Raynaud’s syndrome can be a clue of something bigger going on or simply be a part of an individual’s unique qualities. Learn how to tell the difference here!
Mark Mattson is the current Chief of the Laboratory of Neurosciences at the National Institute on Aging. He is also a professor of Neuroscience at The Johns Hopkins University. Mattson is one of the foremost researchers in the area of cellular and molecular mechanisms underlying neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, and amyotrophic lateral sclerosis.
Johnny Ludvigsson, senior professor at Linköping University .CREDIT Anna Nilsen/Linköping University
A clinical study led by Linköping University and financed by pharmaceuticals company Diamyd Medical has investigated whether immunotherapy against type 1 diabetes can preserve the body’s own production of insulin. The results suggest that injection of a protein, GAD, into lymph nodes can be effective in a subgroup of individuals. The results have been published in Diabetes Care.
In type 1 diabetes, the body’s immune system attacks the cells that produce insulin. When the insulin-producing cells have disappeared, the body can no longer regulate blood sugar level, and a person with type 1 diabetes must take exogenous insulin for the rest of his or her life.
A highly topical question in research into type 1 diabetes is whether, and if so how, the attack of the immune system can be slowed or even completely stopped. One possible strategy is based on altering the immune defence by injecting a protein that the cells of the immune system react to, in a form of vaccination. One of the proteins against which the immune system often forms antibodies in type 1 diabetes is known as GAD65 (glutamic acid decarboxylase). Professor Johnny Ludvigsson at Linköping University has studied for many years the possibility of vaccinating people who have newly diagnosed type 1 diabetes with GAD. It is hoped that the immune system will become more tolerant against the body’s own GAD, and stop damaging the insulin-producing cells, such that the body can continue to form some insulin.
“Studies have shown that even an extremely small production of insulin in the body is highly beneficial for patient health. People with diabetes who produce a certain amount of insulin naturally do not develop low blood sugar levels, hypoglycaemia, so easily. They have also a lower risk of developing the life-threatening condition ketoacidosis, which can arise when the insulin level is low”, says Johnny Ludvigsson, senior professor in the Department of Biomedical and Clinical Sciences at Linköping University.
Johnny Ludvigsson has led DIAGNODE-2, a clinical phase 2 study in which researchers investigated the effect of GAD-alum (Diamyd) injections into the lymph nodes of 109 young people with recently diagnosed type 1 diabetes. The natural insulin production of the participants was measured at the start of the study and again after 15 months. Several other outcome measures were also followed, such as change in long-term blood sugar levels (HbA1c), and how much supplementary insulin the patients needed to take every day.
Previous studies of immunotherapy in diabetes have suggested that genetic factors play a role in how patients respond to the treatment. This led the researchers in DIAGNODE-2 to look at several variants of what are known as “HLA genes”. These genes code for proteins located on the surface of some cells. They function as holders of proteins, and expose them to immune system cells passing by. If the protein fragment exposed in this way comes from, for example, bacteria, the immune system should form antibodies against the foreign protein. However, the immune system sometimes reacts against the body’s own substances, and certain types of HLA are associated with an increased risk of type 1 diabetes. The HLA variant HLA-DR3-DQ2 exposes the GAD65 protein to cells of the immune system, and patients with this variant often form antibodies against GAD65 at an early stage of the disease. Around half of the participants in the study had the HLA-DR3-DQ2 variant.
For the complete patient group, there was no difference between treatment and placebo in the degree to which insulin production was preserved. GAD-alum did, however, have a positive effect for the subgroup of patients who had the DR3-DQ2 variant of HLA genes.
“The patients in the subgroup with the DR3-DQ2 type of HLA genes did not lose insulin production as quickly as the other patients. In contrast, we did not see any significant effect in the patients who did not have this HLA type”, says Johnny Ludvigsson.
No undesired effects that could be related to treatment with GAD-alum were seen during the study.
“Treatment with GAD-alum seems to be a promising, simple and safe way to preserve insulin production in around half of patients with type 1 diabetes, the ones who have the right type of HLA. This is why we are looking forward to carrying out larger studies, and we hope these will lead to a drug that can change the progress of type 1 diabetes”, says Johnny Ludvigsson.
The study has been financed by Diamyd Medical AB, the Swedish Child Diabetes Foundation, and the Swedish Diabetes Foundation. The pharmaceutical company Diamyd Medical was involved in planning and the collection of data. One of the authors, Ulf Hannelius, is employed by Diamyd Medical.
The study:
The 109 participants, aged between 12 and 24 years, had been diagnosed with type 1 diabetes within the preceding 6 months, and were allocated at random to one of two groups. One group received three injections of GAD-alum at intervals of 1 month and vitamin D in tablet form, while the other group (controls) received placebo. Neither the participants nor the researchers knew which patients received treatment with GAD-alum (the study was randomised and double-blind).
