Posted on Diabetes

Incidence rates of diabetes continue to increase in children and young adults.

Lynne E. Wagenknecht, Dr.P.H.


Lynne E. Wagenknecht, Dr.P.H., professor and director of public health sciences at Wake Forest University School of Medicine CREDIT Wake Forest University School of Medicine

Study also shows that Asian or Pacific Islander, non-Hispanic Black and Hispanic children have higher incidence rates of both type 1 and type 2 diabetes.

New findings from researchers at Wake Forest University School of Medicine confirm that the rates of Type 1 and Type 2 diabetes continue to increase in children and young adults. Non-Hispanic Black and Hispanic children and young adults also had higher incidence rates of diabetes.

The study appears online in the current issue of The Lancet Diabetes & Endocrinology.

“Our research suggests a growing population of young adults with diabetes who are at risk of developing complications from the disease,” said Lynne E. Wagenknecht, Dr.P.H., professor and director of public health sciences at Wake Forest University School of Medicine and principal investigator. “It’s a troubling trend in young people whose health care needs will exceed those of their peers.”

The findings are from the final report from the SEARCH for Diabetes in Youth study, the largest surveillance effort of diabetes among youth under the age of 20 conducted in the U.S. to date. Wake Forest University School of Medicine served as the coordinating center of the multi-site study, which was launched in 2000 and supported by the Centers for Disease Control and Prevention and the National Institutes of Health.

The research team identified more than 18,000 children and young people from infants to 19 years of age with a physician diagnosis of Type 1 diabetes and more than 5,200 young people between the ages of 10 and 19 with Type 2 diabetes at five centers in the U.S. between 2002 and 2018. The annual incidence of Type 1 diabetes was 22.2 per 100,000 in 2017–18 and 17.9 per 100,000 for Type 2 diabetes.

“In our 17-year analysis, we found that the incidence of Type 1 diabetes increased by 2% per year, and the incidence of Type 2 diabetes increased by 5.3% per year,” Wagenknecht said.

The rates of increase were also higher among racial and ethnic groups than among non-Hispanic white children. Specifically, annual percentage increases for Type 1 diabetes and Type 2 diabetes were highest for Asian or Pacific Islander, Hispanic and non-Hispanic Black children and young people.

The peak age at diagnosis was 10 years for Type 1 diabetes and 16 years for Type 2 diabetes. Researchers also noted that the onset of Type 1 diabetes typically occurs in winter with a peak in January. Possible explanations for this seasonality include the fluctuation in daylight hours, lower levels of vitamin D and an increase in viral infections.

For Type 2 diabetes, the peak onset was August. Researchers attribute this to the increase in sports physicals and routine health screenings that occur more frequently at the beginning of the academic school year.

“These findings will help guide focused prevention efforts,” Wagenknecht said. “Now that we have a better understanding of risk factors, our next phase of research will be studying the underlying pathophysiology of youth-onset diabetes.”

Posted on autoimmune conditions, Multiple Sclerosis, Rheumatoid arthritis

Potential treatment of autoimmune diseases revealed in the new study like multiple sclerosis and rheumatoid arthritis.

Diagram showing the results of mice that were treated with PEP


Mice that have neuroinflammation caused by autoimmunity were treated with PEP. The results found that PEP-treated mice showed improved signs of recovery compared to mice not treated with PEP. CREDI Tsung-Yen Huang (OIST)

Scientists in Japan have revealed a chemical compound that could be used for the treatment of various autoimmune diseases like multiple sclerosis and rheumatoid arthritis. These diseases occur when the body’s immune response goes wiry. The immune system, which normally attacks pathogens and infections, instead attacks healthy cells and tissues. For the millions of people who suffer from autoimmune diseases worldwide, the result can be debilitating—rheumatoid arthritis causes excessive joint pain, while multiple sclerosis can disable one’s brain and spinal cord function.

