“We will rock you”: ETH Zurich researchers are developing a gene switch that triggers insulin release in designer cells by playing certain rock and pop songs.

Diabetes is a condition in which the body produces too little or no insulin. Diabetics thus depend on an external supply of this hormone via injection or pump. Researchers led by Martin Fussenegger from the Department of Biosystems Science and Engineering at ETH Zurich in Basel want to make the lives of these people easier and are looking for solutions to produce and administer insulin directly in the body.

One such solution the scientists are pursuing is enclosing insulin-producing designer cells in capsules that can be implanted in the body. To be able to control from the outside when and how much insulin the cells release into the blood, researchers have studied and applied different triggers in recent years: light, temperature and electric fields.

Fussenegger and his colleagues have now developed another, novel stimulation method: they use music to trigger the cells to release insulin within minutes. This works especially well with “We Will Rock You,” a global hit by British rock band, Queen.

Equipping cells to receive sound waves

To make the insulin-producing cells receptive to sound waves, the researchers used a protein from the bacterium E. coli. Such proteins respond to mechanical stimuli and are common in animals and bacteria. The protein is located in the membrane of the bacterium and regulates the influx of calcium ions into the cell interior.  The researchers have incorporated the blueprint of this bacterial ion channel into human insulin-producing cells. This lets these cells create the ion channel themselves and embed it in their membrane.

As the scientists have been able to show, the channel in these cells opens in response to sound, allowing positively charged calcium ions to flow into the cell. This leads to a charge reversal in the cell membrane, which in turn causes the tiny insulin-filled vesicles inside the cell to fuse with the cell membrane and release the insulin to the outside.

Booming bass boosts insulin secretion

In cell cultures, the researchers first determined which frequencies and volume levels activated the ion channels most strongly. They found that volume levels around 60 decibels (dB) and bass frequencies of 50 hertz were the most effective in triggering the ion channels. To trigger maximum insulin release, the sound or the music had to continue for a minimum of three seconds and pause for a maximum of five seconds. If the intervals were too far apart, substantially less insulin was released.

Finally, the researchers looked into which music genres caused the strongest insulin response at a volume of 85 dB. Rock music with booming bass like the song “We Will Rock You”, from Queen, came out on top, followed by the soundtrack to the action movie The Avengers. The insulin response to classical music and guitar music was rather weak by comparison.

“We Will Rock You” triggered roughly 70 percent of the insulin response within 5 minutes, and all of it within 15 minutes. This is comparable to the natural glucose-induced insulin response of healthy individuals, Fussenegger says.

Sound source must be directly above the implant

To test the system as a whole, the researchers implanted the insulin-producing cells into mice and placed the animals so that their bellies were directly on the loudspeaker. This was the only way the researchers could observe an insulin response. If, however, the animals were able to move freely in a “mouse disco,” the music failed to trigger insulin release.

“Our designer cells release insulin only when the sound source with the right sound is played directly on the skin above the implant,” Fussenegger explains. The release of the hormone was not triggered by ambient noise such as aircraft noise, lawnmowers, fire brigade sirens or conversations.

No triggering through ambient noise

As far as he can tell from tests on cell cultures and mice, Fussenegger sees little risk that the implanted cells in humans would release insulin constantly and at the slightest noise.

Another safety buffer is that insulin depots need four hours to fully replenish after they have been depleted. So even if the cells were exposed to sound at hourly intervals, they would not be able to release a full load of insulin each time and thereby cause life-threatening hypoglycaemia. “It could, however, cover the typical needs of a diabetes patient who eats three meals a day,” Fussenegger says. He explains that insulin remains in the vesicles for a long time, even if a person doesn’t eat for more than four hours. “There’s no depletion or unintentional discharge taking place.”

But clinical application is a long way off. The researchers have merely provided a proof of concept, showing that genetic networks can be controlled by mechanical stimuli such as sound waves. Whether this principle will ever be put to practical use depends on whether a pharmaceutical company is interested in doing so. It could, after all, be applied broadly: the system works not only with insulin, but with any protein that lends itself to therapeutic use.

The longer a person has type 2 diabetes, the more likely they may be to experience changes in brain structure, a Michigan Medicine study finds.

Researchers analyzing data from 51 middle-aged Pima American Indians living with type 2 diabetes used a series of memory and language tests developed by the National Institutes of Health, called the NIH Toolbox Cognitive Battery, as well as MRI, to determine the relationship between diabetes, cognition and makeup of the brain.

Brain imaging suggested that study participants with longer durations of type 2 diabetes had decreased mean cortical thickness and gray matter volumes, and an increased volume of white matter hyperintensities.

The MRI results, researchers say, indicate the negative effects longstanding diabetes may have on brain health outcomes and emphasize the importance of preventing early onset type 2 diabetes.  

