Summarize the types of diabetes mellitus and the workup required for each type.

Types of Diabetes Mellitus and Required Workup

Diabetes mellitus comprises four main categories requiring distinct diagnostic approaches: Type 1 (autoimmune β-cell destruction), Type 2 (insulin resistance with progressive secretory defect), Gestational (pregnancy-onset), and specific types from other causes including monogenic forms. 1, 2, 3

Classification Overview

Type 1 Diabetes

• Pathophysiology: Autoimmune β-cell destruction leading to absolute insulin deficiency 1, 2
• Clinical presentation:
  • Children: Classic polyuria/polydipsia, ~33% present with DKA 1
  • Adults: More variable onset, may lack classic symptoms 4, 2
  • Can occur at any age despite traditional paradigms 4, 1

Required Workup:

• Autoantibody panel (essential for diagnosis):
  • GAD65 (glutamic acid decarboxylase)
  • IA-2 (tyrosine phosphatase)
  • ZnT8 (zinc transporter)
  • Insulin autoantibodies 3
• Glucose testing: FPG ≥126 mg/dL OR 2-h PG ≥200 mg/dL OR random PG ≥200 mg/dL with symptoms OR A1C ≥6.5% 3
• C-peptide: Assess residual β-cell function (typically low/absent)

Critical caveat: Antibody testing is underutilized in suspected Type 2 diabetes but overused in obvious Type 1 cases 5. Test when clinical diagnosis is ambiguous, particularly in adults presenting with diabetes.

Type 2 Diabetes

• Pathophysiology: Progressive insulin secretory defect on background of insulin resistance 1, 2
• Clinical presentation:
  • Often asymptomatic for years 3
  • Age >40, obesity, metabolic syndrome markers 5
  • Positive family history
  • Gradual symptom development
  • Can present with DKA (though uncommon) 4

Required Workup:

• Screening criteria (test if ANY present) 6:
  • Age ≥35 years (all individuals)
  • BMI ≥25 kg/m² (≥23 kg/m² in Asian ancestry) PLUS one risk factor:
    • First-degree relative with diabetes
    • High-risk ethnicity (African American, Latino, Native American, Asian American)
    • History of CVD
    • Hypertension (≥130/80 mmHg)
    • HDL <35 mg/dL or triglycerides >250 mg/dL
    • PCOS
    • Physical inactivity
    • Acanthosis nigricans, MASLD

Diagnostic tests (any of the following) 3, 6:

• FPG ≥126 mg/dL (after ≥8h fast)
• 2-h PG ≥200 mg/dL during 75g OGTT
• A1C ≥6.5% (NGSP-certified method)
• Random PG ≥200 mg/dL with symptoms

Confirmation: Requires two abnormal results from same or different samples on different days, UNLESS glucose ≥200 mg/dL with symptoms 3

Repeat screening: Minimum 3-year intervals if normal; annually if prediabetes 6

Gestational Diabetes Mellitus (GDM)

• Definition: Carbohydrate intolerance beginning or first recognized during pregnancy (2nd/3rd trimester), not clearly overt diabetes 1, 2
• Significance: ~70% develop diabetes long-term 7

Required Workup:

First prenatal visit (for high-risk patients) 3:

• Screen using standard diabetes criteria (FPG, 2-h PG, A1C)
• If meets diabetes criteria → diagnose as overt diabetes, not GDM

At 24-28 weeks gestation (all pregnant women) 3:

One-step approach:

• 75g OGTT (after ≥8h fast)
• Diagnose GDM if ≥1 value meets threshold:
  • FPG ≥92 mg/dL
  • 1-h PG ≥180 mg/dL
  • 2-h PG ≥153 mg/dL

Two-step approach:

• Step 1: 50g glucose challenge (non-fasting), 1-h PG threshold 130 or 140 mg/dL
• Step 2 (if positive): 100g OGTT, diagnose if ≥2 values meet:
  • FPG ≥95 mg/dL
  • 1-h ≥180 mg/dL
  • 2-h ≥155 mg/dL
  • 3-h ≥140 mg/dL

Postpartum: Test at least every 1-3 years 6

Specific Types/Monogenic Diabetes

• Causes: MODY, neonatal diabetes, cystic fibrosis, drug-induced (glucocorticoids, HIV treatment, post-transplant), pancreatitis 1, 2

Required Workup:

Consider monogenic diabetes when 3:

• Diabetes onset <6 months of age (autoimmune T1D rare before this)
• Atypical presentation/course/treatment response in children or young adults
• Strong family history across multiple generations
• Diabetes without typical autoimmune or metabolic features

Specific testing:

• Genetic testing: Identify specific mutations (HNF1A, HNF4A, GCK, HNF1B most common) 8
• Autoantibody panel: Should be negative (distinguishes from Type 1)
• C-peptide: Variable depending on specific mutation
• Standard glucose criteria: Same as above

Prediabetes Identification

Diagnostic criteria (any of the following) 3, 6:

• IFG: FPG 100-125 mg/dL
• IGT: 2-h PG 140-199 mg/dL during 75g OGTT
• A1C 5.7-6.4%

Important note: A1C should only be used for screening prediabetes; confirm diagnosis with glucose testing 3

Common Diagnostic Pitfalls

1. LADA (Latent Autoimmune Diabetes in Adults): Type 1 diabetes in adults often misdiagnosed as Type 2. Always check autoantibodies (especially GADA) when diagnosis unclear 5

2. A1C limitations 2:

   • Hemoglobin variants cause interference
   • Use glucose criteria if: hemoglobinopathy, recent blood loss/transfusion, erythropoietin therapy
   • X-linked G6PD variant (11% African Americans) lowers A1C by ~0.7-0.8%

3. OGTT preparation: Ensure adequate carbohydrate intake (≥150g/day) for 3 days prior 6

4. Discordant results: Substantial discordance between glucose and A1C requires additional follow-up to determine cause 2

5. Type 2 can present with DKA: Don't assume DKA = Type 1 4, 1