What are the key differences between Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM)?

Differentiating Type 1 from Type 2 Diabetes Mellitus

The most reliable way to distinguish T1DM from T2DM is through islet autoantibody testing (GADA, IA-2A, IAA, ZnT8A), combined with C-peptide measurement and clinical assessment using the AABBCC approach (Age, Autoimmunity, Body habitus, Background, Control, Comorbidities). 1

Primary Laboratory Testing

Autoantibody Panel (First-Line Test)

• Test for multiple autoantibodies simultaneously: glutamic acid decarboxylase (GADA), insulinoma-associated antigen-2 (IA-2A), insulin autoantibodies (IAA), and zinc transporter 8 (ZnT8A) to maximize diagnostic accuracy 1
• Multiple positive autoantibodies strongly indicate T1DM or LADA, while negative antibodies suggest T2DM 1, 2
• Perform testing only in accredited laboratories with established quality control programs 1
• Critical caveat: 5-10% of true autoimmune diabetes cases are antibody-negative, so negative results in a lean, young adult with acute onset do not exclude T1DM 2

C-Peptide Measurement (Complementary Test)

• Measure fasting C-peptide when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L) for accurate results 1
• Interpretation: C-peptide <200 pmol/L (<0.6 ng/mL) indicates T1DM with significant beta-cell loss; 200-600 pmol/L (0.6-1.8 ng/mL) suggests LADA; >600 pmol/L (>1.8 ng/mL) indicates T2DM with preserved beta-cell function 2
• Lower C-peptide levels typically indicate T1DM, while higher levels suggest T2DM 1, 3

Clinical Differentiation Algorithm (AABBCC Approach)

Age at Presentation

• T1DM typically occurs in young, slim individuals but can occur at any age 4
• T2DM typically develops after middle age and comprises over 90% of adults with diabetes 4
• Consider autoantibody testing in adults <35 years at diagnosis with ambiguous features 2

Autoimmunity Markers

• Presence of autoantibodies to pancreatic beta-cell proteins (GAD, IA-2, insulin, ZnT8) indicates T1DM 4
• Autoantibodies may not be detectable in all patients and decrease with age 4, 1

Body Habitus

• T1DM: typically lean (BMI <25 kg/m²) with unintentional weight loss 4, 2
• T2DM: typically overweight/obese (BMI ≥85th percentile) with abdominal fat distribution 4

Background/Family History

• T2DM: strong family history of T2DM 4
• T1DM: more common in Caucasian individuals, with personal or family history of autoimmune diseases 4, 2

Control/Presentation

• T1DM: acute onset with polyuria, thirst, weight loss, propensity to ketosis/ketoacidosis 4
• T2DM: insidious onset, often asymptomatic or discovered incidentally 4
• T1DM: rapid progression to insulin dependence 2
• T2DM: substantial residual insulin secretory capacity at diagnosis (normal or elevated insulin and C-peptide) 4

Comorbidities

• T2DM: insulin resistance markers including polycystic ovarian syndrome, acanthosis nigricans, hypertension, dyslipidemia 4
• T1DM: absolute insulin deficiency progressing to complete beta-cell destruction 4

When to Order Autoantibody Testing

Mandatory Testing Scenarios 1, 2

• Adults presenting with age <35 years with ambiguous features
• Unintentional weight loss despite diabetes diagnosis
• Lean body habitus (BMI <25 kg/m²) at presentation
• Ketoacidosis or ketosis in an obese patient
• Rapid progression to insulin dependence despite initial non-insulin therapy
• Personal or family history of autoimmune diseases
• Obese children/adolescents presenting with ketosis or ketoacidosis 1

Pathophysiologic Distinctions

Type 1 Diabetes 4

• Autoimmune destruction of pancreatic beta-cells leading to absolute insulin deficiency
• T cell-mediated destruction with islet-targeting autoantibodies appearing months to years before symptom onset 5

Type 2 Diabetes 4

• Combination of insulin resistance and beta-cell failure
• Impaired first-phase insulin secretion causing post-prandial hyperglycemia in early stages
• Progressive deterioration of second-phase insulin response leading to fasting hyperglycemia

Important Clinical Pitfalls

Overlapping Features

• A diagnosis of T1DM does not preclude having features of T2DM (insulin resistance, obesity) 1
• Some patients have features of both conditions requiring treatment approaches for both 1
• 12% of patients clinically diagnosed with T2DM may have autoantibodies, and 37% of T1DM patients may have insulin resistance 6

LADA (Latent Autoimmune Diabetes in Adults)

• Slowly progressive autoimmune diabetes where insulin dependence develops over several years 4, 2
• Single positive autoantibody: 15% risk of insulin dependence within 10 years 2
• Two or more positive autoantibodies: 70% risk within 10 years, 44% risk at 5 years 2

Testing Limitations

• C-peptide measurement alone may not be clinically necessary in all cases, as response to therapy provides diagnostic information 1
• Insulin or proinsulin testing is not recommended for routine clinical care 1
• Autoantibody prevalence varies by race, affecting test interpretation 2