General Electric (GE) has successfully used ultrasound to regulate insulin levels in diabetic and hyperglycemic animals

Every organ contains nerves that regulate the organ’s function. New medical devices are under development that modulate signals on such nerves to treat disease1,2 (e.g., inflammatory3, hypertension4, diabetes5, obesity6, and gastrointestinal disorders7,8). However, nerve stimulation strategies using permanently implanted electrodes3,9,10, transcutaneous electro-magnetic fields11,12, or adapted brain stimulation technologies13–16 are limited to stimulating large nerves that can be accessed by an implanted device or nerves close to the surface of the skin.

A team of researchers led by General Electric (GE) has successfully used ultrasound to regulate insulin levels in diabetic and hyperglycemic animals. Human trials for type 2 diabetes are currently underway, and the team is optimistic. Scholars working on this project are from several institutions, including the University of California Los Angeles (UCLA), the Yale School of Medicine (YSM), and Albany Medical College (AMC).

The success of these trials could revolutionize the treatment of type 2 diabetes and alleviate the necessity for insulin and glucose monitors. –

Implant-based vagus nerve stimulation (VNS) versus precision ultrasound (U/S) neuromodulation. a A schematic of the neurons within the vagus nerve, exemplary innervated organs, and the common cervical position used for VNS devices. Stimulation of the cervical vagus results in stimulation of both target and non-target efferent and afferent pathways1–10. Clinical implementation of miniature stimulators and advanced electrode designs that can be implanted closer to the target organ (for precision stimulation of axons entering only that organ) is challenging and remains elusive9,17,18. b A schematic of precision organ-based neuromodulation in which the innervation points of known axonal populations are targeted for stimulation using focused pulsed U/S. Targets investigated herein include innervation points within the spleen and sensory terminals within the liver

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Herein, U/S energy is focused directly on specific anatomical targets of neural innervation (Fig. 1b) within the spleen and liver (without scanning the ultrasound transducer). As discussed above, neural innervation within the spleen is thought to affect systemic inflammation through the CAP6,19,20. Nerves in the liver are thought to communicate to the brain and provide a critical component of the nutrient sensing within the glucoregulation system32. Herein, we demonstrate that both pathways can be modulated with targeted U/S, and that the non-invasive U/S technique alleviates endotoxin-induced cytokine production and hyperglycemia at levels commensurate with traditional, invasive VNS. Furthermore, unlike cervical VNS (which broadly stimulates multiple vagal pathways), precision ultrasound neuromodulation enables separate modulation of the splenic (anti-inflammatory) versus the hepatic (metabolic) pathways. The splenic stimulation data demonstrates a clear ultrasound “dose response” to norepinephrine with a distinct power level required for cytokine reduction in the endotoxin model, and an effective power range commensurate with potential clinical use. Both the splenic and hepatic stimulation data are presented with direct measurements of U/S-induced neuromodulation (i.e., neurotransmitter concentration in the spleen experiments, and cFOS and DfMRI data in the liver experiments), and indirect measurements of effects on down-stream signaling pathways (i.e., kinase activities for several important/relevant intracellular signaling pathways). Finally, chemical/mechanical blocking and genetic knock-out experiments are shown for several signaling components in the splenic pathway, and data on the effect of these knock-outs on ultrasound-induced activation of CAP is reported. These results, combined with our companion paper by Zachs et al. (that demonstrates the use of splenic U/S stimulation to reduce disease severity in a preclinical model of inflammatory arthritis), provide the most thorough report to date on the potential for precision ultrasound stimulation to replace implantable devices for the translation of peripheral neuromodulation-based therapies

VNS has been shown to reduce hyperglycemia5,6. To investigate whether this was associated with neuromodulation of hepatic sites, VNS was compared with our precision U/S stimulation technique applied to the liver. Figure 6a shows the U/S-image guidance that enabled locating the U/S stimulus at the porta hepatis region of the liver, which contains glucose-sensitive neurons known to signal to and modulate metabolic control centers within the hypothalamus37. We found that hepatic U/S stimulation provided protection against LPS-induced hyperglycemia, as Fig. 6b shows that U/S stimulation limited the increase in blood glucose levels to within post-prandial concentrations. Furthermore, this effect was anatomically specific. Figure 6b shows that locating the stimulus toward the right or left lobe of the liver reduced the effect of U/S stimulation.

