 Keith, a competitive cyclist from South Africa, developed type 2 diabetes at age 55, despite biking 150 miles (250 km) every week. Type 1 diabetesType 1 diabetes, formerly called juvenile diabetes, is an autoimmune disease where the body's own immune system destroys the insulin-producing beta cells in the pancreas. People with type 1 usually have certain autoantibodies that may appear years before the disease develops, even in utero. These autoantibodies are used as markers of the disease, but do not necessarily cause the beta cell destruction. Some people, in fact, have these autoantibodies but never develop diabetes (Narendran et al. 2005).A number of genes have been identified that are associated with the risk of developing type 1 diabetes. Some people, then, have a higher genetic risk than others, in other words, are more genetically susceptible. The genetic component of type 1 diabetes, however, is "neither sufficient nor necessary" (Vehik et al. 2008). That is, there is some environmental component to the disease: someone with high genetic risk might never develop it, while someone with low genetic risk might. More than 85% of the people who do develop type 1 diabetes do not have a parent or sibling with the disease (Larsson et al. 2004). (See the section at the bottom of this page for more on genetics). Type 1 has been divided into type 1A and type 1B, where type 1A has an autoimmune cause, and type 1B is "idiopathic" diabetes, that is, has no known cause. People diagnosed with type 1B show signs of type 1 but have no evidence of autoimmunity (American Diabetes Association, 2011). A surprisingly high percentage (16%) of children and young adults newly diagnosed with type 1 diabetes in a Colorado diabetes center test negative for the antibodies associated with the disease. The younger the diagnosis, the higher the chance of autoantibodies being positive. Those who tested negative for antibodies had a higher body mass index, and may have a non-immune form of diabetes (perhaps different from either type 1A or type 2) (Wang et al. 2010).
The diabetes spectrum: Type 1, type 2, and LADAI like the idea that diabetes is a spectrum of disease, with autoimmune type 1 in children on one end, and metabolic type 2 in adulthood on the other end.
Young people with type 1 are usually: sensitive to insulin, require insulin immediately, have certain susceptibility genes, and test positive for islet autoantibodies. Type 2, on the other hand, "tends to be defined by the absence of markers associated with type 1 diabetes" (Gale 2005a). Type 2 is generally associated with increased insulin resistance and often obesity, and also has some associated susceptibility genes (Grant et al. 2009).
While type 1 and type 2 diabetes are now classified as separate diseases, there is some overlap between them (Tuomi 2005). For example:
And, there is growing evidence that immune system abnormalities may play a role in type 2, not only type 1. While type 2 diabetes is not considered an autoimmune disease, 15-35% of type 2 patients diagnosed before age 45 test positive for antibodies to GAD, as do 7-9% of patients diagnosed at an older age (Tuomi 2005). (These antibodies are also a marker of type 1 diabetes; see the autoimmunity page for more information on the antibodies associated with type 1 diabetes). Researchers who have taken a closer look at youth diagnosed with type 2 have found that almost 10% of patients tested positive for autoantibodies (GAD and islet autoantibodies, also associated with type 1) (Klingensmith et al. 2010), and 21% of youth over age 10 tested positive to GAD autoantibodies (Dabelea et al. 2007). Interestingly, there is increasing evidence that islet cell autoimmunity plays a role in the development of type 2 diabetes. Some type 2 patients may even test negative for islet autoantibodies, but positive for islet reactive T cells-- these authors refer to this characteristic as "autoantibody negative autoimmune type 2" (Brooks-Worrell et al. 2010). LADA, Latent Autoimmune Diabetes in Adults, is defined by an adult age of onset, the presence of islet autoantibodies (another marker of type 1), and the lack of a need for insulin until at least 6 months after diagnosis. LADA (sometimes called "type 1.5 diabetes") may actually be the same as adult-onset type 1 diabetes-- the only difference is whether or not insulin is required at diagnosis, and that can depend on when and how the diagnosis is made, as well as who makes it (Fourlanos et al. 2005). These authors suggest that we use the term "autoimmune diabetes" instead of LADA, until we determine whether LADA is actually different than adult-onset type 1 or not. The World Health Organization considers LADA to be a slowly progressing form of type 1 diabetes (Grant et al. 2009), and some researchers propose that the term LADA be retired altogether (while acknowledging that the term helped "put the existence of autoimmune diabetes in adults on the scientific map" (Rolandsson and Palmer 2010). They also point out that considering LADA as a form of type 1 diabetes means that more adults than children are affected by autoimmune diabetes.
