"Diabetes mellitus" of any type develops when the body cannot produce as much insulin as it needs, resulting in high blood glucose levels (Gale 2005). Diabetes used to be considered one disease. Then it was divided into two main types called "juvenile" and "adult onset." These were later renamed "insulin dependent diabetes mellitus (IDDM)" and "non-insulin dependent diabetes mellitus (NIDDM)." Now they are called "type 1" and "type 2." Complications from any type of diabetes may include neuropathy (nerve damage), retinopathy (eye damage), nephropathy (kidney damage), and premature death. These may occur even with good glucose control (Narendran et al. 2005). Taking insulin can treat the disease, but is not a cure.
While obesity increases the risk of developing type 2 diabetes, obesity alone cannot account for all cases of type 2 diabetes. A large U.S. study has found that of adults with diabetes, 80% were overweight, and 49% were obese. It is interesting to note, however, that 20% of the adults with diabetes in this study were not overweight or obese (Nguyen et al. 2011). A subset of the U.S. minority population with diabetes are actually lean and have rapid failure of the insulin-producing beta cells; it is not clear why (Coleman et al. 2014).
autoantibodies that may appear years before the disease develops, even in the womb. 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). (The immune cells that cause the beta cell destruction are thought to be largely T-cells (CD4+ and CD8+), although other immune cells may also play a role.)
Scientists have identified stages in the development of type 1 diabetes. Stage 1 is the presence of autoimmunity (two or more islet autoantibodies) with normal blood glucose levels. State 2 is autoimmunity with higher blood sugar (but before other symptoms appear), and Stage 3 is development of the disease with symptoms (Insel et al. 2015).
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. 2011).
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).
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 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. Research shows that it may be at the "genetic intersection" of type 1 and type 2 diabetes, since one of the genes linked to LADA is also linked to type 2 diabetes (Grant et al. 2010). Insulin secretion is also mid-way between type 1 and type 2 diabetes (Hernandez et al. 2015).
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.
A review of the literature on type 1 diabetes incidence in adults (age 15 and over) finds that the geographic incidence parallels that in children, but is higher in males than females. Overall, they found that incidence decreased after age 14 (that is, fewer were diagnosed at older ages, although as above, more adults than children could still be affected by the disease, as children do grow into adults. Usually.) (Diaz-Valencia et al. 2015).
New research from human pancreatic tissue shows that type 1 diabetes is complex, and that many factors may contribute to its development. They find that type 1 can look very different in different people; that even in one person's pancreas, parts may have functional beta cells while other parts don't; that beta cell dysfunction may be a cause of high blood sugar (not just beta cell death)-- in sum, that we have much to still learn (Pugliese et al. 2014). Interestingly, a significant number of people with type 1 still secrete a small amount of insulin-- even after having long-term diabetes-- especially if they were diagnosed in adulthood (Davis et al. 2014; Oram et al. 2014; Williams et al. 2016). A new marker has been found that helps distinguish type 1 diagnosed at early and later ages. Those diagnosed before age 7 have a more aggressive form of beta cell destruction, and those diagnosed after 13 have a less aggressive form (Leete et al. 2016).
Insulitis, which is inflammation of the islet cells of the pancreas, is thought to contribute to type 1 diabetes. Yet samples from the pancreatic tissue of people with diabetes have found that 28% of people with type 2 had insulitis, and 31% of those with type 1 (the authors therefore propose a new definition of insulitis, as it now does not distinguish between type 1 and type 2 diabetes) (Lundberg et al. 2017).
LADA, for example, is heterogeneous. Levels of various antibodies differ among individuals, and these antibodies come and go over time. Some who lost antibodies over time resembled type 2 patients-- although with lower beta cell function-- and some who gained antibodies more closely resembled people with "classic" type 1 (Sørgjerd et al. 2012).
The Network for Pancreatic Organ Donors with Diabetes (nPOD), a project that sends the pancreas tissue of people with diabetes (primarily type 1) who have died to researchers for examination, has found that the disease is highly heterogeneous (Kaddis et al. 2015).
People with type 1 diabetes have higher insulin resistance than those without diabetes, even in lean patients (e.g., Donga et al. 2013). A Colorado study found that insulin resistance was a significant feature in adults with type 1. This insulin resistance was not explained by body mass index, percentage fat, visceral fat, lipids/cholesterol, exercise, or high blood glucose (Bergman et al. 2012).
Curiously, in a study of Malaysian people, those with LADA had higher insulin resistance levels than antibody-negative adults with diabetes, despite a lower body mass index (Salem et al. 2014).
Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by extremely rapid onset and complete deficiency of insulin due to the destruction of pancreatic beta cells, more common in Asians. Autoimmunity may (or may not) play a role in fulimant type 1 diabetes, although this is under investigation (Wang et al. 2016). One study defines it as, "characterized by remarkably rapid and complete β-cell destruction. The established diagnostic criteria include the occurrence of diabetic ketosis soon after the onset of hyperglycemic symptoms, elevated plasma glucose with relatively low HbA1c at the first visit, and extremely low C-peptide." This study, however, describes a case where the patient recovered some beta cell function over time, taking a small amount of insulin. The authors point out that the disease is heterogeneous (Kaneko et al. 2017).
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).
A German study of children diagnosed with type 2 diabetes found that 15% tested positive for islet autoantibodies (Awa et al. 2013). A similar UK study found that 30% of children with type 2 tested positive for autoantibodies, while 26% of those with type 1 tested negative (Perchard et al. 2014). A U.S. study found that of 145 obese youth diagnosed with type 2 diabetes, 70 tested positive for autoantibodies-- that's 48% (Rivera-Vega et al. 2015).
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).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). In the UK, about 10% of adults who had been thought to have type 2 diabetes tested positive for islet cell or GAD autoantibodies (Fourlanos et al. 2005). The levels of antibodies vary by body mass index (BMI); certain antibodies are higher in those more obese, while others are lower (Buzzetti et al. 2015). A Czech study found 13% of people originally thought to have type 2 tested positive for GAD autoantibodies (Martinka et al. 2016). In non-European populations, the levels are lower; a study of adults with type 2 diabetes in India found that very few tested positive for autoantibodies, about 1.5% (Sachan et al. 2014). A percentage of people who were thought to have type 2 diabetes, then, might actually have a form of autoimmune 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).
In both adults and children, then, a percentage of people with type 2 diabetes show signs of autoimmunity. It may be that these people were simply misdiagnosed, and really have type 1 diabetes.
However, chronic inflammation (a sign of immune dysfunction), is also involved in type 2 diabetes, insulin resistance, and obesity. Some authors are questioning whether or not type 2 diabetes may also involve some sort of autoimmune response (Itariu and Stulnig, 2014;Velloso et al. 2013). Immune cells have been found in the islet cells of people with type 2 diabetes, showing islet inflammation likely plays a role in the beta cell failure found in type 2 diabetes (Westwell-Roper and Ehses, 2014).
There is 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. 2011). For example, certain inflammatory autoreactive T-cells are found in people with type 1 and type 2 diabetes (CD-4+ T-cells), while other autoreactive cells are only found in people with type 1 (CD-8+ T-cells) ( Sarikonda et al. 2014).
Other authors have found that additional autoantibodies are found in people with type 1 diabetes, and a small percentage (5%) of people with type 2. These are "IA-2ec autoantibodies," which are "autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2." I do not know what that means, but the authors suggest that, "islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed (Acevedo-Calado et al. 2017).
I like the idea that diabetes is a spectrum of disease, with type 1 on one end, and type 2 on the other.
While type 1 and type 2 diabetes are now classified as separate diseases, there is some overlap between them (Tuomi 2005). For example:
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).
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.
Clinicians tend to just use clinical features (like BMI) to distinguish type 1 from type 2, but this results in a high rate of misclassification (7-15%). A review finds that age of diagnosis and time to insulin were the best clinical characteristics to use (and not BMI) (Shields et al. 2015). I personally think these are not adequate and that other measurements should be used.
Autoimmunity remains the main distinction between type 1 and type 2 diabetes, although even then there are limitations in measuring autoimmunity (Gale 2005). 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 diabetes develops during pregnancy, and disappears after the pregnancy ends. Yet women who have had gestational diabetes are at increased risk of developing type 2 diabetes later in life.
Interestingly, some women (myself included), from populations around the world, develop type 1 diabetes following gestational diabetes (e.g., see Unnikrishnan et al. 2016). 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). There are apparently some genetic links between gestational diabetes and type 1 diabetes as well (Guo et al. 2016).
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.
There are also case reports of fulimant type 1 diabetes appearing during pregnancy (Farrant et al. 2016). MODY, Maturity Onset Diabetes of the Young, also known as monogenic diabetes), those caused by a genetic defect of insulin action, and more (American Diabetes Association, 2011). In fact, in a nation-wide screening of all Norwegian children with diabetes, fully 6.5% of those who were antibody-negative had MODY, which can sometimes be treated without insulin (Johansson et al. 2016). A UK study found that 2.5% of children with diabetes had monogenic diabetes (Shepherd et al. 2016).
