Scientists Reveal How Genetic Mutations May Cause Type 1 Diabetes! ! By Mika Ono! !

Scientists from The Scripps Research Institute have provided an answer to the 40-year-old mystery of how certain genetic mutations lead to Type 1 diabetes. This new molecular understanding could lead to novel therapies for Type 1 diabetes and other autoimmune diseases.! ! The study appears in the May print edition of the Journal of Clinical Investigation.! ! "People have been looking for the mechanism linking HLA and autoimmunity for 40 years," said Scripps Research Professor Luc Teyton, who led the study with Scripps Research Professor Ian Wilson. "This study provides a big leap forward in understanding and suggests a critical new target to intervene in type 1 diabetes."! ! Teyton notes that his lab has been trying to solve the mystery of autoimmune mechanisms and related conditions like celiac disease for some 25 years.! ! A Life-Threatening Condition! ! This new study focuses on Type 1, or insulin-dependent diabetes, a rapidly progressive disease of the young that leads to high blood sugar, coma, and death if not treated with replacement insulin.! ! Type 1 diabetes occurs when the body's immune system attacks insulinproducing " cells in the pancreas. Without insulin, the glucose in the bloodstream increases dramatically; early symptoms are unusual thirst, increased output of urine, fatigue, and unusual hunger accompanied by weight loss.! ! Currently, the only therapy available is to compensate for the destruction of the body's insulin-producing cells by injecting insulin on an ongoing basis.! !

While genes predispose people to many di#erent types of diseases in many di#erent ways, specic genetic variations are an especially strong predictor of the development of type 1 diabetes. Three genetic variations in particular (HLA-DQ2, HLA-DQ8, and HLA-DR0405)all located in the region of the genome called HLA for "human leukocyte antigen"are known to dramatically increase risk of coming down with the condition.! ! These three genes encode molecules that present peptides (protein fragments) to the body's T cells. T cells then determine whether the peptide being presented is dangerous and needs to be eliminated from the bodyas in the case of foreign invaders such as bacteria or viruses or whether the peptide is "self," part of the host and something the immune system needs to leave alone. However, in the context of type 1 diabetes, T cells aggressively attackbv the body's own cells.! ! The scientists wanted to know on a molecular level how mutations in the immune surveillance machinery could lead to type 1 diabetes.! ! ! ! A mutation of the gene SIRT1, involved in regulating metabolism and protecting against age-related disease, led to multiple cases of type 1 diabetes within one family. Results from the JDRF-funded study out of Switzerland were published today in Cell Metabolism.! ! Contact:! Tara Wilcox-Ghanoonparvar, 212-479-7524; twilcoxghanoonparvar@jdrf.org! ! New York, NY, March 5, 2013 A JDRF-funded study out of Switzerland has shown that a single gene called SIRT1 may be involved in the development of type 1 diabetes (T1D) and other autoimmune diseases. The study, Identication of a SIRT1 Mutation in a Family with Type 1 Diabetes, was published today in Cell Metabolism and represents the rst demonstration of a monogenetic defect leading to the onset of T1D.! ! The research began when Marc Donath, M.D., endocrinologist and researcher at the University Hospital Basel in Switzerland, discovered an

interesting pattern of autoimmune disease within the family of one of his patients, a 26-year-old male who had recently been diagnosed with T1D. The patient showed an uncommonly strong family history of T1D; his sister, father, and paternal cousin had also been diagnosed earlier in their lives. Additionally, another family member had developed ulcerative colitis, also an autoimmune disease.! ! This pattern of inheritance was indicative of dominant genetic mutation, and we therefore decided to attempt to identify it, Dr. Donath said.! ! Four years of analysis using three di#erent genotyping and sequencing techniques pointed to a mutation on the SIRT1 gene as the common indicator of autoimmune disease within the family. The SIRT1 gene plays a role in regulating metabolism and protecting against age-related disease. To gain more understanding of how this genetic change in SIRT1 leads to T1D, Dr. Donath and his team performed additional studies with animal models of T1D. When the mutant SIRT1 gene found in the families was expressed in beta cells, those beta cells generated more mediators that were destructive to them. Furthermore, knocking out the normal SIRT1 gene in mice resulted in their becoming more susceptible to diabetes with greatly increased islet destruction. Dr. Donath speculates that the beta cell impairment and death due to the SIRT1 mutation subsequently activates the immune system toward T1D.! ! The identication of a gene leading to type 1 diabetes could allow us to understand the mechanism responsible for the disease and may open up new treatment options, Dr. Donath explained.! ! Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF, concurred, and said that the development is exciting for many reasons: While the change in the genetic makeup within this family with type 1 diabetes is rare, the discovery of the role of the SIRT1 pathway in a#ecting beta cells could help scientists nd ways to enhance beta cell survival and function in more common forms of the disease. This study also reinforces increasing evidence that abnormal beta cell function has a role in the development of type 1 diabetes, and that blocking or reversing early stages of beta cell dysfunction may help prevent or signicantly delay the diseases onset. Drug companies are already in the process of