More and more children, meanwhile, have characteristics of both type 1 and 2 diabetes, including autoantibodies to beta cells, as well as signs of increased insulin resistance or obesity. Some call this "double" or "hybrid" diabetes (Pozzilli et al. 2007; Pozzilli et al. 2011). In fact, a large number of people with diabetes may have both type 1 and type 2 associated processes contributing to their diabetes (Tuomi 2005). Interestingly, one research group took another look at the diagnosis of children with diabetes (mostly type 1), after an average of 7 years. Fully 20% of the patients had a different diagnosis that what was originally given, after reevaluation. And, 10% of the children were determined to have both type 1 and type 2, a "mixed diabetes phenotype" (Lipton et al. 2011).
Some researchers have proposed that diabetes should be considered more as a continuum, since clinical characteristics change gradually from type 2 to LADA to type 1 (van Deutekom et al. 2008). Genetic background also seems to support this idea of a continuous spectrum of diabetes (Lin et al. 2008). People with a family history that includes both type 1 and type 2 probably have a more intermediate type of diabetes (Tuomi 2005). This would imply some genetic similarities, and indeed, while there are differences in the susceptibility genes found in type 1 versus type 2 diabetes, LADA may be at the "genetic intersection" of both (Grant et al. 2009). Other authors have described a "bidimensional spectrum" in diabetes. They analyzed US children diagnosed with diabetes, and tested their autoantibody levels and levels of insulin resistance. They found that 55% of the children could be classified as autoimmune and insulin sensitive (traditional type 1), and 16% as non-autoimmune and insulin resistant (traditional type 2). Almost 20% had autoimmunity and insulin resistance, signs of both type 1 and type 2, perhaps including those who are overweight with type 1. Then 10% were non-autoimmune but insulin sensitive, showing signs of neither type 1 or type 2, perhaps indicating a different type altogether (such as Maturity Onset Diabetes of the Young (MODY), or monogenic diabetes) (Dabelea et al. 2011).
The distinctions between type 1 and 2 are most clear when comparing the extreme ends of the diabetes spectrum: a young child diagnosed with diabetes whose body produces no or very little insulin, who requires insulin immediately to stay alive, who is sensitive to insulin, and who tests positive for islet cell autoantibodies (type 1); compared to an adult whose pancreas still produces insulin, who is insulin resistant, who never requires insulin treatment, and who tests negative for certain antibodies (type 2). Things get more fuzzy when dealing with those diagnosed as adults who may or may not require insulin either immediately or after a few years, may or may not test positive for various autoantibodies, and who have varying amounts of pancreatic beta cell function remaining. The onset of type 1 diabetes tends to be slower at an older age of diagnosis, and faster at a younger age.
A recent study looked at all new cases of diabetes diagnosed during a three year period in an area of Sweden, and tested people of all ages for GAD and/or islet cell antibodies (if positive, they were classified as type 1). It found that almost 60% of newly diagnosed type 1 patients were over age 40, with incidence peaks in ages 0-9 and 50-80. Among adults, 6.9% of people with diabetes had type 1, which is similar to or slightly lower than other studies have found (Thunander 2008). In the UK, about 10% of adults who had been thought to have type 2 diabetes had islet cell or GAD autoantibodies, implying that autoimmune diabetes may be more common than we think (Fourlanos et al. 2005). A percentage of people who were thought to have type 2 diabetes, then, might actually have a form of autoimmune diabetes.
