abdominal vagal trunks. This is presumably due to stray current exciting esophageal smooth muscle. Feasibility: Demonstrated by determining thresholds of TDN induced esophageal contractions & heart rate changes. Demonstrating minimal to no acute cardiovascular effects would set TDN apart from all other VNS approaches and give TDN commercial advantages. We envision the future commercial TDN device with Bluetooth capabilities allowing patients device/therapy interaction through smart devices with a possible closed-loop system to work with non-calibrating continuous glucose monitors and therapy refinement with the use of AI and machine learning.