“The key to the development of autoimmune diseases, and thus the way to inhibit this development, lies in our cells, but the underlying mechanism has always been unclear,” stated Prof. Hiroki Ishikawa, who leads the Immune Signal Unit at the Okinawa Institute of Science and Technology (OIST). “Now, our recent research has shed light on a compound that could suppress the development of these diseases.”

Prof. Ishikawa went on to explain that this research, published in Cell Reports, could lead to the development of treatments for autoimmune diseases.

The research focused on T helper 17 cells, or Th17 cells. Th17 cells are a type of T cell—a group of cells, which form major parts of the immune system. These cells, which exist in high numbers in our guts, evolved to help us fight invasive pathogens but, sometimes, they’re overactivated and mistake normal, healthy tissue as pathogens, resulting in autoimmunity. The generation of Th17 cells requires glycolysis, a metabolic process in which glucose is broken down and converted to energy to support the metabolic needs of cells. Glycolysis is essential for the growth of not only Th17 cells but also a variety of cells in our body.

“What’s interesting in that excessive glycolysis seems to suppress Th17 cell activity,” stated first author, Mr. Tsung-Yen Huang, a PhD candidate in the Immune Signal Unit. “So, we hypothesized that molecules produced during glycolysis may inhibit the cells.”

Enter phosphoenolpyruvate, or PEP for short. This chemical compound is a metabolite produced when glucose is converted to energy. Since it is part of such an important process, PEP is generated every day in our bodies. The researchers found that treatment with PEP can inhibit the maturation of TH17 cells, leading to resolution of inflammatory response.

Mr. Huang explained how this was, at first, a confusing result, as it went against all other research on the topic, but he decided to persevere and take a closer look at what could be occurring.

The research led them to a protein called JunB, which is essential for the maturation of Th17 cells. JunB promotes Th17 maturation by binding to a set of specific genes. The researchers found that PEP treatment inhibits the generation of Th17 cells by blocking JunB activity.

Armed with this knowledge, the researchers went on to treat mice that had neuroinflammation caused by autoimmunity with PEP. This disease is very similar to multiple sclerosis and these mice showed positive signs of recovery. The scientists have now filed a patent to continue with this research.

“Our results show the clinical potential of PEP,” explained Mr. Huang. “But first we need to increase its efficiency.”

In the past, researchers who were interested in developing a treatment for autoimmune diseases, often looked at inhibiting glycolysis and thus Th17 cells. But glycolysis is essential to various types of cells in the body and inhibiting it could have significant side-effects. PEP has the potential to be used as a treatment without resulting in such side-effects.

Posted on autoimmune conditions

Specialized garbage disposal cell, implicated in autoimmune disease, tracked for the first time.

Australian researchers have made a fundamental discovery about what happens in lymph nodes, shedding light on the causes of immune-related diseases like lupus.

2-Photon microscope image of the germinal centre inside a lymph node, showing B cells (green) moving around and a tingible body macrophage (red) grabbing the dead and dying B cells

2-Photon microscope image of the germinal centre inside a lymph node, showing B cells (green) moving around and a tingible body macrophage (red) grabbing the dead and dying B cells CREDIT Garvan

For almost 140 years, the origin and behaviour of an enigmatic cell type inside lymph nodes, called a tingible body macrophage, has remained a mystery. Now, for the first time, scientists at the Garvan Institute of Medical Research have tracked the cell’s lifecycle and function, with implications for our understanding of autoimmune disorders.

Autoimmune disease, which occurs when the immune system attacks the body, affects 5% of Australians and has a high chronic health burden worldwide, yet its causes are poorly understood.

“In living organisms, death happens all the time – and if you don’t clean up, the contents of the dead cells can trigger autoimmune diseases,” says lead author Professor Tri Phan, Head of the Intravital Microscopy and Gene Expression (IMAGE) Lab and Co-Lead of the Precision Immunology Program at Garvan.

