Project Summary The dominant and increasingly evident role of the central nervous system in glucose metabolism regulation remains an attractive therapeutic target for diabetes. Brain stem and hypothalamic coordinating centers of feeding and glucose homeostasis have been well characterized over the years, yet uncertainty over the vari- ous afferent autonomic pathways relaying information from the GI tract to the brain remains. While animal stud- ies indicate that neuronal sensors relaying information about changes in glucose levels and other nutrients are situated within the hepatic portal vein, less is known about these factors in humans. In fact, constrained by a lack of non-invasive tools to interrogate these regulatory circuits in humans, clinical translation of much of the recent advances in our understanding of feeding and glucose control in rodent models remains an active area of investigation. To overcome this critical limitation our group has recently identified neuromodulation via pe- ripheral focused ultrasound (pFUS) as a promising new tool to non-invasively and selectively alter autonomic nervous system afferents to the brain. Exciting preliminary studies in several rodent models of diabetes have revealed that transient application of ultrasound pulses to the hepatoportal plexus can enact long-lasting nor- malization of the hypothalamic glucose setpoint to restore euglycemia in an insulin-independent manner. The experiments under this proposal are designed to build upon this work to characterize the effect of pFUS di- rected towards the hepatoportal neuronal plexus in humans with newly diagnosed type 2 diabetics. We will quantify pFUS's impact on insulin sensitivity, as measured by euglycemic clamps, hepatic glucose disposal and glycogen synthesis by carbon13 NMR and the durability of these responses by long-term CGM glucose recordings. These studies will be augmented with preclinical diabetes models to identify additional sensory fields relevant to glycemic control. One site that holds great promise is the abdominal superior mesenteric plexus, which we found when combined with hepatoportal stimulation has the capacity to enhance the durabil- ity of the glucose-lowering response, likely by engaging the incretin axis. We will conduct additional transla- tional studies in human subjects to determine whether this encouraging dual site pFUS stimulation response indeed can be reproduced in type 2 diabetic subjects. As such ultrasound neuromodulation by pFUS repre- sents a paradigm shifting new tool to investigate the role of the autonomous nervous system in homeostatic glucose control in human subjects which if confirmed by our studies might lead to entirely new non- pharmaceutical treatment options for patients with diabetes.

Project Narrative Our group as discovered that focused ultrasound stimulation targeted to sensory neurons located at the hepatic portal vein and other sites within the GI tract has the capacity to restore glucose homeostasis in pre- clinical models of type 2 diabetes. Under this proposal we are using hyperinsulinemic-euglycemic clamps, oral glucose tolerance testing and stable isotope NMR imaging methods to characterize the effect of focused ultra- sound treatments targeted towards different afferent sensory fields on insulin sensitivity and hepatic glycogen storage; thereby contributing to normalization of glucose levels in recently diagnosed type 2 diabetic subjects. If confirmed our studies will help establish neuromodulation via focused ultrasound not only as a new tool to interrogate regulation of human glucose homeostasis, but also as a potential non-pharmacologic treatment modality for diabetes.