Autoimmunity remains the main distinction between type 1 and type 2 diabetes, although even then there are limitations in measuring autoimmunity (Gale 2005a). There is good evidence that type 1 diabetes involves immune processes, although we are not really sure if these immune processes are a cause, preexisting condition, or result of the disease. Actually, both immune and non-immune processes may be involved in the development of type 1 diabetes, especially in adults. Also, immune processes may play a role in the development of type 2 diabetes (Gale 2006). Confused yet?
Gestational diabetesGestational diabetes develops during pregnancy, and disappears after the pregnancy ends. Yet women who have had gestational diabetes are at increased risk of developing either type 1 and type 2 diabetes later in life. One study found that about 10% of a group of Finnish women with gestational diabetes developed diabetes over the subsequent six years, and that nearly half of them developed type 1. While most of the women who later developed type 1 initially tested positive for autoantibodies (during pregnancy), two of the 23 women who were determined to have developed type 2 also tested positive for autoantibodies (Järvelä et al. 2006). Wucher et al. (2010) describe an "autoimmune gestational diabetes," where women with gestational diabetes have a high risk of developing type 1 diabetes. These women tend to have a low body mass index, and require insulin during pregnancy (although usually not afterwards for a time). According to these authors, 2-17% of pregnant women develop gestational diabetes, depending on the population studied. Perhaps 15-30% of these women have "pregestational" diabetes, that is, unrecognized type 2 diabetes. About 10% of women with gestational diabetes have "autoimmune gestational diabetes" and may go on to develop type 1. That is what happened to me. At the time, the doctors just looked at me as if I was some kind of anomaly; no one had ever heard of a patient developing type 1 after gestational diabetes. Other types of diabetesType 1, type 2, and gestational diabetes are the most common types of diabetes. Yet looking at the list provided by the American Diabetes Association, I count 48 other types of diabetes, plus "others." These include those that are drug or chemical induced, those caused by a genetic defect of the beta cells (such as MODY, Maturity Onset Diabetes of the Young), those caused by a genetic defect of insulin action, and more (American Diabetes Association, 2011). The classification of diabetes is more complicated than I had assumed, and distinguishing one from another can be difficult. Genes and EnvironmentA large amount of research has focused on identifying gene variants that affect the risk of a person developing diabetes, as well as other diseases. These Genome-Wide Association (GWA) studies have identified a large number of genetic variants associated with various diseases. Yet most variants so far yield only small changes in risk levels. Only 6% of type 2 diabetes can be explained by heritable factors, for example (Manolio et al. 2010). GWAS studies are showing that "the magnitude of genetic effects is uniformly very small" (Dermitzakis and Clark, 2009). Twin studies are also useful for looking at the role of genes. For type 1 diabetes, if one member of an identical twin pair has type 1, the majority of their twins do not develop the disease, although the younger the diagnosis, the higher the risk . To assess the role of genetics, however, most twin studies compare the rates of disease between identical versus non-identical twins. Twin studies of type 1 show that disease risk is higher among identical twins than non-identical twins, showing a role for genetic background (Hyttinen et al. 2003). For type 2, a study from Denmark has found that the risk of type 2 diabetes does not differ between identical and non-identical twins (Petersen et al. 2011). Note that the environment, including the prenatal environment, is shared by both twins, if they are raised together, except that they may be exposed to different environmental factors during life, e.g., one might get a virus but the other does not.
An interesting study adapted the techniques used in GWA studies, and instead conducted a pilot Environment-Wide Association study to consider 266 separate environmental factors with diabetes, using a large U.S. dataset. It found that the factors most associated with diabetes include the pesticide heptachlor epoxide, PCBs, and a form of vitamin E. Protective factors included beta carotenes. The size of the effects that these factors have on type 2 diabetes are comparable to the highest risk gene loci found in GWA studies. This study is only the first EWA study ever done; there have been at least 16 GWAS studies on type 2 diabetes alone. Future studies might benefit from combining GWA and EWA data and methodologies, to consider the combined effects of genes and environment (Patel et al. 2010). |