2-Photon microscope image of the germinal centre inside a lymph node, showing tingible body macrophages (red)

3. 2-Photon microscope image of the germinal centre inside a lymph node, showing tingible body macrophages (red) CREDIT Garvan

Macrophages in many parts of the body are responsible for clearing foreign material like bacteria and viruses, but the researchers discovered that these tingible body macrophages, found inside lymph nodes, specialise in cleaning up the immune system’s own waste: the B cells that proliferate when we fight infection.

During an immune response, a massive number of B cells are made inside the lymph nodes and then tested for their ability to neutralise the infection. B cells that fail the test are destined to die, but on the way out, they can trigger the body to attack itself. The contents of these cells – especially those in the cell’s central nucleus – are inflammatory and can inadvertently activate some B cells to make antibodies against that waste, leading to autoimmunity. Removing this waste is therefore a critical housekeeping function.

The new research is published in the journal Cell.

Insights into a microscopic ecosystem

The scientists used state-of-the-art intravital imaging techniques at the ACRF INCITe Centre to observe how the macrophages form within the lymph nodes and how they behave in real time. Their analysis shows that, unlike other immune cells, tingible body macrophages do not chase their targets, but disperse evenly and lie in wait. When a dead or dying B cell comes close, the macrophage reaches out and wraps around the target, pulling it in to be ingested.

2-Photon microscope image of the germinal centre inside a lymph node, showing B cells (green) moving around and tingible body macrophages (red) evenly dispersed to grab the dead and dying cells

2-Photon microscope image of the germinal centre inside a lymph node, showing B cells (green) moving around and tingible body macrophages (red) evenly dispersed to grab the dead and dying cells CREDIT Garvan

“We know so very little about tingible body macrophages because it was not possible until now, with next-generation two-photon microscopes, to get inside the microstructures inside the lymph nodes of a living animal and watch the cells in action in real time. That’s why it’s taken 140 years – from when tingible body macrophages were first described in 1885 – to get where we are now,” says Professor Phan.

“A lot of what we do is like shooting a David Attenborough documentary but at a microscopic scale – capturing the hidden life of these rare cells ‘in the wild’, to show how these cellular ecosystems work to keep us healthy,” Abigail Grootveld, PhD student at Garvan and co-first author of the study.

“This research is exciting because it helps us to understand causes of autoimmune conditions like lupus. Understanding why somebody gets the disease in the first place and why it keeps coming back, is an important step towards future treatments for these diseases,” says Wunna Kyaw, PhD student at Garvan and co-first author of the study.

In systemic lupus, the immune system struggles to control the production of its fighter T cells and B cells. Their overactivity causes inflammation, autoantibodies and long-term damage throughout the body. This research shows that tingible body macrophages, with their B cell clean-up function, could be responsible for setting the chain of events in motion if they fail.

So far, the study has examined what happens with the macrophages in animal models of a healthy system. The researchers’ next step is to expand the experiment to an autoimmune model, to see if they can rescue the failing system and prevent autoimmunity at its root cause.

Posted on Lupus

Targeting type of B cell could reduce lupus disease, study suggests

Targeting type of B cell could reduce lupus disease, study suggests
Targeting type of B cell could reduce lupus disease, study suggests


A group of University of Pittsburgh researchers has given new meaning to “knowing your ABCs.” In a new study, published in the Journal of Experimental Medicine, the team showed that a type of immune cell called age-associated B cells, or ABCs, are important drivers of lupus and that targeting these cells in a mouse model reduced disease, pointing the way to new therapies.

The immune system usually does a good job of discriminating between healthy body tissues and potential threats such as bacterial or viral infections. When exposed to a pathogen, B cells make antibodies, which help the body to recognize and eliminate the threat. The immune system then returns to less-active surveillance mode, while retaining a long-lived “memory” of prior infection.

However, in autoimmune disorders such as lupus, B cells become abnormally activated and begin attacking the patient’s organs, including the kidneys, lungs and skin.

“A hallmark of lupus is high levels of autoantibodies that bind to a patient’s own DNA or RNA,” said lead author Dr. Kevin Nickerson, research assistant professor in Pitt’s Department of Immunology.



