Define type 1 diabetes mellitus.

Definition of Type 1 Diabetes

Type 1 diabetes is an autoimmune disease characterized by absolute insulin deficiency resulting from immune-mediated destruction of pancreatic β-cells, requiring lifelong insulin therapy for survival. 1

Pathophysiology

• Type 1 diabetes results from cellular-mediated autoimmune destruction of pancreatic β-cells, leading to progressive loss of insulin production and eventual complete insulin deficiency 1
• The disease has strong HLA associations, particularly with DQA and DQB genes, with specific alleles being either predisposing (DR3-DQ2, DR4-DQ8) or protective (DRB11501, DQA10102-DQB1*0602) 1
• Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD65, insulin (IAA), IA-2, IA-2b, and ZnT8, with one or more present in 85-90% of individuals at diagnosis 1

Clinical Presentation

• The rate of β-cell destruction is highly variable—rapid in some individuals (particularly infants and children) and slow in others (mainly adults) 1
• Children and adolescents often present with diabetic ketoacidosis (DKA) as the first manifestation, with approximately 50% presenting this way 1
• Adults may retain sufficient β-cell function to prevent DKA for many years but eventually become insulin-dependent and remain at risk for ketoacidosis 1
• Classic presenting symptoms include polyuria, polydipsia, unintentional weight loss, and hyperglycemia, though adults may have more variable presentations 1, 2

Diagnostic Features

• Features most useful for identifying type 1 diabetes include younger age at diagnosis (<35 years), BMI <25 kg/m², unintentional weight loss, ketoacidosis, and glucose >360 mg/dL (20 mmol/L) at presentation 1
• At the time of clinical diagnosis (Stage 3), there is little or no insulin secretion, manifested by low or undetectable C-peptide levels (<200 pmol/L or <0.6 ng/mL) 1, 2
• The disease can occur at any age, even in the 8th and 9th decades of life, making the traditional "juvenile-onset" terminology inaccurate 1

Disease Staging

• Stage 1 is defined by the presence of two or more islet autoantibodies with normoglycemia and carries a 44% 5-year risk of developing symptomatic diabetes 1
• Stage 2 includes multiple islet autoantibodies with dysglycemia (impaired fasting glucose or glucose tolerance), with 60% risk by 2 years and 75% risk within 5 years of progressing to symptomatic disease 1
• Stage 3 represents clinical diabetes with overt hyperglycemia and symptoms, often with DKA in children and adolescents 1

Epidemiology and Classification

• Type 1 diabetes accounts for 5-10% of all diabetes cases and was previously called "insulin-dependent diabetes" or "juvenile-onset diabetes" 1
• The disease is distinct from type 2 diabetes, which results from progressive loss of β-cell insulin secretion on a background of insulin resistance rather than autoimmune destruction 1
• A small subset (5-10%) of type 1 diabetes is idiopathic (type 1B), with permanent insulinopenia and DKA risk but no evidence of β-cell autoimmunity 1, 2

Associated Conditions

• Patients with type 1 diabetes are prone to other autoimmune disorders including Hashimoto thyroiditis, Graves disease, Addison disease, celiac disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia 1

Key Clinical Pitfalls

• Classification at diagnosis is not always straightforward, and misdiagnosis is common—particularly adults with type 1 diabetes misdiagnosed as type 2 diabetes 1
• Obesity does not exclude type 1 diabetes, as the traditional paradigm of type 1 occurring only in lean individuals is outdated 1
• Occasionally patients with type 2 diabetes may present with DKA, particularly in ethnic and racial minorities, which can complicate classification 1
• Some adults may experience temporary remission from insulin requirements (the "honeymoon period") but will eventually require lifelong insulin therapy 1