Primary Cause of Type 1 Diabetes Mellitus
Type 1 diabetes is primarily caused by autoimmune destruction of pancreatic beta-cells, leading to absolute insulin deficiency. 1
Autoimmune Mechanism
The fundamental pathogenic process involves cellular-mediated autoimmune destruction of insulin-producing beta-cells in the pancreatic islets of Langerhans. 1 This autoimmune attack is characterized by:
- Presence of autoantibodies against beta-cell proteins including glutamic acid decarboxylase (GAD65), insulin, tyrosine phosphatases IA-2 and IA-2β, and zinc transporter protein (ZnT8). 1
- Detection of one or more autoantibodies in 85-90% of individuals when fasting hyperglycemia is initially detected. 1
- Progressive beta-cell destruction that ultimately results in little or no insulin secretion, manifested by low or undetectable plasma C-peptide levels. 1
Genetic Predisposition
The autoimmune process occurs in genetically susceptible individuals with strong HLA associations:
- HLA-DR/DQ genes provide the strongest genetic risk, with linkage to DQA, DQB, and DRB genes that can be either predisposing or protective. 1
- Multiple genetic predispositions exist beyond HLA genes, though these are less well-defined. 1
- Over 60 genes are linked to type 1 diabetes risk, most affecting immune system function. 2
Environmental Triggers
While autoimmunity is the predominant effector mechanism, environmental factors likely initiate the process:
- Environmental factors remain poorly defined but are believed to trigger disease in genetically susceptible individuals. 1
- Enteroviral infections have been suggested as potential triggers based on epidemiological studies. 3, 2
- The exact environmental causes that initiate beta-cell autoimmunity are still unknown. 2
Clinical Implications
The rate of beta-cell destruction varies considerably:
- Rapid destruction occurs mainly in infants and children, often presenting with diabetic ketoacidosis (DKA) as the first manifestation. 1
- Slow destruction occurs mainly in adults, who may retain sufficient beta-cell function to prevent DKA for many years (latent autoimmune diabetes in adults - LADA). 1
- Progressive insulin dependence eventually develops in all cases as beta-cell mass declines. 1
Idiopathic Type 1 Diabetes
A minority of type 1 diabetes cases have no identifiable autoimmune markers:
- No evidence of beta-cell autoimmunity is present in these rare cases, though patients still have permanent insulinopenia and DKA risk. 1
- Strongly inherited but not HLA-associated, more common in individuals of African or Asian ancestry. 1
- Unknown etiology distinguishes this form from immune-mediated type 1 diabetes. 1
Associated Autoimmune Conditions
Patients with type 1 diabetes have increased susceptibility to other autoimmune disorders:
- Common associations include Hashimoto thyroiditis, Graves disease, Addison disease, celiac disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. 1