develo ping SIRT1 activators, which could eventually speed our ability to translate these new research ndings into meaningful therapies for patients.! ! JDRF is continuing to fund research by Dr. Donath that builds o# of these latest ndings.! ! ###! ! About JDRF! ! JDRF is the leading global organization focused on type 1 diabetes (T1D) research. Driven by passionate, grassroots volunteers connected to children, adolescents, and adults with this disease, JDRF is now the largest charitable supporter of T1D research. The goal of JDRF research is to improve the lives of all people a#ected by T1D by accelerating progress on the most promising opportunities for curing, better treating, and preventing T1D. JDRF collaborates with a wide spectrum of partners who share this goal.! ! Since its founding in 1970, JDRF has awarded more than $1.7 billion to diabetes research. Past JDRF e#orts have helped to signicantly advance the care of people with this disease, and have expanded the critical scientic understanding of T1D. JDRF will not rest until T1D is fully conquered. More than 80 percent of JDRFs expenditures directly support research and research-related education.! ! ! ! ! ! ! ! Diabetes is a complex group of diseases with a variety of causes. People with diabetes have high blood glucose, also called high blood sugar or hyperglycemia.!

Diabetes is a disorder of metabolismthe way the body uses digested food for energy. The digestive tract breaks down carbohydratessugars and starches found in many foodsinto glucose, a form of sugar that enters the bloodstream. With the help of the hormone insulin, cells throughout the body absorb glucose and use it for energy. Diabetes develops when the body doesnt make enough insulin or is not able to use insulin e#ectively, or both.! Insulin is made in the pancreas, an organ located behind the stomach. The pancreas contains clusters of cells called islets. Beta cells within the islets make insulin and release it into the blood.! ! Islets within the pancreas contain beta cells, ! which make insulin and release it into the blood.! ! If beta cells dont produce enough insulin, or the body doesnt respond to the insulin that is present, glucose builds up in the blood instead of being absorbed by cells in the body, leading to prediabetes or diabetes. Prediabetes is a condition in which blood glucose levels or A1C levels which reect average blood glucose levelsare higher than normal but not high enough to be diagnosed as diabetes. In diabetes, the bodys cells are starved of energy despite high blood glucose levels.! Over time, high blood glucose damages nerves and blood vessels, leading to complications such as heart disease, stroke, kidney disease, blindness, dental disease, and amputations. Other complications of diabetes may include increased susceptibility to other diseases, loss of mobility with aging, depression, and pregnancy problems. No one is certain what starts the processes that cause diabetes, but scientists believe genes and environmental factors interact to cause diabetes in most cases.! The two main types of diabetes are type 1 diabetes and type 2 diabetes. A third type, gestational diabetes, develops only during pregnancy. Other types of diabetes are caused by defects in specic genes, diseases of the pancreas, certain drugs or chemicals, infections, and other conditions. Some people show signs of both type 1 and type 2 diabetes.! [Top]! What causes type 1 diabetes?! Type 1 diabetes is caused by a lack of insulin due to the destruction of insulin-producing beta cells in the pancreas. In type 1 diabetesan

