Andrey Nailor, M.D.·Published 7 June 2010·11 min read
Key points
Insulin is produced by the beta cells in the pancreas.
Scientists have long suspected that genetics play a role in type 1 diabetes.
The immune system protects you from disease by killing germs and other foreign invaders.
Perhaps surprisingly, many scientists also suspect that viruses may cause type 1 diabetes.
Insulin is produced by the beta cells in the pancreas. In people with type 1 diabetes, the immune system mistakenly destroys these cells. The body responds to the beta cells as if they were foreign invaders. This is called an autoimmune response.
Autoimmune responses also occur in other diseases such as multiple sclerosis, lupus, and thyroid diseases such as hypothyroidism (Hashimoto's disease) and hyperthyroidism (Graves' disease). Researchers do not know exactly why this happens.
But for diabetes, researchers have found many factors that appear to be linked to type 1 diabetes. These include genetics, autoantibodies, viruses, cow's milk, and oxygen free radicals.
Genetics
Scientists have long suspected that genetics play a role in type 1 diabetes. If your mother or father had diabetes, for example, you are more likely to develop the disease than someone without a family history. Also, type 1 diabetes seems to be more common in certain racial groups. Caucasians, for example, are more likely to develop the disease than are people from other racial backgrounds. Type 1 diabetes occurs in less than 1 of 100,000 people in Shanghai, China, but occurs in more than 35 of 100,000 people in Finland.
Everyone is born with a set of instructions that tells the cells in your body how to grow, live, and function. These instructions lie in the particular chemical sequence of units known as bases, which make up the DNA in every cell in your body. Each cell in your body contains 46 chromosomes, which are made up of DNA and protein. Each DNA strand is like a long string that contains millions of bases. Along the strand lie the genes, unique segments of DNA that tell your cells what kind of protein to make.
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But just as books sometimes contain typographical errors, so too does the sequence of DNA. If there is a mistake, or mutation, in the DNA within a gene, then a faulty protein may be made that can't do its job. Scientists are trying to determine how mistakes in specific genes cause diabetes. If mutated genes occur in germ cells-the eggs and sperm-then the DNA mutations can be passed on from generation to generation.
Researchers have identified several different genes that might make a person more likely to develop type 1 diabetes. However, they have not found one single gene that makes all people who inherit it develop the disease. Instead, it seems that there are several genes known as "diabetes susceptibility" genes.
One particular set of genes that may predispose a person to diabetes is responsible for a set of proteins known as the human leukocyte antigens, or HLAs. These genes code for certain proteins called antigens, which identify a person's own cells as "self." They tell the immune cells not to destroy the cells that are part of a person's body. Scientists believe that some HLAs incorrectly tag a person's own beta cells as "non-self." Then the immune cells, which normally destroy foreign invading cells, destroy these cells. This is called autoimmunity-an immune attack on a person's own cells. In type 1 diabetes, the beta cells of the pancreas are destroyed in an autoimmune attack, and the body can no longer make insulin. This destructive process occurs over many months or years.
Written and revised by
Andrey Nailor, M.D.
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Each person has many kinds of HLA genes, and thus there are many types of HLAs. Each person inherits one of each kind of HLA gene from each parent. One type of HLA gene, known as HLA-DR, is most strongly linked to type 1 diabetes. There are many variations of HLA-DR, but 95 percent of people with type 1 diabetes have the DR3 form, the DR4 form, or both.
This makes researchers suspect that having the DR3 and DR4 variants may make a person more likely to get type 1 diabetes.
However, this is not the whole answer, because 45 percent of people without type 1 diabetes have the DR3 or DR4 variants.
Also, variants of another HLA gene, known as HLA-DQ, may also play a role in type 1 diabetes.
Just because a person inherits a susceptible HLA variant doesn't mean that person will develop diabetes. Most people with DR3 or DR4 variants remain healthy. But if there is a family history of type 1 diabetes, then screening may help predict the risk of developing the disease. For example, brothers and sisters of a person with diabetes who have two of the same HLA-DR variants have a 15 percent chance of getting type 1 diabetes. But if they share only one variant, the risk is only 5 percent. If no variants are the same, the risk of developing type 1 diabetes is 1 percent or less.
