Publisher Health

A University of Arizona Health Sciences researcher examined the role of cholesterol in both Alzheimer’s disease and Type 2 diabetes to identify a small molecule that may help regulate cholesterol levels in the brain, making it a potential new therapeutic target for Alzheimer’s disease.
There is no known cure for Alzheimer’s disease, which affects more than 5.5 million people in the United States. In the last decade, scientists have found increasing evidence linking the underlying causes of Type 2 diabetes and Alzheimer’s disease.
Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer’s disease, but rather than affecting the body as a whole, the effects are localized in the brain.
“Alzheimer’s and diabetes share many common causes,” said Gregory Thatcher, PhD, professor of pharmacology and toxicology in the UArizona College of Pharmacy and the newly named R. Ken and Donna Coit Endowed Chair in Drug Discovery. “Our goal was to develop a way of identifying compounds that would counteract many detrimental changes that contribute to both Alzheimer’s and Type 2 diabetes.”
The paper, “Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes,” was published in the journal ACS Pharmacology and Translational Science.
When cholesterol rises, due to insulin resistence or other factors, the body starts a process known as reverse cholestrol transport, during which specific molecules carry excess cholesterol to the liver to be excreted. Apolipoprotein E (APOE) is one of the proteins involved in reverse cholesterol transport.
APOE is also the strongest risk factor gene for Alzheimer’s disease and related dementia, and an independent risk factor for Type 2 diabetes and cardiovascular disease. Similarly, reduced activity of another cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), correlates with increased risk of cardiovascular disease, Type 2 diabetes and Alzheimer’s disease.
“While most people are aware of so-called ‘good cholesterol,’ and ‘bad cholesterol,’ associated with risk of heart attack and stroke, these broad concepts are also applicable to a healthy brain,” said Dr. Thatcher, who has been working to develop advanced therapeutics for Alzheimer’s for more than 20 years. “Moving cholesterol to where it is needed in the body has positive effects on many physiological processes and can help clear misfolded proteins that accumulate in the brain.”
Increasing the activity of ABCA1 is expected to positively influence insulin signaling and reduce inflammation in the brain, making it a potential therapy for both Type 2 diabetes and Alzheimer’s disease. In this study, Dr. Thatcher and the research team designed a way to identify small molecules that improve the function of ABCA1 in the body while avoiding unwanted effects to the liver.
In a March 20 paper in the journal EBioMedicine, “Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic development,” Dr. Thatcher’s team honed in on a specific small molecule, CL2-57, due to its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.
Their future research will seek to improve the properties of the small molecules to increase the levels in the brain. Their long-term goal is to understand which patients suffering from the cognitive and neuropsychiatric symptoms of Alzheimer’s and dementia will benefit from the treatment.
“During the Covid-19 pandemic we hear about the mounting deaths in nursing homes and it’s important to remember that Alzheimer’s and related dementia is a major cause of the elderly moving to nursing homes,” Dr. Thatcher said. “It would be good to think of a future in which healthspan was extended, especially a healthy brain; maybe that’s more important than lifespan.”

Expectant women are more likely to give birth early if they have high blood levels of a chemical used in flame retardants compared with those who have limited exposure, a new study finds.
These polybrominated diphenyl ethers (PBDEs) are used in the manufacture of furniture, carpeting, and other products to reduce flammability. Previous studies have found that the substances can leach into household dust and build up in the body where they may interfere with the thyroid, an organ that secretes brain-developing hormones. Childhood exposure to PBDEs has been linked to learning disabilities, autistic symptoms, and behavioral issues, among other developmental problems.
In an investigation led by an NYU Long Island School of Medicine researcher, nearly all pregnant women enrolled in the study had detectable levels of PBDEs in their blood. The findings revealed that women with concentrations above 4 nanograms per milliliter of blood were roughly twice as likely to deliver their children early via cesarean section or intentionally induced labor due to safety concerns for the mother or infant. By contrast, there was no elevated risk for preterm birth among women with PBDE levels below that threshold.
“Our findings illustrate that flame retardants may have a tremendous impact on childbirth even if exposure occurred early on in the pregnancy,” says study lead author Morgan Peltier, PhD. “Although PBDE chemicals are used with good intentions, they may pose a serious health concern that may have lasting consequences for children.” Peltier is an associate professor in the departments of Clinical Obstetrics, Gynecology, and Reproductive Medicine at NYU Long Island School of Medicine, part of NYU Langone Health.