The classification of diabetes is more complicated than I had assumed, and distinguishing one from another can be difficult.thyroid disease, celiac disease, autoimmune gastritis, and Addison's disease (Krzewska and Ben-Skowronek, 2016). Of patients with type 1 diabetes, perhaps 25% will have thyroid disease (the most common other autoimmune disease associated with type 1), around 7% will have celiac disease, up to 20% will have markers of pernicious anemia (associated with autoimmune gastritis), and about 2% will have markers of Addison's disease (Narendran et al. 2005). Having both type 1 diabetes and celiac disease leads to an increased risk of autoimmune thyroid disease (Kurien et al. 2015).
Autoimmune diseases may show up early, or late. One clinic screened patients for thyroid, celiac, and Addison's disease association antibodies when they were diagnosed with type 1, and found that one-third of new type 1s had autoantibodies for these other autoimmune diseases, already at diagnosis (although not necessarily the disease yet) (Triolo et al. 2011). A study looking at celiac disease in people with type 1 found that it tends to appear in people who have had long-standing type 1 (over 15 years duration). Curiously, celiac disease was more common in people with adult-onset type 1 than in those who had been diagnosed with type 1 during childhood (Tiberti et al. 2014).
There are two main categories of autoimmune diseases: systemic autoimmune diseases, that target multiple organs or tissues; and organ-specific autoimmune diseases, that target one organ (such as the pancreas in type 1 diabetes). Some researchers propose that many autoimmune diseases may share a common mechanism, especially organ-specific autoimmune diseases. Under this hypothesis, a single environmental factor may lead to the occurrence of different autoimmune diseases, frequently more than one, in a single individual. Also, different environmental factors might lead to a single type of autoimmune disease in individuals genetically susceptible to that disease (Sakaguchi 2004). Thus, the role that environmental exposures may play in other autoimmune diseases may be relevant for type 1 diabetes.
Various differing autoimmune diseases have also been found to have common susceptibility genes (e.g., see Maiti et al. 2010). Type 1 diabetes and celiac disease, for example, are both associated with some of the same susceptibility genes (Smyth et al. 2008).
The incidence of many immune disorders, including many other autoimmune diseases, is rising (Bach 2002). In Finland, for example, the increasing incidence of the autoimmune disease multiple sclerosis follows the same pattern as type 1 diabetes (Holmberg et al. 2013).
The role of environmental factors in various autoimmune diseases is a growing area of research. The current state of this research is summarized nicely for the public in this article, Questions Persist: Environmental Factors in Autoimmune Disease, published in the peer-reviewed journal, Environmental Health Perspectives (Schmidt 2011).
Metabolic syndrome (also known as syndrome X, or insulin resistance syndrome) is a cluster of medical conditions that increases the risk of developing cardiovascular disease (and sometimes diabetes). The WHO defines the syndrome as the presence of either diabetes, impaired fasting glucose or insulin resistance, AND, two of the following: high blood pressure, high "bad" cholesterol or triglyerides, central obesity, or microalbuminuria. (Different organizations have differing definitions; a standard definition has yet to be determined).
While type 2 diabetes is often associated with the metabolic syndrome, it is interesting that people with type 1 diabetes also have higher risk of the metabolic syndrome as well, even without the obesity. One study from Brazil found that 45% of the young women with type 1 diabetes they studied had the metabolic syndrome, despite the fact that none were obese (Momesso et al. 2011). This number, surprisingly, is consistent with other, larger studies. A Finnish study found in that 38% of men and 40% of women with type 1 diabetes also had the metabolic syndrome. These numbers are three times higher than those seen in Finns without diabetes, but lower than in people with type 2 diabetes (78-84%) (Thorn et al. 2005). An Australian study found that 15% of a group of people with type 1 diabetes had metabolic syndrome (McGill et al. 2008). These studies used different definitions of metabolic syndrome, and it remains to be determined whether this syndrome is really the same in people with different types of diabetes.
Various metabolic changes are seen in both humans and animals during the period leading up to type 1 diabetes. Together they involve increased insulin secretion and increased stress on the beta cells (Sysi-Aho et al. 2011).
Like diabetes incidence, metabolic syndrome incidence is increasing. In the U.S., incidence has increased over the past 20 years in adults, and especially in young women (Mozumdar and Liguori 2011).
A 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. 2009). GWAS studies are showing that "the magnitude of genetic effects is uniformly very small" (Dermitzakis and Clark, 2009).
Studies of twins 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).
To download or see a list of all the references cited on this page, as well as additional references on LADA, double diabetes, and other issues in diabetes classification, see the collection Classification and types of diabetes in PubMed.