February 28, 2025 | Among potential therapies for treating type-2 diabetes, GLP-1 receptor agonists such as semaglutide work primarily by slowing digestion and enhancing insulin secretion, but they don’t address the root cause: abnormal glucose metabolism in muscle and fat tissue. We discussed this topic a year ago, where we mentioned unsuccessful efforts by bioelectronic medicine startups MetaCure, Cyberonics (now LivaNova), EnteroMedics (formerly ReShape Lifesciences and now Biorad Medisys), Intrapace, Beta-Stim, Transneuronix, Leptos Biomedical, and EndoVx. Their approach was similar to GLP-1 agonists, primarily targeting appetite and digestion speed by applying VNS at large abdominal branches of the vagus nerve.
The next generation of VNS therapies may include integration with implantable glucose sensors from companies like Senseonics and Glucotrack for precise VNS timing, for example to stimulate insulin release while eating and glucagon release while fasting. A recent study in healthy volunteers at the Burrell College of Osteopathic Medicine (Las Cruces, NM) demonstrated that suppression of a hunger hormone ghrelin was effective, when VNS was applied while eating but not while fasting. So, VNS can help with getting a greater sense of fullness with less food.
Recently, thin films started replacing silicone as the substrate material for VNS cuffs to allow cuff placement on smaller vagal branches. Two examples of such thin films include Parylene for <1 mm cuffs developed at the Center for Autonomic Nerve Recording and Stimulation Systems (consisting of University of Southern California, Medipace, and Med-Ally) and polyimide for 2-mm cuffs developed at San Diego State University. Such thin-film cuffs can enable a next generation of VNS therapies for targeting small branches of the abdominal vagus to provide a precise control of glucose metabolism. In a pig model of T2D, ReShape Lifesciences demonstrated selective targeting of celiac and hepatic branches to control glucose metabolism: low-frequency VNS was applied on the celiac branch to activate insulin release from the pancreas while high-frequency VNS was applied on the hepatic branch to block glucose release from the liver.
Perhaps, the most exciting yet the least explored opportunity for the next generation of VNS therapies might be in reversing progression of T2D. This could be accomplished by targeting underlying cause of T2D – a production of autoantibodies against both insulin and the insulin receptor, leading to a low-grade inflammation. The anti-inflammatory effect of VNS is already well established for other autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease based on recent work of SetPoint Medical and Galvani Bioelectronics. Similarly, the autoimmune aspect of T2D might be suppressed either by cervical VNS or by splenic nerve stimulation to provide a radically new strategy for slowing down and potentially reversing progression of T2D. Such anti-inflammatory VNS therapy could be complementary to a short-lasting effect of GLP-1 agonists, leading to a development of combined pharma/device T2D therapies.