According to Peltier, preterm birth is a leading cause of newborn death and occurs annually in about 15 million pregnancies worldwide. Experts have linked the phenomenon to long-term neurological disorders including cerebral palsy, schizophrenia, and learning problems that can extend into adulthood. Earlier research has pointed to PBDE exposure as a possible culprit behind preterm birth. However, these investigations only looked at exposure to the chemicals late in pregnancy and only examined white and African-American mothers.
The new study, published online Dec. 1 in the Journal of Perinatal Medicine, is the first to explore the link between PBDE exposure in the first trimester of pregnancy, says Peltier. He notes that the investigation looked at a wider demographic group as well, adding Asian and Hispanic women to the analysis.

Extending California’s stringent diesel emissions standards to the rest of the U.S. could dramatically improve the nation’s air quality and health, particularly in lower income communities of color, finds a new analysis published today in the journal Science.
Since 1990, California has used its authority under the federal Clean Air Act to enact more aggressive rules on emissions from diesel vehicles and engines compared to the rest of the U.S. These policies, crafted by the California Air Resources Board (CARB), have helped the state reduce diesel emissions by 78% between 1990 and 2014, while diesel emissions in the rest of the U.S. dropped by just 51% during the same time period, the new analysis found.
The study estimates that by 2014, improved air quality cut the annual number of diesel-related cardiopulmonary deaths in the state in half, compared to the number of deaths that would have occurred if California had followed the same trajectory as the rest of the U.S. Adopting similar rules nationwide could produce the same kinds of benefits, particularly for communities that have suffered the worst impacts of air pollution.
“Everybody benefits from cleaner air, but we see time and again that it’s predominantly lower income communities of color that are living and working in close proximity to sources of air pollution, like freight yards, highways and ports. When you target these sources, it’s the highly exposed communities that stand to benefit most,” said study lead author Megan Schwarzman, a physician and environmental health scientist at the University of California, Berkeley’s School of Public Health. “It’s about time, because these communities have suffered a disproportionate burden of harm.”
The study also points out that exposure to fine particulate matter (PM2.5) has been linked to poor outcomes from COVID-19, adding urgency to the need to reduce air pollution, par¬ticularly for communities of color that are disproportionately affected by both.
Diesel exhaust consists of both particles and gases and contributes significantly to PM2.5 air pollution worldwide. PM2.5 exposure from any source can compromise children’s lung development and can trigger airway inflammation and exacerbate asthma and cardiopulmonary diseases. Diesel exhaust has also been designated a human carcinogen by California’s Office of Environmental Health Hazard Assessment (OEHHA).

In the largest study of its kind to date, researchers at Massachusetts General Hospital, Brigham and Women’s Hospital and the Ragon Institute of MGH, MIT and Harvard have found the new mRNA COVID-19 vaccines to be highly effective in producing antibodies against the SARS-CoV-2 virus in pregnant and lactating women. They also demonstrated the vaccines confer protective immunity to newborns through breastmilk and the placenta.
The study, published in the American Journal of Obstetrics and Gynecology (AJOG), looked at 131 women of reproductive age (84 pregnant, 31 lactating and 16 non-pregnant), all of whom received one of the two new mRNA vaccines: Pfizer/BioNTech or Moderna. The vaccine-induced titers — or antibody levels — were equivalent in all three groups. Reassuringly, side effects after vaccination were rare and comparable across the study participants.
“This news of excellent vaccine efficacy is very encouraging for pregnant and breastfeeding women, who were left out of the initial COVID-19 vaccine trials,” says Andrea Edlow, MD, MSc, a maternal-fetal medicine specialist at MGH, director of the Edlow Lab in the Vincent Center for Reproductive Biology and co-senior author of the new study. “Filling in the information gaps with real data is key — especially for our pregnant patients who are at greater risk for complications from COVID-19. This study also highlights how eager pregnant and lactating individuals are to participate in research.”
According to the Centers for Disease Control and Prevention, individuals who are pregnant are more likely to become severely ill with COVID-19, require hospitalization, intensive care or ventilation — and may be at increased risk for adverse pregnancy outcomes. The team also compared vaccination-induced antibody levels to those induced by natural infection with COVID-19 in pregnancy, and found significantly higher levels of antibodies from vaccination.
Vaccine-generated antibodies were also present in all umbilical cord blood and breastmilk samples taken from the study, showing the transfer of antibodies from mothers to newborns.