“Because these genetic materials are never eliminated from the body, the immune system is continually reactivated, leading to inflammation that, over time, causes a great deal of damage to the patient’s body.”

According to Nickerson, existing therapies that broadly target B cells can be effective in some lupus patients, but because they also impair B cells that produce infection-fighting antibodies, these treatments can compromise immunity, suggesting a need for more narrowly focused approaches.

In the new study, Nickerson, senior author Dr. Mark Shlomchik, distinguished professor of immunology at Pitt, and their team set out to better understand the role of ABCs in lupus. Nickerson explains the study’s findings and what they could mean for the future of lupus treatments.

What are age-associated B cells?

KN: Age-associated B cells, or ABCs, are a sub-category of B cell that were first identified as being more frequent in older individuals than younger individuals. It quickly became apparent to researchers that these cells are also found in greater numbers in patients with certain autoimmune diseases, including lupus, and during certain chronic infections such as malaria and HIV. These and other findings led researchers to propose that ABCs are a type of immune memory cell that form during some types of chronic inflammatory immune responses. They might accumulate very slowly over a healthy individual’s entire lifetime, or much more rapidly in a younger patient with lupus.

What motivated this study?

KN: Previous research had shown that higher numbers of ABCs in a lupus patient’s blood often correlated with the severity of their symptoms, particularly lupus nephritis (kidney disease). ABCs were thought to be autoimmune memory B cells that develop into cells that make lupus autoantibodies. In this study, we set out to test whether ABCs were indeed a driver of lupus disease. Using a preclinical mouse model of lupus, we examined ABCs in great detail, studied their relationship to other types of B cells and genetically depleted these cells right after they are formed to see what effect they have on disease.

What were your main findings?

KN: Our most important finding was that reducing the number of ABCs by eliminating them as soon as they form slowed or reduced disease progression in the kidneys in mice, directly demonstrating that ABCs drive disease in this lupus model.  We also found that ABCs are a more diverse subset of B cells than previously known, which could suggest that they have different functions or that multiple pathways are involved in their formation.

We also demonstrated that ABCs are indeed a direct precursor to the cells that make lupus autoantibodies. Although they resemble anti-pathogen memory B cells in some respects, they seem to undergo continual cycles of reactivation, proliferation and differentiation. This makes sense because the DNA and RNA to which they respond are always present, so they can’t fully enter a resting state, unlike the memory response in B cells that recognize pathogens, which are eventually eliminated.

What are the implications of these findings and what do they tell you about potential therapies for lupus?

KN: Several lupus therapeutics in the clinic today aim to reduce B cell numbers by directly killing them or by blocking the factors necessary for their survival. However, these currently available therapies are nonspecific, meaning that they affect all B cells, whether those B cells are autoreactive or directed against pathogens. While depleting all B cells prevents lupus progression and organ damage, it significantly impairs a patient’s ability to respond to infections.

If ABCs are the pathogenic population of B cells in lupus, as our study suggests, then narrowly targeted therapies that focus on eliminating these “bad” cells, while sparing “good” B cells, could be beneficial. To do this, we need a more complete understanding of ABCs and where they come from to help design the best approaches. Our study contributes to this understanding.

What are the next steps for this research?

KN:  An important unresolved question is what makes ABCs so pathogenic? And how are they actually promoting disease? One part of that could be their role in making autoantibodies, but we have reason to believe that ABCs could also activate the T cell arm of the immune system in lupus. Autoreactive T cells, when activated, infiltrate organs and tissues from the bloodstream, causing injury by damaging cells and disrupting normal organ function. We want to know if ABCs are directly promoting this pathogenic process and if they are also found within the inflamed tissues at the sites of damage.  In addition, we want to develop methods to deplete ABCs during ongoing disease in a preclinical model to determine if and how that could slow down or treat disease.

Posted on Pain Management

Researchers identify gene mutations capable of regulating pain.