The article: “Intralymphatic glutamic acid decarboxylase with Vitamin D supplementation in recent onset Type 1 diabetes: a double-blind randomized placebo-controlled Phase IIb trial”, Johnny Ludvigsson, Zdenek Sumnik, Terezie Pelikanova, Lia Nattero Chavez, Elena Lundberg, Itxaso Rica, Maria A Martínez-Brocca, MariSol Ruiz de Adana, Jeanette Wahlberg, Anastasia Katsarou, Ragnar Hanas, Cristina Hernandez, Maria Clemente León, Ana Gómez-Gila, Marcus Lind, Marta Ferrer Lozano, Theo Sas, Ulf Samuelsson, Stepanka Pruhova, Fabricia Dietrich, Sara Puente Marin, Anders Nordlund, Ulf Hannelius and Rosaura Casas, (2021), Diabetes Care, published online on May 21 2021, doi: 10.2337/dc21-0318
Reducing glucose concentration enhances cell proliferation of muscle stem cells, suggesting that excess glucose impedes cell proliferation capacity. CREDIT Tokyo Metropolitan University
Researchers from Tokyo Metropolitan University have shown that skeletal muscle satellite cells, key players in muscle repair, proliferate better in low glucose environments. This is contrary to conventional wisdom that says mammalian cells fare better when there is more sugar to fuel their activities. Because ultra-low glucose environments do not allow other cell types to proliferate, the team could produce pure cultures of satellite cells, potentially a significant boost for biomedical research.
Healthy muscles are an important part of a healthy life. With the wear and tear of everyday use, our muscles continuously repair themselves to keep them in top condition. In recent years, scientists have begun to understand how muscle repair works at the cellular level. Skeletal muscle satellite cells have been found to be particularly important, a special type of stem cell that resides between the two layers of sheathing, the sarcolemma and basal lamina, that envelopes myofiber cells in individual muscle fibers. When myofiber cells get damaged, the satellite cells go into overdrive, multiplying and finally fusing with myofiber cells. This not only helps repair damage, but also maintains muscle mass. To understand how we lose muscles due to illness, inactivity, or age, getting to grips with the specific mechanisms involved is a key challenge for medical science.
A team of scientists from Tokyo Metropolitan University led by Assistant Professor Yasuro Furuichi, Associate Professor Yasuko Manabe and Professor Nobuharu L Fujii have been studying how skeletal muscle satellite cells multiply outside the body. Looking at cells multiplying in petri dishes in a growth medium, they noticed that higher levels of glucose had an adverse effect on the rate at which they grew. This is counterintuitive; glucose is considered to be essential for cellular growth. It is converted into ATP, the fuel that drives a lot of cellular activity. Yet, the team confirmed that lower glucose media led to a larger number of cells, with all the biochemical markers expected for greater degrees of cell proliferation.
They also confirmed that this doesn’t apply to all cells, something they successfully managed to use to their advantage. In experiments in high glucose media, cultures of satellite cells always ended up as a mixture, simply due to other cell types in the original sample also multiplying. By keeping the glucose levels low, they were able to create a situation where satellite cells could proliferate, but other cell types could not, giving a very pure culture of skeletal muscle satellite cells. This is a key prerequisite for studying these cells in a variety of settings, including regenerative medicine. So, was the amount of glucose in their original experiment somehow “just right”? The team added glucose oxidase, a glucose digesting enzyme, to get to even lower levels of glucose, and grew the satellite cells in this glucose-depleted medium. Shockingly, the cells seemed to fare just fine, and proliferated normally. The conclusion is that these particular stem cells seem to derive their energy from a completely different source. Work is ongoing to try to pin down what this is.
The team notes that the sugar levels used in previous experiments matched those found in diabetics. This might explain why loss of muscle mass is seen in diabetic patients, and may have significant implications for how we might keep our muscles healthier for longer.
Training babies’ brains and bodies might delay the onset of Rett syndrome, a devastating neurological disorder that affects about 1 in 10,000 girls worldwide.
In experiments with mice that replicate the genetic disorder, scientists discovered that intense behavioral training before symptoms develop staves off both memory loss and motor control decline. Compared to untrained mice, those trained early in life were up to five times better at performing tasks that tested their coordination or their ability to learn, Howard Hughes Medical Institute Investigator Huda Zoghbi and her colleagues report March 24, 2021, in the journal Nature.
Those data, from animals whose symptoms closely mimic the human disease, offers a clear rationale for genetically screening newborns for Rett syndrome, says Zoghbi, a physician and geneticist at Baylor College of Medicine who has been studying the disorder for more than 30 years.