autoimmune diseasethe bodys immune system attacks and destroys the beta cells. Normally, the immune system protects the body from infection by identifying and destroying bacteria, viruses, and other potentially harmful foreign substances. But in autoimmune diseases, the immune system attacks the bodys own cells. In type 1 diabetes, beta cell destruction may take place over several years, but symptoms of the disease usually develop over a short period of time.! Type 1 diabetes typically occurs in children and young adults, though it can appear at any age. In the past, type 1 diabetes was called juvenile diabetes or insulin-dependent diabetes mellitus.! Latent autoimmune diabetes in adults (LADA) may be a slowly developing kind of type 1 diabetes. Diagnosis usually occurs after age 30. In LADA, as in type 1 diabetes, the bodys immune system destroys the beta cells. At the time of diagnosis, people with LADA may still produce their own insulin, but eventually most will need insulin shots or an insulin pump to control blood glucose levels.! Genetic Susceptibility! Heredity plays an important part in determining who is likely to develop type 1 diabetes. Genes are passed down from biological parent to child. Genes carry instructions for making proteins that are needed for the bodys cells to function. Many genes, as well as interactions among genes, are thought to inuence susceptibility to and protection from type 1 diabetes. The key genes may vary in di#erent population groups. Variations in genes that a#ect more than 1 percent of a population group are called gene variants.! Certain gene variants that carry instructions for making proteins called human leukocyte antigens (HLAs) on white blood cells are linked to the risk of developing type 1 diabetes. The proteins produced by HLA genes help determine whether the immune system recognizes a cell as part of the body or as foreign material. Some combinations of HLA gene variants predict that a person will be at higher risk for type 1 diabetes, while other combinations are protective or have no e#ect on risk.! While HLA genes are the major risk genes for type 1 diabetes, many additional risk genes or gene regions have been found. Not only can these genes help identify people at risk for type 1 diabetes, but they also provide important clues to help scientists better understand how the disease develops and identify potential targets for therapy and prevention.!

Genetic testing can show what types of HLA genes a person carries and can reveal other genes linked to diabetes. However, most genetic testing is done in a research setting and is not yet available to individuals. Scientists are studying how the results of genetic testing can be used to improve type 1 diabetes prevention or treatment.! Autoimmune Destruction of Beta Cells! In type 1 diabetes, white blood cells called T cells attack and destroy beta cells. The process begins well before diabetes symptoms appear and continues after diagnosis. Often, type 1 diabetes is not diagnosed until most beta cells have already been destroyed. At this point, a person needs daily insulin treatment to survive. Finding ways to modify or stop this autoimmune process and preserve beta cell function is a major focus of current scientic research.! Recent research suggests insulin itself may be a key trigger of the immune attack on beta cells. The immune systems of people who are susceptible to developing type 1 diabetes respond to insulin as if it were a foreign substance, or antigen. To combat antigens, the body makes proteins called antibodies. Antibodies to insulin and other proteins produced by beta cells are found in people with type 1 diabetes. Researchers test for these antibodies to help identify people at increased risk of developing the disease. Testing the types and levels of antibodies in the blood can help determine whether a person has type 1 diabetes, LADA, or another type of diabetes.! Environmental Factors! Environmental factors, such as foods, viruses, and toxins, may play a role in the development of type 1 diabetes, but the exact nature of their role has not been determined. Some theories suggest that environmental factors trigger the autoimmune destruction of beta cells in people with a genetic susceptibility to diabetes. Other theories suggest that environmental factors play an ongoing role in diabetes, even after diagnosis.! Viruses and infections. A virus cannot cause diabetes on its own, but people are sometimes diagnosed with type 1 diabetes during or after a viral infection, suggesting a link between the two. Also, the onset of type 1 diabetes occurs more frequently during the winter when viral infections are more common. Viruses possibly associated with type 1 diabetes include coxsackievirus B, cytomegalovirus, adenovirus, rubella, and mumps. Scientists have described several ways these viruses may

