Type 1 Diabetes Mellitus Definition
Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic β-cells leading to absolute insulin deficiency, requiring lifelong insulin replacement therapy. 1
Core Pathophysiologic Features
T1DM results from cellular-mediated autoimmune destruction of insulin-producing β-cells in the pancreas, causing progressive insulin deficiency that ultimately becomes complete. 1 This autoimmune process is marked by the presence of islet autoantibodies targeting β-cell proteins, including:
- Glutamic acid decarboxylase (GAD65) antibodies 1
- Insulin autoantibodies (IAA) 1
- Islet antigen 2 (IA-2) and IA-2β antibodies 1
- Zinc transporter 8 (ZnT8) antibodies 1
The presence of one or more of these autoimmune markers defines T1DM, though autoantibodies may not be detectable in all patients and decrease with age. 1
Clinical Presentation Characteristics
T1DM typically presents in young, slim individuals with polyuria, polydipsia, and weight loss, with a propensity to ketoacidosis. 1 However, the disease can occur at any age, sometimes with slow progression. 1
Rate of β-Cell Destruction
The rate of β-cell destruction varies considerably:
- Rapid progression: Mainly in infants and children, often presenting with diabetic ketoacidosis (DKA) as the first manifestation 1
- Slow progression: Mainly in adults, who may retain sufficient β-cell function to prevent ketoacidosis for years before becoming insulin-dependent 1
Latent Autoimmune Diabetes in Adults (LADA)
In adults with slow progression (LADA), insulin dependence develops over several years rather than acutely. 1 These individuals have positive islet autoantibodies but initially may not require insulin therapy. 1
Staging Classification
The American Diabetes Association recognizes three stages of T1DM based on autoimmunity and glycemic status:
- Stage 1: Presence of two or more islet autoantibodies with normoglycemia; 5-year risk of symptomatic diabetes is 44% overall 1
- Stage 2: Multiple islet autoantibodies with dysglycemia; 60% risk by 2 years and 75% risk within 5 years of developing symptomatic diabetes 1
- Stage 3: Symptomatic hyperglycemia requiring insulin therapy 1
Genetic Associations
T1DM has strong HLA associations, particularly with DQB1 and DRB1 haplotypes. 1 Specific alleles can be:
- Predisposing: DRB10301-DQB10201 (DR3-DQ2) and DRB10401-DQB10302 (DR4-DQ8) 1
- Protective: DRB11501 and DQA10102-DQB1*0602 1
Key Distinguishing Features from Type 2 Diabetes
T1DM accounts for 5-10% of all diabetes cases and is fundamentally different from type 2 diabetes, which results from insulin resistance combined with β-cell dysfunction rather than autoimmune destruction. 1
Critical differentiating features include:
- Absolute insulin deficiency with low or undetectable C-peptide levels (<200 pmol/L) in established disease 2
- Presence of islet autoantibodies (absent in type 2 diabetes unless LADA) 2, 3
- Lean body habitus typically (BMI <25 kg/m²), though obesity does not exclude T1DM 2
- Younger age at onset typically, though can occur at any age 1, 2
Clinical Caveats
A diagnosis of T1DM does not preclude having features of type 2 diabetes, such as insulin resistance and obesity. 2, 3 Some patients may have features of both conditions, requiring treatment approaches addressing both insulin deficiency and insulin resistance. 2, 3
The distinction between T1DM and type 2 diabetes in obese adolescents can be particularly challenging, and autoantibody testing should be considered in obese children presenting with ketosis or ketoacidosis. 3