The findings, published in Nature Communications, show that a phenomenon known as interfacial polarization can be used to adjust the surface work function of metallic ruthenium dioxide (RuO2) by more than 1 electron volt (eV). The effect was achieved simply by changing the thickness of an ultra-thin film by a few nanometers.

Atomic-Scale Control of Metal Properties

Polarization is typically associated with insulating materials and ferroelectrics rather than metals. However, the researchers found a way to stabilize polarization within a metallic system and use it to influence electronic behavior.

“We often think of polarization as something that belongs to insulators or ferroelectrics — not metals,” said Bharat Jalan, professor and Shell Chair in the Department of Chemical Engineering and Materials Science at the University of Minnesota. “Our work shows that, through careful interface design, you can stabilize polarization in a metallic system and use it as a knob to tune electronic properties. This opens an entirely new way of thinking about controlling metals.”

The team discovered that the effect depends strongly on the thickness of the metal layer. The most dramatic changes occurred when the ruthenium dioxide film reached approximately 4 nanometers thick, which is about the width of a single DNA strand.

A Critical Transition at 4 Nanometers

At this thickness, the metal undergoes a transition from a strained state caused by the underlying material to a more relaxed atomic arrangement. The results provide direct evidence that the way atoms are organized inside a material can have a measurable influence on its electronic characteristics.

“This was surprising,” said Seung Gyo Jeong, first author of the study and a researcher in Jalan’s group. “We expected subtle interface effects, but not such a large and controllable change in work function. Being able to visualize the polar displacements at the atomic scale and connect them directly to electronic measurements was especially exciting.”

By observing tiny atomic movements and linking them to large electronic changes, the researchers were able to show how interface engineering can be used as a powerful tool for controlling metals.

Potential Applications in Electronics and Quantum Technology

In addition to advancing scientists’ understanding of fundamental physics, the discovery could help guide the development of future electronic devices, catalytic systems, and quantum technologies.

The research involved collaborators from the University of Minnesota Twin Cities, the Massachusetts Institute of Technology, Texas A&M University, Gwangju Institute of Science and Technology, and the School of Physics at the University of Minnesota Twin Cities.

Funding for the work was provided by the U.S. Department of Energy and the Air Force Office of Scientific Research.

The study found that about 10% of people carry genetic variants linked to a phenomenon known as GLP-1 resistance. Individuals with these variants appear to produce higher levels of the hormone GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar, yet the hormone does not seem to work as effectively in their bodies.

Researchers focused on blood sugar control and did not reach firm conclusions about weight loss effects. Drugs such as Ozempic and Wegovy are typically prescribed at higher doses for obesity treatment than for diabetes management, and more research is needed to determine whether the same genetic factors influence weight loss outcomes.

Published in Genome Medicine, the study brought together scientists from multiple countries over a period of 10 years. The work included experiments in both humans and mice, along with analyses of data from clinical trials involving diabetes medications.

“In some of the trials, we saw that individuals who had those variants were unable to lower their blood glucose levels as effectively after six months of treatment,” said Anna Gloyn, DPhil, professor of pediatrics and of genetics at Stanford Medicine and one of the study’s senior authors. At that stage, physicians would often consider changing a patient’s treatment plan. Identifying likely responders in advance could help patients reach the most effective therapy sooner and move diabetes care closer to precision medicine, she said.

The study’s other senior author is Markus Stoffel, MD, PhD, professor of metabolic diseases at the Institute of Molecular Health Sciences at ETH Zurich in Switzerland. Lead authors include Mahesh Umapathysivam, MBBS, DPhil, an endocrinologist and clinical researcher at Adelaide University in Australia and a former trainee with Gloyn, and Elisa Araldi, PhD, associate professor of medicine and surgery at the University of Parma in Italy and a former trainee with Stoffel.

“When I treat patients in the diabetes clinic, I see a huge variation in response to these GLP-1-based medications and it is difficult to predict this response clinically,” Umapathysivam said. “This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process.”

Scientists Investigate a Diabetes Drug Mystery

This research represents the first detailed examination of GLP-1 resistance, but scientists still do not know exactly what causes it.

“That is the million-dollar question,” Gloyn said. “We have ticked off this enormous list of all the ways in which we thought GLP-1 resistance might come about. No matter what we’ve done, we’ve not been able to nail precisely why they are resistant.”

The team concentrated on two genetic variants that reduce the activity of an enzyme called PAM (peptidyl-glycine alpha-amidating monooxygenase). This enzyme plays a unique role in the body because it activates a variety of hormones, including GLP-1.