The more we study how people get type 1 diabetes, the more we understand that the answers are not simple. No one event or characteristic seems to bring on diabetes. Researchers have identified several other gene clusters on different chromosomes in addition to these HLA variants that may also play a role in type 1 diabetes.
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Autoantibodies
The immune system protects you from disease by killing germs and other foreign invaders. It does this largely through the action of white blood cells, or lymphocytes. T lymphocytes, or T cells, can attack foreign cells directly. B lymphocytes, or B cells, produce special proteins called antibodies that recognize the shapes of molecules on the surface of specific invaders.
B cells sometimes manufacture antibodies that recognize a person's own cells. These self-recognizing antibodies are called autoantibodies. Autoantibodies are found in many people with autoimmune disorders, but three autoantibodies are especially common in people with type 1 diabetes. These antibodies recognize the following:
islet cells (beta cells are just one type of islet cell in the pancreas)
insulin
glutamic acid decarboxylase (GAD, or the 64K protein), a protein made by the beta cells in the pancreas
These three types of autoantibodies all seem to act as markers. Researchers believe that these antibodies contribute to the demise of the beta cells of the pancreas by identifying which cells are to be attacked. It is really the T cells that ultimately destroy the insulin-producing cells of the pancreas. Of people newly diagnosed with type 1 diabetes, 70 to 80 percent have antibodies to islet cells, 30 to 50 percent have antibodies to insulin, and 80 to 95 percent have antibodies to GAD.
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The antibodies may be present several years before diabetes is diagnosed. The islet cell antibodies disappear later on.
Because these antibodies are so common in people with type 1 diabetes and because they so often appear before the symptoms of diabetes appear, researchers are finding that they are useful in screening people for type 1 diabetes who are at high risk for the disease. Although the risk for developing diabetes may only be 1 to 10 percent for people with a parent or sibling with the disease, a much higher percentage of people who also have antibodies to islet cells develop type 1 diabetes within 5 years. And for many, having combinations of these antibodies and certain HLA genes results in an even higher risk.
Viruses
Perhaps surprisingly, many scientists also suspect that viruses may cause type 1 diabetes. This is because people who develop type 1 diabetes have often recently had a viral infection, and "epidemics" of type 1 diabetes often occur after viral epidemics.
Viruses, such as those that cause mumps and German measles and the Coxsackie family of viruses, which is related to the virus that causes polio, may play some role in causing type 1 diabetes.
A small region of the GAD molecule is almost identical to a region of a protein found in the virus known as Coxsackie B4.
The two similar protein regions probably have similar shapes and may be recognized by the same T cells. Thus, to a T cell hunting for foreign invaders, the GAD protein, which is part of the body, might look the same as the Coxsackie virus protein, which is part of an invading cell. After a viral infection by the Coxsackie virus, the T cell, bent on destroying the invading virus, might actually destroy the body's own beta cells that bear the GAD protein. This would destroy the cells that produce insulin and result in type 1 diabetes.
Other theories may also explain how a viral infection might lead to diabetes. Some researchers believe that when a virus infects a body, it might somehow change the structure of the antigens on the surface of the islet cells. If this occurs, then the altered antigen might appear to be foreign to the immune system, and a person's own insulin-producing islet cells might be destroyed.
Another well-known diabetes researcher has a different theory. He believes that diabetes is a relatively new disease caused by a slow-acting virus. Although such a virus has not been found, he holds that the virus causes the immune system to attack proteins in the pancreas. A drastic increase in the number of cases of type 1 diabetes occurred on the island of Sardinia, Italy, in the 1960s and in Finland in the 1970s, and he believes that such a slow-acting virus could be the culprit.