Cognition in study participants with type 2 diabetes did not differ compared to those without the condition. Results are published in Annals of Clinical and Translational Neurology.

“This is among the first times that alterations of the brain’s structure have been associated with duration of diabetes,” said first author Evan Reynolds, Ph.D., research fellow and lead statistician for the NeuroNetwork for Emerging Therapies at Michigan Medicine

“Although we did not find reduced cognition through the NIH Toolbox, this might not give the entire picture. The fact that we saw negative changes in the brain itself provides evidence for the need for early screening for cognitive disorders in patients with type 2 diabetes to improve patient care and quality of life.”

Investigators also found that diabetes complications, such as chronic kidney disease and damage to the nerves in the heart and blood vessels, are linked to structural changes to the brain. This falls in line with another of the team’s studies, which found that diabetic complications increased the odds of developing a cognitive disorder by 2.45 times in 40 to 60-year-olds.

Researchers were surprised that neuropathy, by which up to 50% of people with diabetes can be affected, was not associated with cognitive function in the study.

“This study is critical to our understanding of how diabetes affects brain health and lays the groundwork for a larger, longitudinal study addressing how persons with diabetes can maintain a healthy brain,” said senior author Eva Feldman, M.D., Ph.D., James W. Albers Distinguished Professor at U-M, the Russell N. DeJong Professor of Neurology at U-M Medical School and director of the NeuroNetwork for Emerging Therapies at Michigan Medicine.

“Regardless of the underlying mechanisms, preventing these conditions in people with type 2 diabetes is critical to maintaining brain health. Educating the public on the risks that diabetes poses to a preserving a healthy brain is part of our mission.”

Can the humble feijoa help the world tackle type 2 diabetes? University of Auckland scientists are investigating.

With more than 200,000 people in New Zealand living with type 2 diabetes, prevention is key to tackling this important health issue. Could a solution be found growing in New Zealand backyards?

The feijoa study, named FERDINAND, is a six-month weight-loss and maintenance programme, during which adults with raised blood sugar will be given about a gram of whole-fruit feijoa powder (or a placebo) each day.

Principal Investigator and self-described ‘feijoa addict’ Associate Professor Jennifer Miles-Chan is excited about the potential of feijoa powder to reverse pre-diabetes. “In theory, the feijoa powder will boost the benefits of weight loss, leading to improvements in blood sugar levels.”

A short-term study in Iran pointed to the benefits of feijoa for patients with type 2 diabetes. FERDINAND will build on that study as the world’s first long-term clinical trial into the benefits of feijoa with an aim of reversing the risk of diabetes in those with pre-diabetes (people with high blood sugar, but who do not yet have diabetes).

In the first two months of the study, participants will likely lose five to ten percent of their weight through a free meal replacement programme – think soups, shakes and porridge, but also pasta and rice dishes – overseen by a Registered Dietitian. The following four months will focus on maintaining this weight loss.

Participants should be overweight or have obesity, aged between 18 and 70, and at high risk of type 2 diabetes (but not have diabetes) based on a fasting blood glucose test.

“We are really wanting to help those people who are on the borderline of developing diabetes to lower their risk, yet many people may not be aware their blood sugar levels are high,” says Miles-Chan. “So you don’t need to already know if you have pre-diabetes. We can test that for you.”

As well as the potential to reverse their diabetes risk and the many benefits of weight loss, participants will discover more about their health. “Participants will get extensive diet and weight loss advice, detailed blood tests, body composition scans and glucose checks. An added benefit is the two months’ worth of free meals,” says Miles-Chan.

 People with type-II diabetes who drank the fermented tea drink kombucha for four weeks had lower fasting blood glucose levels compared to when they consumed a similar-tasting placebo beverage, according to results from a clinical trial conducted by researchers at Georgetown University’s School of Health, the University of Nebraska-Lincoln and MedStar Health. This finding, from a pilot 12-person feasibility trial, points to the potential for a dietary intervention that could help lower blood sugar levels in people with diabetes and also establishes the basis for a larger trial to confirm and expand upon these results.

This finding was reported in Frontiers in Nutrition on August 1, 2023.

Kombucha is a tea fermented with bacteria and yeasts and was consumed as early as 200 B.C. in China, but it did not become popular in the U.S. until the 1990s. Its popularity has been bolstered by anecdotal claims of improved immunity and energy and reductions in food cravings and inflammation, but proof of these benefits has been limited.

“Some laboratory and rodent studies of kombucha have shown promise and one small study in people without diabetes showed kombucha lowered blood sugar, but to our knowledge this is the first clinical trial examining effects of kombucha in people with diabetes,” says study author Dan Merenstein, M.D., professor of Human Sciences in Georgetown’s School of Health and professor of family medicine at Georgetown University School of Medicine. “A lot more research needs to be done but this is very promising.”

