The study showed that people whose gut bacteria are dominated by Lachnospiraceae tend to have higher levels of insulin resistance and higher fecal monosaccharide content. Those with more Bacteroidales tended to have lower insulin resistance and lower fecal monosaccharide content. CREDIT RIKEN

Researchers led by Hiroshi Ohno at the RIKEN Center for Integrative Medical Sciences (IMS) in Japan have discovered a type of gut bacteria that might help improve insulin resistance, and thus protect against the development of obesity and type-2 diabetes. The study, published August 30 in the scientific journal Nature, involved genetic and metabolic analysis of human fecal microbiomes and then corroborating experiments in obese mice.

Insulin is a hormone released by the pancreas in response to blood sugar. Normally, it helps get the sugar into the muscles and liver so that they can use the energy. When someone develops insulin resistance, it means that insulin is prevented from doing its job, and as a result, more sugar stays in their blood and their pancreas continues to make more insulin. Insulin resistance can lead to obesity, pre-diabetes, and full-blown type-2 diabetes.

Our guts contain trillions of bacteria, many of which break down the carbohydrates that we eat when they would otherwise remain undigested. While many have proposed that this phenomenon is related to obesity and pre-diabetes, the facts remain unclear because there are so many different bacteria and there is a lack of metabolic data. Ohno and his team at RIKEN IMS have addressed this lack with their comprehensive study, and in the process, discovered a type of bacteria that might help reduce insulin resistance.

First, they examined as many metabolites as they could detect in the feces provided by over 300 adults at their regular health checkups. They compared this metabolome with the insulin resistance levels obtained from the same people. “We found that higher insulin resistance was associated with excessive carbohydrates in the fecal matter,” says Ohno, “especially monosaccharides like glucose, fructose, galactose, and mannose.”

Next, they characterized the gut microbiota of the study participants and their relationship with insulin resistance and fecal carbohydrates. The guts of people with higher insulin resistance contained more bacteria from the taxonomic order Lachnospiraceae than from other orders. Additionally, microbiomes that included Lachnospiraceae were associated with excess fecal carbohydrates. Thus, a gut microbiota dominated by Lachnospiraceae was related to both insulin resistance and feces with excessive monosaccharides. At the same time, insulin resistance and monosaccharide levels were lower in participants whose guts contained more Bacteroidales-type bacteria than other types.

The team then set out to see the direct effect of bacteria on metabolism in culture and then in mice. In culture, Bacteroidales bacteria consumed the same kinds of monosaccharides that were found in the feces of people with high insulin resistance, with the species Alistipes indistinctus consuming the greatest variety. In obese mice, the team looked at how treatment with different bacteria affected blood sugar levels. They found that A. indistinctus lowered blood sugar and reduced insulin resistance and the amount of carbohydrates available to the mice. 

These results were compatible with the findings from human patients and have implications for diagnosis and treatment. As Ohno explains, “Because of its association with insulin resistance, the presence of gut Lachnospiraceae bacteria could be a good biomarker for pre-diabetes. Likewise, treatment with probiotics containing A. indistinctus might improve glucose intolerance in those with pre-diabetes.”

Although most over-the-counter probiotics do not currently contain the bacteria identified in this study, Ohno urges caution should they become available. “These findings need to be verified in human clinical trials before we can recommend any probiotic as treatment for insulin resistance.”

Metformin, the most commonly used drug to treat type 2 diabetes, not only lowers blood sugar levels but has revealed to extend lifespan in C. Elegans — an animal model that shares similar metabolic systems with humans and are often used to model human diseases.

New research led by investigators at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system, reveals that metformin promotes longevity by stimulating the body’s production of molecules called ether lipids, a major structural component of cell membranes.

The findings, which are published in eLife, suggest that boosting production of ether lipids in humans may support healthy aging and reduce the impact of aging-related diseases.

To identify the genes required to enable lifespan extension in response to metformin and its sister drug phenformin (drugs called biguanides), the scientists silenced individual genes in the roundworm Caenorhabditis elegans (which shares over 80% of its proteins with humans and has an average lifespan of about two weeks) and examined what happens to the altered worms after exposure to the medications.

The experiments reveal that genes that Increase production of ether lipids are required to extend lifespan in response to the biguanides..

Inactivation of the genes that encode for these enzymes completely prevented the longevity-promoting effects of biguanides.

Importantly, inactivation of these genes prevented lifespan extension in a variety of situations that are also known to promote longevity, including dietary restriction.

The team also found that increasing ether lipid synthesis alone (by overexpressing a single, key ether lipid biosynthetic enzyme called fard-1) was sufficient to extend C. elegans’ lifespan, orchestrating a metabolic stress defense response through a factor called SKN-1, which is the worm counterpart to the mammalian protein Nrf. This response altered metabolism to promote a longer lifespan.

“Our study implicates promotion of ether lipid biosynthesis as a novel therapeutic target to promote healthy aging. This suggests that dietary or pharmacologic intervention to promote ether lipid synthesis might one day represent a strategy to treat aging and aging-related diseases,” says senior author Alexander A. Soukas, MD, PhD, Associate Director of the MGH Center for Genomic Medicine, an Associate Professor at Harvard Medical School and Weissman Family MGH Research Scholar 2018-2023.

“Because our studies focused solely on interventions in C. elegans, further studies in mammalian models (such as human cells and mice), epidemiological observation, and rigorous clinical trials are required to determine the viability of promoting ether lipid synthesis to promote human health-span and lifespan.”

“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.