Cow's Milk
Although it seems unlikely, different kinds of food may play a role in the development of type 1 diabetes. For example, one group of researchers found a connection between being fed cow's milk early in life (before 3 or 4 months old) and type 1 diabetes. They showed that children newly diagnosed with type 1 diabetes have higher amounts of antibodies that recognize a specific protein in cow's milk. These autoantibodies appear to bind to a protein that sometimes appears on the surface of the insulin-producing beta cells in the pancreas after an illness. The researchers speculate that, after an illness, the transient protein may appear on the surface of beta cells. The immune response to the milk protein might be to then recognize the beta cell surface proteins and attack the beta cells, leading to a destruction of the insulin-producing cells of the pancreas and, thus, to type 1 diabetes.
However, other researchers have looked for but not found an increased risk of type 1 diabetes if cow's milk is given early in life and if breastfeeding is done for a short period. Cow's milk is only one kind of food that may play a role in the development of type 1 diabetes. Studies in diabetes-prone rats show that withholding wheat and soy helps delay or prevent diabetes.
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Oxygen Free Radicals
Oxygen free radicals, formed as a by-product of many chemical reactions in the body, wreak havoc wherever they go.
Normally, the body has ways of quenching free radicals. But smoke, air pollution, diet, and even genetics can contribute to the formation of excessive amounts of free radicals, which the body cannot always handle. Uncontrolled, the reactive molecules can destroy the body's own cells as well as bacteria.
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Oxygen free radicals contribute significantly to the aging process and to the development of several other diseases.
Researchers have implicated free radicals in the development of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, a degenerative neuromuscular disease.
Some researchers believe that oxygen free radicals may also contribute to type 1 diabetes. Islet cells have very low levels of the enzymes that break down free radicals. Thus, agents that increase free radical production could result in destruction of pancreatic cells. If this is true, then researchers may be able to develop drugs that block the formation of free radicals in the islet cells.
Chemicals and Drugs
Several chemicals have been shown to trigger diabetes. Pyriminil (Vacor), a poison used to kill rats, can trigger type 1 diabetes. Two prescription drugs, pentamidine, used to treat pneumonia, and L-asparaginase, an anticancer drug, can also cause type 1 diabetes. Other chemicals have been shown to cause diabetes in animals, but scientists don't know for sure whether they have the same effect in humans.
In summary, it is unlikely that either genetics or environmental factors alone cause diabetes. But it does appear that a person could start with a genetic susceptibility-the inheritance of a particular set of genes. If this person is then exposed to some environmental "triggering" factor, such as a virus or a chemical, then diabetes may develop. Although no one is destined to develop diabetes with certainty, a person's heredity may increase the odds.
Prevention of Type 1 Diabetes
By testing relatives of people with type 1 diabetes for autoantibodies, researchers can often predict who is likely to develop the disease. This could be especially useful as new therapies emerge, because they can be started before damage to the pancreas is too extensive. For example, it was thought that by identifying people who are likely to develop type 1 diabetes at an early stage, researchers might be able to treat them with insulin or drugs that suppress the immune system (anti-rejection medications) and thus prevent the T cells from destroying the beta cells in the pancreas. Recent studies do not support that this is possible at this time.
Some people with a high risk of getting type 1 diabetes have participated in studies to see whether immunosuppressants such as azathioprine or cyclosporine delay or prevent the onset of the disease. These studies suggest that azathioprine or cyclosporine can reduce the dose of insulin needed in people who have already developed type 1 diabetes, if the drug is started at the time the disease is diagnosed. Researchers have also been studying whether insulin can prevent type 1 diabetes.
In the Diabetes Prevention Trial (DPT), researchers found that giving insulin by injection or orally does not prevent type 1 diabetes in people at high risk.
Other therapies may also be tested as researchers learn more about the causes of type 1 diabetes. For example, if autoimmunity to GAD turns out to be a primary trigger of type 1 diabetes, it might be possible to develop a vaccine that would protect people from developing the disease.
-- Martha M. Funnell, MS, RN, CDE Michigan Diabetes Research and Training Center University of Michigan Medical School Ann Arbor, Michigan
Robert M. Anderson, EdD
Michigan Diabetes Research and Training Center University of Michigan Medical School Ann Arbor, Michigan
Shereen Arent, JD
National Director of Legal Advocacy American Diabetes Association
American Diabetes Association Complete Guide to Diabetes
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