Merenstein continued, “A strength of our trial was that we didn’t tell people what to eat because we used a crossover design that limited the effects of any variability in a person’s diet.”

The crossover design had one group of people drinking about eight ounces of kombucha or placebo beverage daily for four weeks and then after a two-month period to ‘wash out’ the biological effects of the beverages, the kombucha and placebo were swapped between groups with another four weeks of drinking the beverages. Neither group was told which drink they were receiving at the time.

Kombucha appeared to lower average fasting blood glucose levels after four weeks from 164 to 116 milligrams per deciliter while the difference after four weeks with the placebo was not statistically significant. Guidelines from the American Diabetes Association recommended blood sugar levels before meals should be between 70 to 130 milligrams per deciliter.

The researchers also looked at the makeup of fermenting micro-organisms in kombucha to determine which ingredients might be the most active. They found that the beverage was mainly comprised of lactic acid bacteria, acetic acid bacteria, and a form of yeast called Dekkera, with each microbe present in about equal measure; the finding was confirmed with RNA gene sequencing.

The kombucha used in this study was produced by Craft Kombucha, a commercial manufacturer in the Washington, DC, area. It has been re-branded as Brindle Boxer Kombucha.

“Different studies of different brands of kombucha by different manufacturers reveal slightly different microbial mixtures and abundances,” says Robert Hutkins, Ph.D., University of Nebraska-Lincoln and the study’s senior author. “However, the major bacteria and yeasts are highly reproducible and likely to be functionally similar between brands and batches, which was reassuring for our trial.”

“An estimated 96 million Americans have pre-diabetes — and diabetes itself is the eighth leading cause of death in the U.S. as well as being a major risk factor for heart disease, stroke and kidney failure,” says Chagai Mendelson, M.D., lead author who was working in Merenstein’s lab at Georgetown while completing his residency at MedStar Health. “We were able to provide preliminary evidence that a common drink could have an effect on diabetes. We hope that a much larger trial, using the lessons we learned in this trial, could be undertaken to give a more definitive answer to the effectiveness of kombucha in reducing blood glucose levels, and hence prevent or help treat type-II diabetes.”

Conventional wisdom holds that storing fat around your belly puts you at increased risk for type 2 diabetes. But surprising new findings from the University of Virginia School of Medicine suggest that naturally occurring variations in our genes can lead some people to store fat at the waist but also protect them from diabetes.

The unexpected discovery provides a more nuanced view of the role of obesity in diabetes and related health conditions. It also could pave the way for more personalized medicine – treatments tailored to the individual. For example, doctors might prioritize weight loss for patients whose genes put them at increased risk but place less emphasis on it for patients with protective gene variants, the researchers say.

“There is a growing body of evidence for metabolically healthy obesity. In this condition, people who would normally be at risk for cardiovascular diseases and diabetes because they are obese are actually protected from adverse effects of their obesity. In our study, we found a genetic link that may explain how this occurs in certain individuals,” said researcher Mete Civelek, PhD, of UVA’s Center for Public Health Genomics. “Understanding various forms of obesity is important to tailor treatments for individuals who are at high risk for adverse effects of obesity.”

As medicine grows more sophisticated, understanding the role of naturally occurring gene variations will play an important role in ensuring patients get the best, most tailored treatments. The new work by Civelek and his team, for example, indicates that variants can simultaneously predispose some people to store fat at the abdomen – thought to put them at increased risk for a cluster of health problems called metabolic syndrome – while also protecting them from type 2 diabetes. (Metabolic syndrome raises the risk for diabetes, stroke and other serious health issues.)

One of the metrics doctors use to determine if a patient has metabolic syndrome is abdominal obesity. This is often calculated by comparing the patient’s waist and hip measurements. But Civelek’s research suggest that, for at least some patients, it may not be that simple. In the future, doctors may want to check a patient’s genes to determine how to best guide the person down the road to good health. 

“We found that among the hundreds of regions in our genomes which increase our propensity to accumulate excess fat in our abdomens, there are five which have an unexpected role,” said Yonathan Aberra, the lead author of the study and a PhD candidate at UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering. “To our surprise, these five regions decrease an individual’s risk for type 2 diabetes.”

In addition to producing surprising findings, Civelek’s research provides important new tools for his fellow researchers seeking to understand the complexities of gene variations. The sophisticated approach Civelek and his collaborators developed to identify the relevant variants and their potential effects will be useful for future research into metabolic syndrome and other conditions.

The tools could also prove invaluable in the development of new and better treatments for metabolic syndrome, the scientists say.

“We now need to expand our studies in more women and people from different genetic ancestries to identify even more genes that underlie the metabolically health obesity phenomenon,” Civelek said. “We plan to build on our findings to perform more experiments to potentially identify a therapeutic target.”