“We now have clear evidence the COVID vaccines can induce immunity that will protect infants,” says Galit Alter, PhD, core member of the Ragon Institute and co-senior author of the study. “We hope this study will catalyze vaccine developers to recognize the importance of studying pregnant and lactating individuals, and include them in trials. The potential for rational vaccine design to drive improved outcomes for mothers and infants is limitless, but developers must realize that pregnancy is a distinct immunological state, where two lives can be saved simultaneously with a powerful vaccine. We look forward to studying all vaccine platforms in pregnancy as they become available.”
The study was also able to provide insight into potential differences between the immune response elicited by the Pfizer vaccine compared to the Moderna vaccine, finding the levels of mucosal (IgA) antibodies were higher after the second dose of Moderna compared to the second dose of Pfizer.
“This finding is important for all individuals, since SARS-CoV-2 is acquired through mucosal surfaces like the nose, mouth and eyes,” says Kathryn Gray, MD, PhD, an obstetrician at Brigham and Women’s Hospital and a first author of the paper. “But it also holds special importance for pregnant and lactating women because IgA is a key antibody present in breastmilk.”
Gray’s co-first authors on the study are Evan Bordt, PhD, of MGH and Caroline Atyeo of the Ragon Institute.
Funding for the study included grants from the National Institute of Child Health and Human Development (NICHD), the Gates Foundation, the Massachusetts Consortium on Pathogen Readiness (MassCPR) and the Musk Foundation.
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Pregnant women who consumed the caffeine equivalent of as little as half a cup of coffee a day on average had slightly smaller babies than pregnant women who did not consume caffeinated beverages, according to a study by researchers at the National Institutes of Health. The researchers found corresponding reductions in size and lean body mass for infants whose mothers consumed below the 200 milligrams of caffeine per day — about two cups of coffee — believed to increase risks to the fetus. Smaller birth size can place infants at higher risk of obesity, heart disease and diabetes later in life.
The researchers were led by Katherine L. Grantz, M.D., M.S., of the Division of Intramural Population Health Research at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The study appears in JAMA Network Open.
“Until we learn more, our results suggest it might be prudent to limit or forego caffeine-containing beverages during pregnancy,” Dr. Grantz said. “It’s also a good idea for women to consult their physicians about caffeine consumption during pregnancy.”
Previous studies have linked high caffeine consumption (more than 200 milligrams of caffeine per day) during pregnancy to infants being small for their gestational age (stage of pregnancy) or at risk for intrauterine growth restriction — being in the lowest 10th percentile for infants of the same gestational age. However, studies on moderate daily caffeine consumption (200 milligrams or less) during pregnancy have produced mixed results. Some have found similar elevated risks for low birth weight and other poor birth outcomes, while others have found no such links. The current study authors noted that many of the earlier studies did not account for other factors that could influence infant birth size, such as variation in caffeine content of different beverages and maternal smoking during pregnancy.
For their study, the authors analyzed data on more than 2,000 racially and ethnically diverse women at 12 clinical sites who were enrolled from 8 to 13 weeks of pregnancy. The women were non-smokers and did not have any health problems before pregnancy. From weeks 10 to 13 of pregnancy, the women provided a blood sample that was later analyzed for caffeine and paraxanthine, a compound produced when caffeine is broken down in the body. The women also reported their daily consumption of caffeinated beverages (coffee, tea, soda and energy drinks) for the past week — once when they enrolled and periodically throughout their pregnancies.
Compared to infants born to women with no or minimal blood levels of caffeine, infants born to women who had the highest blood levels of caffeine at enrollment were an average of 84 grams lighter at birth (about 3 ounces), were .44 centimeters shorter (about .17 inches), and had head circumferences .28 centimeters smaller (about .11 inches).
Based on the women’s own estimates of the beverages they drank, women who consumed about 50 milligrams of caffeine a day (equivalent to a half cup of coffee) had infants 66 grams (about 2.3 ounces) lighter than infants born to non-caffeine consumers. Similarly, infants born to the caffeine consumers also had thigh circumferences .32 centimeters smaller (about .13 inches).
The researchers noted that caffeine is believed to cause blood vessels in the uterus and placenta to constrict, which could reduce the blood supply to the fetus and inhibit growth. Similarly, researchers believe caffeine could potentially disrupt fetal stress hormones, putting infants at risk for rapid weight gain after birth and for later life obesity, heart disease and diabetes.
The authors concluded that their findings suggest that even moderate caffeine consumption may be associated with decreased growth of the fetus.

