Summary of recent progress in the field of diabetes research (01.24)
January 24, 2018 Source: WuXi PharmaTech
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];1. The mechanism by which regulatory T cells protect pancreatic cells was discovered
Type 1 diabetes is an autoimmune disease in which the patient's own immune system attacks and destroys insulin-producing cells, causing blood sugar disorders. The incidence of type 1 diabetes has increased by about 4% annually in recent years, and type 1 diabetes is the most common metabolic disease among children and adolescents. Regulatory T cells (Tregs) play an important role in the development of type 1 diabetes: in healthy people, Tregs can suppress excessive immune responses and thus prevent autoimmune diseases. In patients with type 1 diabetes, Tregs failed to protect islet cells from the immune system. Now, a team led by Dr. Carolin Daniel, head of the Institute of Diabetes Research (IDF) at the Helmholtz Zentrum München Environmental Health Research Center in Germany, reveals the reason for this phenomenon because fewer isogenic Tres are produced during islet autoimmunity. The immune system is out of control and attacks on islet cells. The research paper was published in the Science issue of Science Translational Medicine.
▲ Dr. Carolin Daniel, Head of the Diabetes Research Institute (IDF), Environmental Health Research Center, Helmholtz Zentrum München, Germany (Source: IDF official website)
The results show that miRNA181a and NFAT5 molecules play a key role in the regulation of Tregs. During islet autoimmunity, miRNA181a can activate the transcription factor NFAT5, thus inhibiting the induction of Tregs, thereby increasing the immune activation effect. To test the potential of this discovery into a new therapy, researchers led by the first author of the paper, Ph.D. Isabelle Serr, experimented with preclinical models with early islet autoimmune properties. The results show that if the miRNA181a / NFAT5 signaling axis is inhibited, the activation of the immune system will be significantly reduced and the level of Tregs will increase. Furthermore, pharmacological inhibition of miRNA181a or NFAT5 can achieve this effect.
â–² Professor Anette-Gabriele Ziegler, Director of IDF (Source: IDF official website)
"Targeting inhibition of miRNA181a or NFAT5 has the potential to be a new treatment to reduce the aggressiveness of the immune system to its islet cells," said IDF Director Anette-Gabriele Ziegler. "Combination with other immunomodulatory therapies can also be used as type 1 diabetes. The intervention. "For this idea, the researchers hope to further test these new findings in preclinical trials, and they will use a humanized model to test the combination of insulin vaccine and miRNA181a/NFAT5 axis inhibitors, observed in this Under the treatment, the immune system will be more tolerant to the insulin-producing cells.
2. Can reverse diabetes in the short term! New progress in gene therapy
Type 1 diabetes occurs when the immune system erroneously destroys insulin-producing beta cells in the pancreas. Recently, scientists at the University of Pittsburgh Medical School announced that they have made significant progress in reversing diabetes. In a mouse model of type 1 diabetes, the researchers demonstrated a gene therapy that converts alpha cells in the pancreas into fully functional beta cells. The technology is published in the journal Cell Stem Cell.
The team used adeno-associated virus (AAV) vector technology to secrete the two proteins Pdx1 and MafA into the pancreas. These two proteins can reprogram alpha cells into cells that produce insulin. The mice that used this technique maintained normal blood glucose levels for about four months. One potential advantage of converting alpha cells to beta cells is that the alpha cells themselves are sufficiently visible that the immune system is unlikely to misidentify them as beta cells and attack them. The researchers compared gene expression patterns between normal beta cells and alpha cells transformed into insulin producers, confirming that these cells have completed "almost complete cell reprogramming."
â–² Dr. George Gittes, University of Pittsburgh (Source: University of Pittsburgh official website)
The study's lead author, Dr. George Gittes, said in a statement: "This study is the first to describe a single clinically convertible intervention in autoimmune diabetes that can bring blood sugar to normal levels." He also added This method does not inhibit the immune system, and suppressing the immune system is the main risk of autoimmune disease therapy. Dr. Gittes and his colleagues point out that they still need to do more research to determine whether the efficacy of this therapy can be successfully transferred from mice to humans. Currently, they are testing this therapy in primates. And plans to seek approval from the US FDA to conduct clinical trials in patients with type 1 or type 2 diabetes.
3. Large studies identify chromosome regions associated with type 1 diabetes
Type 1 diabetes is highly prevalent in children. In the United States under the age of 18, one in every 300 people has type 1 diabetes. The autoimmune effect of the immune system on beta cells in the pancreas is the cause of type 1 diabetes. Recently, a team of researchers working with multinational researchers identified a number of large-scale prospective studies in TEDDY (The Environmental Determinants of Diabetes in the Young) that are associated with pancreatic cell autoimmunity and type 1 diabetes. The chromosomal region, related papers published in the Journal of Autoimmunity.
