Ultrasound May Become Alternative To Antidiabetic Drugs
By Deborah Borfitz
June 22, 2022 | Using ultrasound to stimulate neurometabolic pathways in the body to prevent or reverse type 2 diabetes is a centerpiece of research and development efforts at the General Electric (GE) Research Center in Niskayuna, NY. It has been known for many years now that electrical activity within peripheral nerves modulates end-organ function, including those involved in sensing food intake and glucose levels. But there have been limited means to noninvasively control those signals to fight disease, according to Chris Puleo, a senior biomedical engineer at GE Research.
Ultrasound neuromodulation could become a new option in the therapeutic arsenal for treating the predominant form of diabetes worldwide, he says, alongside drugs designed to lower insulin and glucose levels. The potential of peripheral focused ultrasound stimulation (pFUS) has already been demonstrated in small and large animal species, as recently reported in Nature Biomedical Engineering (DOI: 10.1038/s41551-022-00870-w), by activating neurons through ion channels that are sensitive to mechanical forces.
That study concluded several years ago and, since then, multiple clinical trials have launched and some of those are reaching completion, says Puleo.
Over the past five years, GE Research has published a handful of papers that notably includes a 2019 article in Nature Communications (DOI: 10.1038/s41467-019-08750-9) where ultrasound was directed at certain points within the spleen or liver to deliver results on par with implant-based vagus nerve stimulation. Importantly, the ultrasound technique more precisely affected the targeted organ to either reduce cytokine inflammation levels or modulate blood glucose levels, notes Victoria Cotero, co-lead on both the Nature Communications and Nature Biomedical Engineering studies.
Progress to date has been a team effort with industry, academic institutions, and government agencies. The use of ultrasound as a potential non-invasive alternative to current therapies is a major research program at the GE Research Center with both internal funding and external financial support, says Puleo.
Partners for the most recently published study included several scientists and engineers at the Niskayuna site (including co-lead Jeff Ashe), scientists at Albany Medical College who showed that metabolic effects from the ultrasound stimulation changed the nerve firing rate, and others at the University of California, Los Angeles (UCLA), who demonstrated that ultrasound treatments influence cultured neurons that are also dependent on mechanically-sensitive ion channels.
Additionally, team members at the Feinstein Institutes for Medical Research (FIMR) replicated results in diabetic mice and swine. Researchers at Yale School of Medicine used additional techniques such as glucose clamps to further characterize the therapeutic effect in rodents. The tests in swine were performed in a way that gave researchers a real time, before-and-after view of glucose changes when pFUS was turned on, Puleo says.
Ultrasound neuromodulation is part of the broader world of bioelectronic medicine—a term coined by FIMR research scientist and former neurosurgeon Kevin J. Tracey, M.D., and his colleagues to describe the diagnosis and treatment of diseases with devices that regulate electrical signaling within the nervous system. Work in the field began decades ago and notably introduced cardiac pacemakers and computerized implantable devices for treating inflammatory conditions.
Tracey, one of the co-authors on the Nature Biomedical Engineering paper, and his team is behind the discovery of a unique neuroimmune pathway that could be leveraged to tamp down cytokine output. Specifically, Tracey helped identify how tumor necrosis factor (TNF) promotes inflammation when the body suffers injury or shock, and he was the first to apply electrical stimulation to the vagus nerve to stop production of TNF in the body as if it were a dose of a monoclonal anti-TNF inhibitor.
Of course, vagus nerve stimulation involves an implantable device with all the challenges associated with having a surgical procedure.
In the latest report on preclinical experiments led by GE Research with its research partners, multiple diabetic animal models received daily, three-minute ultrasound stimulation of the liver–brain neural pathway that resulted in long-term maintenance of normal blood glucose levels.
The study team has more recently tried stimulating many different spots in the metabolic system with ultrasound to arrive at an optimum dose, says Puleo, and those results are expected to be published soon.
“It is not better or worse [than drugs], it’s a new option,” stresses Puleo. But one day, pFUS tools might become suitable for at-home use given the availability of low-cost wireless ultrasound systems, wearable ultrasound probes, and intelligent image recognition software in lieu of skilled ultrasonographers.
From the physician perspective, one of the biggest potential payoffs of ultrasound treatment of diabetic patients is to improve insulin sensitivity as few currently available drugs can do that. If the promise of pFUS seen in animal studies is confirmed in clinical trials, bioelectronic medicine could offer a convenient and hassle-free way to simultaneously improve both glucose tolerance and insulin resistance.