About two decades after first devising a new kind of vaccine, Oregon Health & Science University researchers are unlocking why it stops and ultimately clears the monkey form of HIV, called SIV, in about half of nonhuman primates — and why it’s a promising candidate to stop HIV in people.
In scientific papers that were simultaneously published today in the journals Science and Science Immunology, creators of the cytomegalovirus, or CMV, vaccine platform describe the unusual biological mechanisms through which it works.
The findings also helped fine-tune VIR-1111, the CMV-based experimental vaccine against HIV that was developed at OHSU and is now being evaluated in a Phase 1 clinical trial. The trial is being conducted by Vir Biotechnology, which licensed the CMV vaccine platform technology from OHSU.
“Knowing the mechanism that the CMV-based SIV vaccine uses to work in rhesus macaques gives us a way to judge the potential of a human vaccine very quickly,” said Louis Picker, M.D., the associate director of the OHSU Vaccine and Gene Therapy Institute and a professor of pathology/molecular microbiology and immunology in the OHSU School of Medicine. “If you have the wrong genes in the CMV vaccine, the critical immune response needed for efficacy won’t develop. You have to thread the CMV vaccine’s needle exactly if you want a high degree of protection, and you have to know what you’re looking for.”
Two of the papers describe that the cytomegalovirus vaccine needs to generate an unusual type of CD8-positive T cell response called MHC-E-restricted T cells to effectively fight off SIV in monkeys.
“We knew for a while that we have unusual T cell responses in monkeys that receive our CMV vaccine against SIV,” said Klaus Frueh, Ph.D., a professor of molecular microbiology and immunology in the OHSU School of Medicine and OHSU Vaccine and Gene Therapy Institute. “But we didn’t know if they were important for protection against SIV. This research shows clearly that, without this special MHC-E-restricted T cell response, we don’t have protection.”
The study published in Science Immunology shows that the vaccine was only able to generate these special T cells to fight off SIV if eight specific genes were missing or inactivated from the natural form of monkey CMV. And a corresponding paper published via Science’s First Release describes how a specific cytomegalovirus protein known as Rh67 is required to generate MHC-E-restricted T cells to protect against SIV. Together, these papers suggest how a CMV-based vaccine needs to be designed to create these unconventional T cell responses.
And, in a separate Science Immunology paper that was also published today, a research team led by Andrew J. McMichael, Ph.D., of Oxford University looked into whether what has been learned from nonhuman primate experiments could be transferrable to humans. These researchers showed that MHC-E-restricted CD8-positive T cells could be increased and suppress HIV in laboratory cell cultures.
This new research is being published as the OHSU Vaccine and Gene Therapy Institute celebrates the 20th anniversary of its first building opening for research in April 2001. Picker and Frueh moved to Oregon to help start the institute: Picker has led its vaccine program since its founding, and Frueh joined forces with Picker in 2006. Picker first received a $3.5 million grant from the National Institutes of Health in 2004 to develop a CMV-based HIV vaccine. Picker says the following in a May 25, 2004, OHSU announcement about the grant: “We believe a persistent viral vector could produce a superior and more durable anti-HIV immune response that would, in effect, hold the line against HIV.”
The following funding was awarded to OHSU in support of the research described in these three studies: the National Institute of Allergy and Infectious Diseases (grants P01 AI094417, U19 AI128741, UM1 AI124377, R37 AI054292, R01AI140888, R01 AI059457), National Institutes of Health Office of the Director (grant P51 OD011092); National Cancer Institute (contract HHSN261200800001E), and the Bill & Melinda Gates Foundation-supported Collaboration for AIDS Vaccine Discovery (OPP1033121).
In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regards to this research, OHSU and several individuals have a significant financial interest in Vir Biotechnology Inc., a company that may have a commercial interest in the results of this research and technology. These individuals include Picker, Frueh, Sacha, Malouli, Hansen and Hancock.

Researchers at the National Institutes of Health (NIH) have discovered specific regions within the DNA of neurons that accumulate a certain type of damage (called single-strand breaks or SSBs). This accumulation of SSBs appears to be unique to neurons, and it challenges what is generally understood about the cause of DNA damage and its potential implications in neurodegenerative diseases.
Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals — toxic compounds that can damage DNA within cells. Normally, this damage occurs randomly. However, in this study, damage within neurons was often found within specific regions of DNA called “enhancers” that control the activity of nearby genes.