Gene mutation capable of regulating pain


Vanessa O. Zambelli and PhD candidate Beatriz Stein Neto. In a study involving mice, the scientists discovered that an avian variant of the TRPV1 receptor CREDIT Rafael Porto

Pain afflicts at least 1.5 billion people worldwide, and despite the availability of various painkilling drugs, not all forms of pain are treatable. Moreover, pain medications can have side-effects such as dependence and tolerance, especially in the case of morphine and other opioids. 

In search of novel painkillers, researchers at Butantan Institute’s Special Pain and Signaling Laboratory (LEDS) in São Paulo, Brazil, studied TRPV1, a sensory neuron receptor that captures noxious stimuli, including heat and the burning sensation conveyed by chili peppers, and discovered a potential pain insensitivity mutation in the gene that encodes this protein. They report their findings in an article published in the Journal of Clinical Investigation.

The study was supported by FAPESP and conducted in partnership with Stanford University and Emory University in the United States, and Münster University Hospital in Germany. The researchers analyzed a number of mutations in humans and also benefited from existing knowledge of birds, which unlike mammals have a TRPV1 receptor that is naturally resistant to noxious insults and even peppery food, yet can still perceive pain.

“There are more than 1,000 TRPV1 mutations in humans, and there’s nothing novel about trying to switch the receptor off in order to relieve pain, but these attempts haven’t been successful until now,” said Vanessa Olzon Zambelli, a researcher at LEDS and co-first author of the article. “First, many drugs resulting from this process interfere with body temperature regulation. Second, TRPV1 is an important channel for signaling heat, and completely altering its activity cancels out physiological pain, interfering with the sensation of burning heat, which has a protective function.”

The researchers began by exploring a genome database to compare the genetic sequences of avian and human TRPV1. Using a computational approach, they identified five avian mutations they believed to be linked to resistance to pain. Cryogenic electron microscopy (which does not require large sample sizes or crystallization and is therefore suited to the visualization of structures at near-atomic resolution) showed that the five avian mutations were located in K710, an amino acid residue believed to control gating (opening and closing) of the TRPV1 channel.

The mutations can also be present in humans, but they are very rare, so the researchers decided to find out what would happen if they were “transplanted” into mammals. When they tested these variants in genetically modified cells, they found that the function of the channel was indeed altered. Next, they used the CRISPR/Cas9 gene editing technique to create mice with the mutation K710N, which they had previously found to reduce the receptor’s reaction to capsaicin in cells. Capsaicin is the active principle in pepper.

The researchers did not observe nociceptive behavior (suggesting avoidance of pain) in mice with the K710N mutation injected with capsaicin and given peppery chicken feed, in contrast with the behavior of normal mice, which lifted their paws to avoid touching the capsaicin, presumably because even skin contact caused pain.

The mice with the K710N mutation also showed less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking the K710 region in normal mice limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels.

In addition to modulating pain, TRPV1 also plays an important role in protection against other stimuli. For example, recent evidence suggests that it serves in non-neuronal cells as an intracellular molecular sensor that protects against glucose-induced cellular stress or tissue ischemia. Additional tests performed as part of this study involving cardiomyocytes (heart muscle cells) insulted with hydrogen peroxide, high levels of glucose and a cerebral ischemia model confirmed the protective effect even with the mutation.

Translational analysis

The second part of the study consisted of an attempt to reduce the receptor’s function pharmacologically. To this end, the researchers developed a peptide, V1-cal, which acted selectively on the K710 region. Mice treated with V1-cal and given capsaicin displayed less nociceptive behavior and diminished release of neuropeptides leading to neurogenic inflammation and edema without altering temperature. Lastly, chronic pain also improved considerably.

“We now want to add value to this study by validating the results under best-practice laboratory conditions [required by regulatory agencies], identify other small molecules besides the peptide that can more easily be synthesized, conduct preclinical trials and, if these are successful, begin a clinical trial,” Zambelli said.