Rett syndrome primarily affects girls, who are typically diagnosed around age three ¬- well after symptoms first appear. An earlier diagnosis could offer a window of opportunity for treatment, she says – potentially delaying disease progression in children, or even making them better able to benefit from future therapies. “We are losing precious time,” Zoghbi says. “If we could screen these girls and put them through training, maybe the time we gain prior to overt onset of symptoms will also create more opportunity for other treatments to work.”
A rapid decline
There are no effective treatments for Rett syndrome, and the unrelenting barrage of symptoms is grim. After developing normally for roughly the first one to two years of life, children progressively lose skills they’ve learned. By 18 months, kids may have trouble using their hands. By two years, their ability to balance deteriorates and language skills fade. When symptoms are full-blown, almost every part of the brain is affected. In severe cases, girls cannot talk, feed themselves, or even open their mouths. They can also experience seizures, teeth grinding, and difficulty breathing.
For parents watching their daughters regress, “it’s the most painful thing you can imagine,” Zoghbi says. Her journey with Rett syndrome began in 1983, after meeting two young patients who repetitively wrung their hands, a hallmark of the disorder. Zoghbi was convinced that Rett syndrome had a genetic root. In 1999, her team discovered that mutations in a gene on the X chromosome were to blame. A defective copy of the gene, called MECP2, disables about half the brain’s neurons, so that they function at only about 50-70% of their normal capacity, the team reported in 2011 and 2016.
Correcting MECP2 via gene therapy would be an ideal treatment, Zoghbi’s team writes, but delivering the right dose to the right neurons poses a challenge. Too much MECP2 can cause neurological problems, too. Scientists are currently pursuing a gene therapy candidate for Rett syndrome, though clinical trials have not yet begun.
Zoghbi’s team took an alternative approach. What if researchers could somehow prod those sluggish neurons into action? Using electrodes implanted in the brains of “Rett mice,” Zoghbi and her colleagues discovered that stimulating key neurons at the base of the brain activated hippocampal neurons and improved learning and memory, cranking neural activity back up to normal. The team reported the results of this deep brain stimulation in Nature in 2015. “That was really, really exciting,” Zoghbi says. “It gave us the idea that boosting the neurons’ activity could help them.”
Implanting electrodes into the brain isn’t ideal for children, though. For one thing, all brain regions are affected by Rett syndrome. So Zoghbi’s team tried to mimic the effects of deep brain stimulation with something non-invasive – intensive behavioral training.
“We thought it might work,” she says, “because both techniques are doing the same thing – stimulating neurons.”
Training time
The team trained Rett mice in two skills that wither in people with the disorder: coordination and learning ability. Instead of training only mice with symptoms, Zoghbi and colleagues tested an unconventional idea, too: They also trained mice before any symptoms had developed.
One type of training included a “rotarod” apparatus, a rolling log-like treadmill that requires mice to continuously walk to keep their balance. Twice a week, four times per day, researchers placed mice on the device for a five-minute session. Those trained early in life outperformed those trained later, and they stayed on the apparatus roughly five times longer than mice with no training.
The team saw something similar in a water maze test, where mice use pictures on the wall to learn where an underwater platform is hidden. Again, mice trained early performed better those trained after symptoms developed, the researchers found. “The results were really quite stunning,” Zoghbi says. “The difference is huge.” Training was task-specific: mice that received memory training did not make improvements in coordination, for example.
In lab experiments, the team traced improved performance to specific sets of neurons responsible for each training task. Under a microscope, those neurons actually looked different than those from late-trained mice, with more branches and connection points to other neurons. That difference suggests that intense early training physically changes the brain, in a way that counters the disease, Zoghbi says.
In fact, continued training of the animals even held off symptoms, her team discovered. These mice were symptom-free for up to four months longer than untrained mice. That’s a hefty chunk of time for the animals, which, like healthy mice, live about two years. Zoghbi thinks a clinical trial in humans is the next big step for this work. She imagines infant training could take many forms, including extra “tummy time” where babies lie on their stomachs to strengthen their core, or focused language training lessons to help the infants gain a few words.
Screening girls at birth could give doctors the heads-up they need to begin such training – and potentially buy these children some time before the disease begins to encroach. The MECP2 genetic test is widely available and covered by insurance, Zoghbi says.
The team’s findings warrant genetic screening of infant girls, agrees HHMI Investigator Nat Heintz, who was not involved in the research. Whether or not the work will translate to humans is still unknown, “but there are many reasons why it might,” he says. And the payoff could be considerable. Not only could early treatment delay symptoms, “it’s possible that training may have lasting benefits,” says Heintz, a neuroscientist at The Rockefeller University. “I think people are going to find this exciting.”
Even a delay of six months would be “absolutely worthwhile,” Zoghbi adds. “I’m hopeful that we have a path forward to make a difference in the lives of these individuals.”