Fully mature cells like neurons do not need all of their genes to be active at any one time. One way that cells can control gene activity involves the presence or absence of a chemical tag called a methyl group on a specific building block of DNA. Closer inspection of the neurons revealed that a significant number of SSBs occurred when methyl groups were removed, which typically makes that gene available to be activated.
An explanation proposed by the researchers is that the removal of the methyl group from DNA itself creates an SSB, and neurons have multiple repair mechanisms at the ready to repair that damage as soon as it occurs. This challenges the common wisdom that DNA damage is inherently a process to be prevented. Instead, at least in neurons, it is part of the normal process of switching genes on and off. Furthermore, it implies that defects in the repair process, not the DNA damage itself, can potentially lead to developmental or neurodegenerative diseases.
This study was made possible through the collaboration between two labs at the NIH: one run by Michael E. Ward, M.D., Ph.D. at the National Institute of Neurological Disorders and Stroke (NINDS) and the other by Andre Nussenzweig, Ph.D. at the National Cancer Institute (NCI). Dr. Nussenzweig developed a method for mapping DNA errors within the genome. This highly sensitive technique requires a considerable number of cells in order to work effectively, and Dr. Ward’s lab provided the expertise in generating a large population of neurons using induced pluripotent stem cells (iPSCs) derived from one human donor. Keith Caldecott, Ph.D. at the University of Sussex also provided his expertise in single strand break repair pathways.
The two labs are now looking more closely at the repair mechanisms involved in reversing neuronal SSBs and the potential connection to neuronal dysfunction and degeneration.
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The evolving science of wisdom rests on the idea that wisdom’s defined traits correspond to distinct regions of the brain, and that greater wisdom translates into greater happiness and life satisfaction while being less wise results in opposite, negative consequences.
Scientists have found in multiple studies that persons deemed to be wiser are less prone to feel lonely while those who are lonelier also tend to be less wise. In a new study, published in the March 25, 2021 issue of the journal Frontiers in Psychiatry, researchers at University of California San Diego School of Medicine take the connection between wisdom, loneliness and biology further, reporting that wisdom and loneliness appear to influence — and/or be influenced by — microbial diversity of the gut.
The human gut microbiota is comprised of trillions of microbes — bacteria, viruses, fungi — that reside within the digestive tract. Researchers have known for a while about the “gut-brain axis,” which is a complex network that links intestinal function to the emotional and cognitive centers of the brain.
This two-way communication system is regulated by neural activity, hormones and the immune system; alterations can result in disruptions to stress response and behaviors, said the authors, from emotional arousal to higher-order cognitive abilities, such as decision-making.
Past studies have associated gut microbiota with mental health disorders including depression, bipolar disorder and schizophrenia, as well as personality and psychological traits regarded as key, biologically based components of wisdom. Recent research has connected the gut microbiome to social behavior, including findings that people with larger social networks tend to have more diverse gut microbiotas.
The new Frontiers in Psychiatry study involved 187 participants, ages 28 to 97, who completed validated self-report-based measures of loneliness, wisdom, compassion, social support and social engagement. The gut microbiota was analyzed using fecal samples. Microbial gut diversity was measured in two ways: alpha-diversity, referring to the ecological richness of microbial species within each individual and beta-diversity, referring to the differences in the microbial community composition between individuals.

Researchers from Charité — Universitätsmedizin Berlin and the Francis Crick Institute have developed a mass spectrometry-based technique capable of measuring samples containing thousands of proteins within just a few minutes. It is faster and cheaper than a conventional blood count. To demonstrate the technique’s potential, the researchers used blood plasma collected from COVID-19 patients. Using the new technology, they identified eleven previously unknown proteins which are markers of disease severity. The work has been published in Nature Biotechnology.
Thousands of proteins are active inside the human body at any given time, providing its structure and enabling reactions which are essential to life. The body raises and lowers the activity levels of specific proteins as required, including when responding to external factors such as pathogens and drugs. The detailed patterns of the proteins found inside cells, tissues and blood samples can therefore help researchers to better understand diseases or make diagnoses and prognoses. In order to obtain this ‘protein fingerprint’, researchers use mass spectrometry, a technology known to be both time-consuming and cost-intensive. ‘Scanning SWATH’, a new mass-spectrometry-based technology, promises to change this. Developed under the leadership of Prof. Dr. Markus Ralser, Director of Charité’s Institute of Biochemistry, this technology, which is much faster and cost-effective than previous methods, enables researchers to measure several hundred samples per day.