“PAM is a truly fascinating enzyme because it’s the only enzyme we have that’s capable of a chemical process called amidation, which increases the half-life or the potency of biologically active peptides,” Gloyn said.

“We thought, if you have a problem with this enzyme, there’s going to be multiple aspects of your biology that are not working properly.”

Previous research had already shown that PAM variants occur more often in people with diabetes. Gloyn had also demonstrated that these variants impair the pancreas’s ability to release insulin. Researchers wanted to determine whether the same genetic changes also affected GLP-1, a hormone released from the gut that helps control blood sugar after eating by stimulating insulin production, slowing stomach emptying, and reducing appetite. GLP-1 receptor agonists work by mimicking this hormone.

An Unexpected Discovery About GLP-1 Levels

To investigate, researchers recruited adults with and without a PAM variant known as p.S539W. Participants drank a sugary solution, and blood samples were collected every five minutes over a four-hour period. The study involved people without diabetes to reduce the influence of other factors that could affect the results.

Scientists initially expected participants with the PAM variant to have lower levels of GLP-1 because the hormone might be less stable without proper amidation.

“What we actually saw was they had increased levels of GLP-1,” Gloyn said. “This was the opposite of what we imagined we would find.”

“Despite people with the PAM variant having higher circulating levels of GLP-1, we saw no evidence of higher biological activity. They were not reducing their blood sugar levels more quickly. More GLP-1 was needed to have the same biological effect, meaning they were resistant to GLP-1.”

Mouse Studies Confirm GLP-1 Resistance

The findings were so unexpected that the researchers spent several years testing whether the result was real.

“We couldn’t understand this, which is why we looked as many different ways as we could to see if this was a really robust observation,” Gloyn said.

To verify the findings, the team partnered with scientists in Zurich who had developed mice lacking the PAM gene. These animals displayed similar signs of GLP-1 resistance. They had elevated GLP-1 levels, yet the hormone was less effective at controlling blood sugar.

One of GLP-1’s major functions is slowing gastric emptying, which is the rate at which food leaves the stomach. This effect contributes to both blood sugar regulation and weight loss. Mice without the PAM gene showed faster gastric emptying, and treatment with a GLP-1 receptor agonist failed to slow the process.

Researchers also detected weaker responses to GLP-1 in both the pancreas and digestive tract of these mice. However, levels of GLP-1 receptors themselves remained unchanged.

Working with scientists in Copenhagen, the researchers further demonstrated that PAM defects do not interfere with GLP-1 binding to its receptor or with signaling at the receptor level. These findings suggest the source of GLP-1 resistance likely occurs farther downstream in the biological pathway.

Genetic Variants Affect Diabetes Drug Response

The team next examined whether GLP-1 resistance influenced real-world treatment outcomes.

Using data from three clinical trials that included 1,119 participants with diabetes, researchers found that people carrying PAM variants generally responded less well to GLP-1 receptor agonists. Their HbA1c levels, a measure of long-term blood sugar control, improved less than those of non-carriers.

After six months of treatment, approximately 25% of participants without the variants reached recommended HbA1c targets. Among carriers of the p.S539W variant, only 11.5% achieved those goals. For carriers of the p.D563G variant, the figure was 18.5%.

Importantly, the genetic variants did not appear to affect responses to several other common diabetes medications, including sulfonylureas, metformin, and DPP-4i drugs.

“What was really striking was that we saw no effect from whether you have a variant on your response to other types of diabetes medications,” Gloyn said. “We can see very clearly that this is specific to medications that are working through GLP-1 receptor pharmacology.”

Two additional pharmaceutical company-sponsored trials produced different results, with carriers and non-carriers responding similarly. Those studies involved longer-acting GLP-1 receptor agonists, which may be better able to overcome GLP-1 resistance, according to Gloyn.

Questions Remain About Weight Loss and Future Treatments

The research team first detected signs of GLP-1 resistance nearly a decade ago, long before GLP-1 drugs became widely known for weight loss.

Only two of the clinical trials included weight loss data. Those results showed no differences between people with and without PAM variants, but the available evidence was too limited to draw firm conclusions.

Gloyn noted that large amounts of genetic data from clinical trials likely already exist and could help answer important questions about why some people respond poorly to GLP-1 therapies.

“It’s very common for pharmaceutical companies to collect genetic data on their participants,” she said. “For the newer GLP-1 medications, it would be useful to look at whether there are genetic variants, like the variants in PAM, that explain poor responders to their medications.”

