This article was first printed in the Special Health Report from Harvard Medical School "Diabetes: A Plan for Living." For more information or to order, please go to http://www.health.harvard.edu/D.)

Types of diabetes

The two main types of diabetes mellitus are designated type 1 and type 2. While the mechanisms that cause them differ, they’re both characterized by high blood glucose levels and, if left untreated, have similar long-term consequences. Gestational diabetes, which occurs during pregnancy, resembles type 2 diabetes. However, it usually disappears after the baby is delivered.

Type 1 diabetes

This type of diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is an autoimmune disease. That means the body’s immune system turns inexplicably against its own cells, destroying them as if they were foreign invaders.

The destruction of the insulin-producing beta cells begins when the T-lymphocytes of the immune system fail to recognize the beta cells as friendly and turn against them. Other immune system cells, the B-lymphocytes, are recruited and the destruction proceeds. One by-product of this destruction is the formation of autoantibodies, which are directed against specific components of the pancreatic beta cells. Autoantibodies that are frequently found in people with type 1 diabetes variously target the islet cells, insulin, and other beta cell proteins such as glutamic acid decarboxylase (GAD) and tyrosine phosphatase. The presence of these antibodies signals the ongoing destruction of the beta cells; they usually appear years before you notice any symptoms or are diagnosed with diabetes.

Eventually, total destruction of the beta cells leaves the body unable to produce insulin and metabolize nutrients properly. As a result, blood sugar levels rise and cells starve, even though they are bathed by glucose-rich blood. A person with type 1 diabetes must have daily insulin injections to survive.

Type 1 diabetes is sometimes referred to as juvenile diabetes because it usually develops in children and adolescents, most often around puberty. It’s the most common serious chronic disorder in children and adolescents. Type 1 can also develop in adulthood, although this is uncommon.

Type 1 diabetes is an inherited disease, so people with a family history of it are at greatest risk. For instance, if you have an identical twin with type 1, you have a 50% chance of getting it as well. If you have a sibling with the disorder, your risk of developing it is 5%–10%; that’s 10 times the rate of someone without a diabetic sibling. White people of northern European heritage are more prone to type 1 than members of other racial and ethnic groups.

What causes type 1 diabetes?

Scientists don’t know what triggers the autoimmune response, but they’ve uncovered several factors that appear to be involved.

Genes. People with type 1 diabetes and their nondiabetic family members are more likely to develop other autoimmune diseases such as thyroiditis, Addison’s disease (adrenal failure), and lupus. The primary gene associated with type 1 is found on chromosome 6 and involves human leukocyte antigens (HLAs). HLAs are proteins on cell surfaces that enable the body to distinguish its own cells from foreign intruders; in effect, they instruct the immune system not to attack the body’s own cells. In type 1 diabetes, an unknown abnormality associated with the HLAs may lead the immune system to mistakenly identify the beta cells as alien. As a result, the immune system attacks and obliterates these cells.

Everyone inherits HLA genes. Among people with type 1 diabetes, 95% have HLA-DR3, HLA-DR4, and a specific HLA-DQ-Beta. However, nearly half of all Americans without diabetes also carry HLA-DR3 and HLA-DR4 genes, so having them doesn’t necessarily mean you’ll have the condition. Studies have shown that the siblings of a person with type 1 who share two of the same HLA variants have a 15% chance of getting the disease, but when only one HLA variant is identical, the risk drops to 5%. Although testing for HLA type can indicate a higher risk for developing diabetes, it’s not conclusive and isn’t used in clinical practice.

Additional genes linked to diabetes susceptibility are located on chromosome 11, near genes coding for insulin and insulin-like growth factor. Genetics doesn’t tell the entire story, though. Other factors probably trigger the disease in people who are genetically vulnerable to developing type 1 diabetes.

The viral connection. Some scientists believe that certain viruses, such as the coxsackievirus or those that cause mumps and German measles, may activate type 1 diabetes. According to this theory, the viruses may resemble some component of the beta cell, leading the immune system, in resisting the viral invaders, to destroy beta cells as well. Others postulate that a viral infection may somehow alter the islet cells, leaving them vulnerable to autoimmune attack. Yet another opinion is that a slow-acting virus causes the disease.

Foods. Some studies have shown an association between drinking cow’s milk and eating wheat products early in life and the development of type 1 diabetes, because some children with type 1 diabetes have antibodies to a protein in cow’s milk or to gluten, a protein component of grains. But this needs further study. It’s still not clear whether children who have a higher risk of developing type 1 diabetes (because they have a diabetic sibling, for example) should avoid cow’s milk.

Type 2 diabetes

A combination of abnormalities is responsible for type 2 diabetes. The first is probably insulin resistance, a condition in which body cells become less responsive to insulin. Therefore, the body must secrete more insulin to maintain normal metabolism. Insulin resistance, which is very common, doesn’t cause type 2 diabetes by itself. The pancreas usually rallies to compensate for the resistance by pumping out more insulin. For most people with insulin resistance, blood sugar levels stay within a normal range. But for some, the insulin-producing cells eventually fail to keep up with the increased demand. Blood sugar levels rise, resulting in type 2 diabetes.

Essentially, type 2 diabetes is a problem of supply and demand. The pancreas supplies too little insulin to keep up with the increased demand that occurs with insulin resistance. For this reason, people with type 2 diabetes can be treated with therapies that decrease insulin demand, including diet, exercise, and drugs; with medications that increase insulin supply, such as sulfonylureas or meglitinides; or with insulin itself.