The study, called TEDDY, is an international study that has tracked nearly 9,000 children for 15 years and observed how genetic and environmental factors interact to cause disease. The original goal of TEDDY was to determine which genetic variants are associated with progression of type 1 diabetes. Most of the genes known to be associated with type 1 diabetes are currently classified as human leukocyte antigen (HLA) genes. The HLA gene regulates our immune system. However, in order to better identify children at high risk of disease, the TEDDY study focused on relatively low-non-HLA genes. At the same time, the researchers also studied 176,586 single nucleotide polymorphisms (SNPs) using ImmunoChip technology. The SNPs studied by TEDDY are known to be associated with other autoimmune diseases such as rheumatoid arthritis or celiac disease, but the link to type 1 diabetes is not fully understood. The investigators identified which SNPs belonged to TEDDY participants with type 1 diabetes and who were undeveloped and compared.
The researchers found that three regions are involved in autoimmune of pancreatic cells, including two known regions (SH2B3: p = 3.58 × 10-7, PTPN22: p = 2.17 × 10-6) and a newly discovered region (PPIL2). :p= 9.64 × 10-7). Two known regions (PTPN22: p = 2.25 × 10-6, INS; p = 1.32 × 10-7) and a novel region (PXK/PDHB: p = 8.99 × 10-6) associated with multiple islet autoantibodies . The researchers also found that the chromosomal region associated with type 1 diabetes includes a known region (INS: p = 3.13 × 10-7) and three new regions (RNASET2, PLEKHA1 and PPIL2; 5.42 × 10-6 > p > 2.31 × 10-6). These results will lead to in-depth research into the genesis and risk-related genes of type 1 diabetes and lead to possible therapies and even preventive measures.
4. Peripheral neuropathy is expected to be cured
Peripheral neuropathy is a potentially disabling disease affecting up to 40 million Americans. Symptoms of the disease include severe pain or numbness in the hands and feet, balance disorders, burning or stinging sensations. Peripheral neuropathy caused by diabetes is one of the most common long-term complications of diabetes. Diabetes affects 28 million people in the United States, affecting more than 300 million people worldwide, with 50%-60% of patients suffering from peripheral neuropathy. At the same time, about 450,000 people in the United States suffer from peripheral neuropathy caused by cancer chemotherapy, and chemotherapy is the second leading cause of the disease. At present, there are only pain-relieving therapies, but due to insufficient understanding of the disease mechanism, stopping or reversing neurodegeneration, the treatment of radical neuropathy is progressing slowly. Recently, Dr. Sandra Rieger, a scientist at the MDI Biological Laboratory in Maine, USA, and his team found that an enzyme that acts on peripheral neuropathy caused by chemotherapy also plays a role in peripheral neuropathy caused by diabetes. The new findings have promoted awareness of the disease and are expected to promote drug development. Related papers are published in the journal Journal of Diabetes and Its Complications.
â–² Dr. Sandra Rieger, MDI Biological Laboratory Scientist, Maine, USA (Source: MDI Biological Laboratory Website)
In a previous study of peripheral neuropathy caused by chemotherapy, Dr. Rieger found that the development of peripheral neuropathy in zebrafish is associated with an increase in matrix metalloproteinase-13 (MMP-13). The tail of a zebrafish resembles the extremities of humans, and MMP-13 is an enzyme that breaks down the collagen between "bonding" skin cells. Dr. Rieger believes that enzyme-induced proteolysis leads to the degradation of nerve endings in the skin. This degradation of nerve endings affects information such as temperature, pain, and mechanical stimuli that are transmitted to the central nervous system and are responsible for the symptoms of peripheral neuropathy. In a recent study of glucose-induced peripheral neuropathy, Dr. Rieger found the same pathway. She also found that oxidative stress (ROS), which may cause tissue damage, plays a role in this process. ROS is also a hallmark of diabetes. Dr. Rieger found that ROS is responsible for the increased activity of MMP-13, and that inhibition of ROS with antioxidants can prevent MMP-13 activation and increased neurological damage.
In a previous study, Dr. Rieger discovered two compounds that prevent and reverse peripheral neuropathy caused by chemotherapy. The new study tested the effectiveness of these compounds in glucose-induced peripheral neuropathy and found that the compound is effective in both zebrafish and mice, suggesting that these compounds may play a role in humans, if clinical trials are available. Has the potential to cure peripheral neuropathy.
â–² Dr. Kevin Strange, Chairman of the MDI Biological Laboratory, Maine, USA (Source: MDI Biolab official website)
Dr. Kevin Strange, chairman of the MDI Biological Laboratory, said: "Peripheral neuropathy is a major and growing health problem. Identifying the mechanisms of glucose-induced peripheral neuropathy means that millions of patients may benefit from this pathway. The development of drugs."
Reference materials:
[1] Autoimmune reaction successfully halted in early stage islet autoimmunity
[2] Gene therapy restores normal blood glucose levels in mice with type 1 diabetes
[3] Genetic discovery may help better identify children at risk for type 1 diabetes
[4] MDI Biological Laboratory discovery could lead to new therapies for diabetics
Original Title: Summary of Recent Progress in Diabetes Research (No. 48)
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