damage or destroy beta cells or possibly trigger an autoimmune response in susceptible people. For example, anti-islet antibodies have been found in patients with congenital rubella syndrome, and cytomegalovirus has been associated with signicant beta cell damage and acute pancreatitisinammation of the pancreas. Scientists are trying to identify a virus that can cause type 1 diabetes so that a vaccine might be developed to prevent the disease.! Infant feeding practices. Some studies have suggested that dietary factors may raise or lower the risk of developing type 1 diabetes. For example, breastfed infants and infants receiving vitamin D supplements may have a reduced risk of developing type 1 diabetes, while early exposure to cows milk and cereal proteins may increase risk. More research is needed to clarify how infant nutrition a#ects the risk for type 1 diabetes.! See the National Diabetes Information Clearinghouses (NDICs) fact sheet Diabetes Overview at www.diabetes.niddk.nih.gov for information about research studies related to type 1 diabetes.! ! ! ! ! ! Researchers have found evidence that a mutation in a single gene causes type 1 diabetes. This discovery may lead to better treatment and perhaps even prevention of diabetes. (Photo: Colourbox)! The highest prevalence of type 1 diabetes occurs in Northern Europe, particularly in Scandinavia.! ! There is still a great deal of uncertainty about the causes of type 1 diabetes (T1D), but now scientists have managed to shed new light on the disease.! ! They have discovered that a mutation in a certain gene may be essential for the development of T1D.! ! Scientists have known for years that type 1 diabetes has a strong genetic component. But this is probably the rst time that a mutation has been discovered in a single gene that causes type 1 diabetes, says

Professor Flemming Pociot, MD, a research group leader at Glostrup Hospital, Denmark, who took part in the international study.! ! Gene mutation discovered in Israeli family! How do scientists determine that gene mutations can cause a disease?! ! It is normally very di$cult to locate the right places in the genome as there are some 20,000 di#erent genes in the human body to go through.! ! For this reason, scientists often search for defective genes in families where many members are a#ected by the same disease. That way we can see whether the a#ected family members share any specic gene mutations, explains Pociot.! ! In the new study, the researchers examined an Israeli family in which four members su#ered from T1D. Having searched through the familys genome, they located a mutation in a gene known as SIRT1.! ! ! When researchers want to nd out whether gene mutations are the cause of a disease, they often search for defective genes in families where many members are a#ected by the same disease. That way we can see whether the a#ected family members share any specic gene mutations. (Photo: Colourbox)! This gene is incredibly interesting because other studies indicate that it could play a part in prolonging life, and that it can for instance prevent cancer and cardiovascular disease.! ! An autoimmune disease! In most T1D patients, the disease is autoimmune, i.e. the patients immune defence attacks the bodys own cells.! ! This was also the case with the Israeli patients, and it soon became clear that the defective sirtuin protein was partly responsible for these faults in the immune system.! ! We compared the cell behaviour in the patients to that of the healthy family members. It turned out that the patients were far more sensitive to

some of the factors we know are central in autoimmune diseases, says the researcher.! ! Protein kills healthy cells! They also carried out a series of experiments on mice to see if they could identify the detailed mechanisms behind the defective sirtuin protein.! ! They noted that the sirtuin proteins appeared to a#ect the so-called cytokines a type of protein that plays a key role in the regulation of the immune system.! ! The researchers theory is, simply stated, that the mutated sirtuin proteins cause the cytokines in the immune system to kill the wrong cells, including those that produce the bodys vital hormone insulin.! ! The lack of insulin, which helps regulate the blood sugar, is one of the hallmarks of T1D.! ! Facts! Type 1 diabetes is a chronic disease in which there are high levels of sugar in the blood.! Incidence of type 1 diabetes varies from 8 to 17 per 100,000 in Northern Europe and the US, with a high of about 35 per 100,000 in Scandinavia to a low of 1 per 100,000 in Japan and China.! Source: Wikipedia! We also carried out some mice trials, which helped conrm that sirtuin plays a part in diabetes. We gave the mice diabetes, and in some of them we knocked out the SIRT gene entirely, leaving the mice with no sirtuin protein, he explains.! ! Compared to the normal mice, these mice developed the disease much quicker and it was much severer too. This is another strong indication that its not good to lack sirtuin.! ! Could lead to prevention of diabetes! Professor Torben Hansen of the Steno Diabetes Center in Copenhagen also sees great potential in the new study:! !

When I look at the diabetes patients in our clinic, there are clear di#erences in their disease. So its great to see a study that explains these di#erences, and that gives us a better opportunity to advise them properly, he says.! ! Ultimately, this could lead to improved treatment and perhaps even prevention of diabetes when as we learn more about the genetics behind the individual patients disease.! ! ---------------------! ! Read the Danish version of this article at videnskab.dk! !