Who’s at risk?

While genes, aging, and medications can all cause insulin resistance, being overweight and failing to get enough exercise are major culprits. Of the approximately 1.3 million Americans who will develop type 2 diabetes this year, about 90% are overweight or obese. (People who are overweight have a body mass index, or BMI, of 25 or more; those who are obese have a BMI of 30 and above. See chart.) Exactly how weight contributes to insulin resistance is a puzzle waiting to be solved. Recent studies have suggested that fat cells are not merely passive storage sites. Fat cells produce fatty acids and secrete proteins such as leptin, resistin, and adiponectin, which interfere with the secretion and action of insulin in the body.

In addition to people who are overweight or sedentary, people over age 65 or who have a family history of type 2 diabetes are at particularly high risk. Recently, a growing number of children and adolescents have been diagnosed with it. Typically, such children are obese and have a family history of the disease. Women who develop diabetes during pregnancy also have a high risk. Gestational diabetes usually disappears after delivery, but as many as 50% of women who have this form of diabetes go on to develop permanent type 2 diabetes, often within 10 years of their pregnancy.

Race and ethnicity also play a crucial role: The disease is far more common among African Americans, Asian Americans, Hispanics, Pacific Islanders, and Native Americans than among whites. One tribe of Native Americans living in Arizona has the highest rate of type 2 diabetes in the world, with the illness affecting about 50% of their adults ages 30–64.

What causes type 2 diabetes?

Predominantly a disease of later life, type 2 diabetes generally develops after age 40. Blood sugar levels usually rise slowly and progressively over the years before they become high enough to be considered in the diabetic range.

Two conditions, impaired glucose tolerance and impaired fasting glucose, often precede type 2 diabetes, and for this reason are known collectively as pre-diabetes. In both types of pre-diabetes, blood sugar levels are above normal, but not high enough to be considered clinical diabetes. A conservative estimate is that more than 20 million U.S. adults have pre-diabetes and, therefore, are much more prone to developing type 2 diabetes. Like people with type 2 diabetes, those with pre-diabetes tend to be overweight, have high blood pressure and abnormal lipid levels, and have a higher risk for cardiovascular disease.

Type 2 diabetes and its underlying causes, insulin resistance and defective insulin secretion, probably have a genetic basis. But in most cases, environmental factors also play a major role. For example, before the 20th century, diabetes was virtually unknown to Native Americans. But as hunting or farming gave way to a sedentary lifestyle, higher-fat diets, and obesity, diabetes became rampant. People from many other cultures have had similar experiences after adopting “Western” habits. Thus, in people who are genetically susceptible, the influences of older age, increasing obesity, and a sedentary lifestyle all unmask the tendency to develop diabetes.

The distribution of body fat also seems to be particularly important. People who tend to store fat in their abdominal area rather than their hips — so-called central obesity — are more likely to become diabetic.

Prevention is possible

Fortunately it is possible to prevent the onset of type 2 diabetes through diet and exercise. This was shown conclusively through a landmark clinical trial, known as the Diabetes Prevention Program (DPP), which looked at 3,234 Americans who had impaired glucose tolerance and therefore were at risk for developing type 2 diabetes. The study found that people who lose 5%–7% of their weight and exercise about 30 minutes a day can reduce their risk by 58%. The same study found that the oral diabetes drug metformin (Glucophage) also lower risk, but less dramatically, by 31%.

Smaller studies in China, Finland, Europe, and Canada have shown that diet and exercise or treatment with the drug acarbose (Precose) can delay type 2 diabetes in at-risk people. However, the DPP, conducted at 27 centers nationwide, was the first major trial to demonstrate the effectiveness of lifestyle changes or drug intervention in a diverse group of overweight, high-risk people.

A new national multicenter trial, known as Look AHEAD (Action for Health in Diabetes) is now under way to determine whether the lifestyle changes that proved so effective in the DPP study can be maintained for a longer period and prevent heart attacks, strokes, and other types of cardiovascular disease in people who already have type 2 diabetes. The Look AHEAD study has enrolled 5,000 participants who will be followed for as long as 111/2 years. Results of the study will be available in the next decade.

Gestational diabetes

Gestational diabetes mellitus occurs in about 135,000 U.S. women each year, usually around weeks 24–28 of pregnancy. Hormones produced by the placenta that hinder the action of the mother’s insulin probably trigger it. This disorder can result in babies who are larger than normal, and it puts the woman and her baby at greater risk for complications at the time of delivery. Diet, insulin therapy, or glucose-lowering medications are often needed to help control blood sugar levels.

Other types of diabetes

Diseases or chemicals that damage or destroy the pancreas can also cause diabetes. Examples include pancreatitis, pancreatic cancer, and hemochromatosis, a disorder in which excessive amounts of iron accumulate in the pancreas and other organs.

Surgical removal of the pancreas, which is sometimes necessary to treat chronic pancreatitis or pancreatic cancer, causes a form of type 1 (insulin-deficient) diabetes. Some medications, such as corticosteroids, diuretics, beta blockers, or a new class of drugs called “atypical” or second-generation antipsychotics, originally developed to treat schizophrenia, can increase insulin resistance or decrease insulin secretion. Such drugs may thus precipitate type 2 diabetes in people who are susceptible.

Toxic substances known to cause beta cell destruction include the rat poison pyriminil (Vacor); pentamidine (Pentam), a drug used to treat a type of pneumonia associated with AIDS; and asparaginase (Elspar), a cancer drug. All can cause a form of insulin-deficient diabetes.