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Furthermore, hepatic concentrations of local signaling molecules associated with glucose metabolism showed that U/S stimulation did not show direct changes within the liver indicative of direct modulation of hepatic glycolytic or glycogenolytic processes (Fig. 6c, gray bars). Instead, it was found that U/S stimulation of the sensory neuron containing porta hepatis region resulted in significantly reduced hypothalamic concentrations of NPY and increased hypothalamic insulin receptor substrate (IRS-1) and protein kinase B (pAkt) activation (Fig. 6c, blue bars). The increase in IRS and pAkt phosphorylation indicates increased insulin signaling in the hypothalamus, which is capable of driving the observed reduction in concentrations of NPY. These results are consistent with previous reports of LPS-induced dysregulation of insulin-mediated IRS1-P13 signaling38. Interestingly, these results also suggest that altered signaling through the central nervous system may be involved in the role that chronic inflammation (i.e., metabolic endotoxemia) has been shown to play in the pathogenesis of insulin resistance39,40.

Credit :

Yale –

Yale researchers are exploring the efficacy of an ultrasound treatment that could regulate blood glucose levels for patients with Type II diabetes.

The Yale scientists are participating in a clinical trial led by GE Research. Raimund Herzog, an assistant professor of endocrinology at the Yale School of Medicine and one of the researchers, explained that the main issue with patients who have Type II diabetes is insulin resistance. Normally, when a person eats, their body releases insulin, which acts as a signal for cells to take up the glucose in the bloodstream. In patients with Type II diabetes, their bodies stop listening to this insulin signal, leading to high levels of blood sugar because cells do not take up the glucose in the bloodstream. This experimental technique aims to target the signaling pathway responsible for regulating glucose uptake through ultrasound treatments. According to a paper published on March 31, scientists were able to lower glucose levels in diabetic rats using this treatment.

“Usually, we think of glucose metabolism as being regulated predominantly by hormones, of which the most important is insulin,” Herzog said. “Over the last couple of years, it has become clear that the nervous system also plays a role in regulating glucose metabolism … In fact, the hypothalamus has emerged as one of the main regulating centers for glucose metabolism.”

Herzog went on to explain that glucose metabolism regulation, meaning how much glucose a person’s cells can take up, is influenced by peripheral nervous system inputs. Specific nerves deliver information from the peripheral nervous system — for example, from the digestive tract — to the hypothalamus. Examples of the information from the peripheral nervous system include when the person in question last ate and whether they live an active lifestyle.

All of the information gathered by the peripheral nervous system is coordinated by the brain and used to decide how much glucose to store or use, thereby affecting glucose uptake of cells. In a published paper, researchers target the nerves responsible for transmitting this peripheral information to the brain using ultrasound treatments.

“We’ve known that these nerves are there,” Herzog said. “Now, we can test what happens when we selectively stimulate or block them. This is called neuromodulation, modulating the activity of certain nerve fibers that transmit information about nutrition.”

The goal of the study is to alter the nerve activity that is responsible for sensing the availability of glucose in the body. Researchers specifically targeted the liver because it is an organ that acts as a storage unit for glucose while also being connected to the brain through peripheral nerve fibers, according to Herzog.

The general idea is to change the information going to the brain about the incoming nutrients, thereby changing the activity levels of neurons in the hypothalamus. In fact, the results in the paper show that certain neurons that respond only to changes in glucose levels, called glucose-excited neurons, exhibited different firing patterns after ultrasound treatment.

This particular project began when GE Research, the research and development division of the General Electric corporation, conducted a study on the effects of ultrasound on the spleen. During those studies, they used the liver as a control tissue. When they applied ultrasound to the liver, the researchers at GE noticed changes in blood sugar and reached out to Raimund Herzog, a specialist in neuronal regulation of metabolism.

“The use of ultrasound could be a game-changer in how bioelectronic medicines are used and applied to disease, such as Type-2 diabetes, in the future,” Christopher Puleo, a senior biomedical engineer at GE Research who co-led the study and is an author of the article published in Nature, wrote to the News. “Non-pharmaceutical and device-based methods to augment or replace the current drug-treatments may add a new therapeutic choice for physicians and patients in the future.”

At the moment, Herzog and GE Research are conducting clinical trials to test the efficacy of this ultrasound technique in pre-diabetic and diabetic patients.

The animal experiments in the published article suggest that the effects of the ultrasound treatment are not acute, but rather linger after the ultrasound treatment. However, researchers have yet to determine how long the effects of the ultrasound treatment last in human patients.

Approximately 90 to 95 percent of American adults with diabetes suffer from Type II diabetes, according to the CDC.

Credit : Yale


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