Bass-heavy rock music applied directly to the abdomen of diabetic mice implanted with music-sensitive insulin-releasing cells attenuates postprandial glycemic excursions and restores normoglycemia, reveals a series of experiments.
The research was published in The Lancet Diabetes & Endocrinology.
After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.
After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.
"With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day," says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.
"This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin."
As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes "straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music."
It therefore "could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues."
It is a "very exciting piece of work, no doubt," commented Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.
He pointed out that the concept of using music to drive gene expression "is something we’ve known for the last 20 years," but bringing the different strands of research together to generate cells that can be implanted into mice is "an amazing idea."
Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence "does not allow for a lot of the detail that I would have expected as an academic," and consequently some questions remain.
The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.
Is Music or Sound the "Trigger?"
Music is "frequency, it's the amplitude of the waveform, and it's the duration for which those waveforms are present," he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.
For Hardikar, the "best control" for the study would be to have no music as well as the edited song, with "bits of pieces" played randomly so "it sounds like it's the same frequency and amplitude."
Then it would be clear whether the effect is owing to the "noise, or we have to appreciate the melody."
The other outstanding question is whether the results "can directly translate to larger animals," such as humans, Hardikar said.
The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.
They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.
With "traceless triggers" such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a "need for new switching modalities."
The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.
They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is "within the safe range for the human ear."
Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the "gold-standard" depolarization control for calcium channels.
The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, "which might protect the cellular device from inadvertent activation during everyday activities."
Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.
Specifically, "We Will Rock You," by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is "similar to the dynamics of glucose-triggered insulin release by human pancreatic islets."
Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which "would be appropriate to attenuate glycemic excursions associated with typical dietary habits."
Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.
Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.
Moreover, "Queen's song 'We Will Rock You' generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests," the team says.
In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.
They also note that the effect was seen only when the sound waves "directly impinge on the skin just above the implantation site" for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.
Consequently, "therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones," the researchers write, and are "compatible with standard drug administration schemes."
The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.
No relevant financial relationships were declared.
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