Type 1 diabetes (T1D) is a chronic autoimmune condition where the body’s immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. This destruction leads to an absolute deficiency of insulin, a hormone necessary for regulating blood sugar levels. While the precise cause of T1D is not fully understood, a combination of genetic and environmental factors is thought to increase an individual’s risk.
Genetic Predisposition
Genetic factors play a substantial role in T1D risk, accounting for approximately 30% to 40% of cases. The Human Leukocyte Antigen (HLA) genes contribute about 50% of the overall genetic risk. These genes are involved in immune system function, presenting antigens to T cells.
Certain variants of HLA class II genes, particularly HLA-DR and HLA-DQ, significantly raise susceptibility. Specific combinations, such as HLA-DR3-DQ2 and HLA-DR4-DQ8, are strongly associated with a higher risk of developing T1D. Individuals heterozygous for both HLA-DR3-DQ2 and HLA-DR4-DQ8 have the highest risk, accounting for 30% to 50% of all childhood T1D cases.
T1D is not inherited in a simple Mendelian fashion; instead, a predisposition is passed down. Beyond the HLA region, many non-HLA genes have been identified as contributing to T1D risk. These genes often influence immune cell or pancreatic beta-cell functions.
Familial risk is also a consideration; having a first-degree relative (parent, sibling, or child) with T1D increases an individual’s risk. For offspring of mothers with T1D, the risk is about 1% to 4%, while for offspring of fathers with T1D, it ranges from 3% to 8%. If both parents have T1D, the risk can be as high as 30%. Siblings of individuals with T1D have a risk ranging from 3% to 8%, with monozygotic twins showing a risk as high as 33% to 50% over several years.
Environmental Triggers
Environmental factors interact with genetic predispositions, initiating the autoimmune process that leads to T1D. Viral infections are potential triggers, with evidence implicating enteroviruses as the most probable culprits. Coxsackie B viruses, a type of enterovirus, show strong associations with beta-cell autoimmunity.
Studies indicate that people with T1D are eight times more likely to have traces of an enterovirus infection. This association is even stronger in those with a genetic predisposition or a first-degree relative with T1D, where the likelihood of an enterovirus infection can be 29 times higher. Other viruses, including mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2, have also been investigated for their potential involvement.
Dietary factors have also been explored, though research remains ongoing and sometimes inconclusive. Early exposure to cow’s milk proteins was once a leading theory, with some studies suggesting a link between early cow’s milk consumption and increased T1D risk. However, major trials found that extensively hydrolyzed formula did not lower the risk of T1D compared to cow’s milk formulas.
Gluten, a protein found in cereals, is another dietary factor under investigation. Animal studies suggest a correlation between gluten intake and increased diabetes susceptibility, with gluten-free diets largely preventing diabetes in some models. However, human studies on the effect of gluten-free diets on autoantibody levels or beta-cell function have yielded mixed results. Vitamin D deficiency has also been linked to T1D risk, with some population studies suggesting that supplementation in early childhood may decrease incidence.
The “hygiene hypothesis” proposes that reduced exposure to diverse microbial agents in industrialized countries may contribute to the rising incidence of autoimmune diseases, including T1D. This theory suggests that a less diverse gut microbiome may be associated with a propensity for inappropriate immune responses against self-antigens. Constant exposure to environmental bacteria from birth onward might reduce the risk of T1D onset.
The Autoimmune Link
The autoimmune attack on insulin-producing beta cells is often indicated by specific autoantibodies in the blood. These autoantibodies can appear years before clinical symptoms manifest.
Common autoantibodies associated with T1D include islet cell autoantibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase (GAD65) autoantibodies, and insulinoma-associated antigen-2 (IA-2) autoantibodies. The presence of multiple autoantibodies, rather than just one, indicates a higher risk of developing T1D. For instance, the presence of two or more autoantibodies significantly increases the five-year risk of diabetes to 28.2% and 66.2%, respectively.
Individuals with other autoimmune diseases have a higher risk of developing T1D due to a shared underlying predisposition to autoimmunity. T1D is frequently associated with conditions such as autoimmune thyroid diseases (like Hashimoto’s thyroiditis and Graves’ disease), affecting 17% to 30% of T1D patients. Celiac disease is another common co-occurring condition, with a prevalence of approximately 8% in T1D patients.
Demographic Considerations
Type 1 diabetes can develop at any age, though it is often diagnosed in childhood or adolescence, typically between ages 4 to 6 and in early puberty (10 to 14 years). However, more than half of new T1D cases are now diagnosed in adults. This adult-onset form is sometimes referred to as Latent Autoimmune Diabetes in Adults (LADA), where the autoimmune process against insulin-producing cells progresses more slowly. Individuals with LADA are often initially misdiagnosed with Type 2 diabetes due to the slower onset and the pancreas still producing some insulin.
There are also notable ethnic and geographical variations in T1D incidence. Historically, the risk has been highest in populations of White European ancestry, particularly in Scandinavian countries like Finland and Sweden. However, the diversity of the T1D population is increasing, with rising incidence in minority populations.
Geographical patterns suggest the influence of environmental factors, with some studies indicating higher rates in rural areas during early childhood. The global incidence of T1D has been increasing, especially in children under the age of five, a trend that cannot be solely explained by genetic changes and points to a growing influence of environmental factors.