Although the biological mechanism remains unclear, Gloyn believes the answer is likely complex and influenced by multiple factors. She compares the situation to insulin resistance, which researchers still do not completely understand despite decades of study.

Even so, treatments have been developed to help overcome insulin resistance, raising the possibility that similar approaches could eventually be created for GLP-1 resistance.

“There are a whole class of medications that are insulin sensitizers, so perhaps we can develop medications that will allow people to be sensitized to GLP-1s or find formulations of GLP-1, like the longer-acting versions, that avoid the GLP-1 resistance.” she said.

Researchers from the University of Oxford, University of Dundee, University of Copenhagen, University of British Columbia, Churchill Hospital, Newcastle University, University of Bath, and University of Exeter also contributed to the study.

Funding was provided by Wellcome, the Medical Research Council, the European Union Horizon 2020 Program, the National Institutes of Health (grants U01-DK105535, U01-DK085545 and UM-1DK126185), the National Institute for Health Research Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim, and Diabetes Australia.

These giant black hole duos are expected to form naturally after galaxies merge. Although astronomers have identified some widely separated supermassive black hole pairs, finding those that orbit much closer together has proven far more difficult.

In a study published in Physical Review Letters, the researchers suggest searching for a distinctive signal. As the black holes orbit each other, their immense gravity could repeatedly magnify the light from stars located behind them, creating recurring flashes that may reveal the hidden systems.

Galaxy Mergers Create Supermassive Black Hole Binaries

Most galaxies contain a supermassive black hole at their center. When galaxies collide and eventually combine, their central black holes can become gravitationally bound, forming what scientists call a supermassive black hole binary.

These systems are important for understanding how galaxies evolve over time. They are also expected to generate some of the strongest gravitational waves in the universe.

Future space-based gravitational wave observatories should be able to detect these binaries directly. However, the new research suggests that astronomers may not have to wait. Existing and upcoming sky surveys could potentially identify them through their effects on visible light.

“Supermassive black holes act as natural telescopes,” said Dr. Miguel Zumalacárregui from the Max Planck Institute for Gravitational Physics. “Because of their enormous mass and compact size, they strongly bend passing light. Starlight from the same host galaxy can be focused into extraordinarily bright images, a phenomenon known as gravitational lensing.”

How Gravitational Lensing Creates Bright Flashes

A single supermassive black hole can dramatically magnify a background star, but only when the alignment is almost perfect.

A binary system behaves differently. With two black holes acting as gravitational lenses, the region where extreme magnification can occur becomes much larger. The pair creates a diamond-shaped feature known as a caustic curve, where stars can appear dramatically brighter.

In theory, a perfectly point-like star could be magnified infinitely. In reality, the finite size of stars places a limit on how bright the effect can become.

“The chances of starlight being hugely amplified increase enormously for a binary compared to a single black hole,” said Professor Bence Kocsis from the University of Oxford’s Department of Physics and a co-author of the study.

Repeating Stellar Flashes Could Reveal Hidden Black Holes

Unlike a single black hole, a black hole binary is constantly changing.

As the two black holes orbit each other, they gradually lose energy through the emission of gravitational waves, a process predicted by Einstein’s theory of general relativity. Over time, this causes the black holes to move closer together and orbit faster.

Graduate student Hanxi Wang is in Professor Kocsis’ group and led the study: “As the binary moves, the caustic curve rotates and changes shape, sweeping across a large volume of stars behind it. If a bright star lies within this region, it can produce an extraordinarily bright flash each time the caustic passes over it. This leads to repeating bursts of starlight, which provide a clear and distinctive signature of a supermassive black hole binary.”

Because the caustic structure continually shifts, the resulting flashes would occur again and again, creating a recognizable pattern that astronomers could search for.

Clues About Black Hole Masses and Orbits

The team found that the timing and intensity of these flashes should follow predictable trends rather than appearing randomly.

As gravitational waves slowly shrink the orbit, they subtly alter the shape and motion of the caustic curve. Those changes leave measurable signatures in both the brightness and frequency of the flashes.

By analyzing these patterns, researchers could estimate important characteristics of the hidden binary, including the masses of the black holes and details of their orbital evolution.

Powerful new observatories, including the Vera C. Rubin Observatory and the Nancy Grace Roman Space Telescope, are expected to dramatically expand the search for these repeating lensing events in the coming years.

“The prospect of identifying inspiraling supermassive black hole binaries years before future space-based gravitational wave detectors come online is extremely exciting,” concludes Professor Kocsis. “It opens the door to true multi-messenger studies of black holes, allowing us to test gravity and black hole physics in entirely new ways.”