“In order to speed up this technology, we changed the mass spectrometer’s electric fields. The data produced are of such extreme complexity that humans can no longer analyze them,” explains Einstein Professor Prof. Ralser, who is also a Group Leader at the Francis Crick Institute in London. He adds: “We therefore developed computer algorithms that are based on neural networks and which use these data to extract the relevant biological information. This enables us to identify thousands of proteins in parallel and greatly reduces measuring timescales. Fortunately, this method is also more precise.”
This high-throughput technology has a broad range of potential applications, ranging from basic research and large-scale drug development to the identification of biological markers (biomarkers), which can be used to estimate an individual patient’s risk. The technology’s suitability for the latter was demonstrated by the researchers’ study on COVID-19. As part of this research, the team analyzed blood plasma samples from 30 Charité inpatients with COVID-19 of varying degrees of disease severity, comparing the protein patterns obtained with those of 15 healthy individuals. The actual measurements conducted on individual samples only took a few minutes.
The researchers were able to identify a total of 54 proteins whose serum levels varied according to the severity of COVID-19. While 43 of these proteins had already been linked to disease severity during earlier studies, no such relationship had been established for 11 of the proteins identified. Several of the previously unknown proteins associated with COVID-19 are involved in the body’s immune response to pathogens which increases clotting tendency. “In the shortest of timeframes, we discovered protein fingerprints in blood samples which we are now able to use to categorize COVID-19 patients according to severity of disease,” says one of the study’s lead authors, Dr. Christoph Messner, who is a researcher at Charité’s Institute of Biochemistry and the Francis Crick Institute. He continues: “This type of objective assessment can be extremely valuable, as patients will occasionally underestimate the severity of their disease. However, in order to be able to use mass spectrometry analysis for the routine categorization of COVID-19 patients, this technology will need to be refined further and turned into a diagnostic test. It may also become possible to use rapid protein pattern analysis to predict the likely course of a case of COVID-19. While the initial findings we have collected are promising, further studies will be needed before this can be used in routine practice.”
Prof. Ralser is convinced that mass spectrometry-based investigations of the blood could one day complement conventional blood count profiles. “Proteome analysis is now cheaper than a complete blood count. By identifying many thousands of proteins at the same time, proteomic analysis also produces far more information. I therefore see enormous potential for widespread use, for instance in the early detection of diseases. We will therefore continue to use our studies to develop proteome technology for this type of application.”
The study is the result of a collaboration with the University of Cambridge, United Kingdom, the Chalmers University of Technology, Sweden, the Bernhardt Nocht Institute for Tropical Medicine in Hamburg, Germany, and SCIEX, a Canadian manufacturer of mass spectrometers.
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Researchers at Baylor College of Medicine, Shandong University in China and other institutions may have found an explanation for dawn phenomenon, an abnormal increase of blood sugar only in the morning, observed in many patients with type 2 diabetes. They report in the journal Nature that mice lacking the circadian clock gene called Rev-erb in the brain show characteristics similar to those of dawn phenomenon.
The researchers then looked at Rev-erb gene expression in patients with type 2 diabetes comparing a group with dawn phenomenon to a group without it and found that the gene’s expression followed a different temporal pattern between these two groups. The findings support the idea that an altered daily rhythm of expression of the Rev-erb gene may underlie dawn phenomenon. Future investigations may lead to therapies.
“We began this study to investigate what was the function of Rev-erb in the brain,” said co-corresponding author Dr. Zheng Sun, associate professor of medicine-endocrinology, diabetes and metabolism at Baylor. “We are interested in this gene because it is a ‘druggable’ component of the circadian clock with potential applications in the clinic. Rev-erb is expressed only during the day but not at night. When we started, we did not know where this was going to lead us.”
The researchers first developed a mouse model by knocking out the Rev-erb gene in GABA neurons. They chose this approach because the gene’s expression is highly enriched in a particular brain area called the suprachiasmatic nucleus that is mainly composed of GABA neurons.
An unexpected finding
“We observed something very interesting in these mice,” Sun said. “They were glucose intolerant — that is they had high glucose levels — only in the evening. Mice are nocturnal, meaning that they become active in the evening as people do in the morning.”
When the body awakes and takes in food, insulin is secreted from the pancreas to signal the body to lower blood sugar. Insulin is more effective in doing this job upon waking than at other times of the day. This high insulin sensitivity is probably because the body is anticipating feeding behaviors upon waking up. In mice, high insulin sensitivity occurs in the evening, while in people it occurs in the morning.