What is the appropriate diagnostic workup and initial treatment plan for an adult patient with suspected diabetes, including differentiation between type 1 and type 2 and first‑line medication choices?

Diagnostic Workup and Initial Treatment for Suspected Diabetes in Adults

For adults with suspected diabetes, confirm the diagnosis with fasting plasma glucose ≥126 mg/dL, HbA1c ≥6.5%, 2-hour OGTT ≥200 mg/dL, or random glucose ≥200 mg/dL with symptoms; then immediately test islet autoantibodies (GAD, IA-2, ZnT8) to distinguish type 1 from type 2, and initiate metformin for type 2 or insulin for type 1 diabetes. 1, 2, 3

Diagnostic Confirmation

Establish Hyperglycemia

• Fasting plasma glucose ≥126 mg/dL (after ≥8-hour fast) on two separate occasions confirms diabetes 2, 4
• HbA1c ≥6.5% using NGSP-certified, DCCT-standardized assay on two occasions 2, 3
• 2-hour plasma glucose ≥200 mg/dL during 75-g oral glucose tolerance test 2, 4
• Random plasma glucose ≥200 mg/dL with classic symptoms (polyuria, polydipsia, weight loss) requires only one test for diagnosis 1, 2, 4

Critical Pitfall

• Two abnormal test results are required unless the patient presents with classic hyperglycemic symptoms and random glucose ≥200 mg/dL—in that case, a single test suffices and you should not delay treatment 1

Differentiating Type 1 from Type 2 Diabetes

Step 1: Clinical Assessment Using AABBCC Framework

Evaluate these features systematically 1:

• Age: <35 years suggests type 1; >35 years suggests type 2 1, 5
• Autoimmunity: Personal or family history of autoimmune disease favors type 1 1
• Body habitus: BMI <25 kg/m² suggests type 1; BMI ≥25 kg/m² suggests type 2 1, 5
• Background: Family history of type 1 diabetes supports type 1 1
• Control: Rapid progression to insulin requirement despite non-insulin therapy suggests type 1 1
• Comorbidities: Metabolic syndrome features (hypertension, dyslipidemia) favor type 2 5

Step 2: Islet Autoantibody Testing

Order autoantibodies when clinical features overlap between type 1 and type 2 5:

• Start with GAD antibodies as the primary test—this is the most frequently positive marker 5
• If GAD is negative, proceed to IA-2 and ZnT8 antibodies where available 1, 5
• Add insulin autoantibodies (IAA) only in patients not yet treated with insulin 1, 5

Interpretation 2, 5:

• Positive autoantibodies = Type 1 diabetes confirmed
• Negative autoantibodies in patients <35 years with classic type 1 features = Still treat as type 1 (5-10% of type 1 patients are antibody-negative) 1, 5
• Negative autoantibodies in patients >35 years = Proceed to clinical decision based on phenotype 1, 5

Step 3: C-Peptide Testing (When Indicated)

Only measure C-peptide if the patient is already on insulin therapy and classification remains uncertain 1, 5:

• Obtain random (non-fasting) sample within 5 hours of eating with concurrent glucose 1, 5
• <200 pmol/L (<0.6 ng/mL) = Type 1 diabetes 1, 5
• 200-600 pmol/L (0.6-1.8 ng/mL) = Indeterminate 1, 5
• >600 pmol/L (>1.8 ng/mL) = Type 2 diabetes 1, 5

Special Considerations

• Do not test C-peptide within 2 weeks of DKA or hyperglycemic emergency 1
• Consider monogenic diabetes (MODY) if HbA1c <7.5% at diagnosis with one parent having diabetes 1, 5
• Ketoacidosis can occur in type 2 diabetes, particularly in obese patients and ethnic minorities—do not assume DKA equals type 1 1, 5

Initial Treatment Plan

Type 2 Diabetes: First-Line Therapy

Metformin is the cornerstone first-line medication for type 2 diabetes 3:

• Initiate metformin immediately upon diagnosis alongside lifestyle modifications 3
• Target HbA1c <7% to reduce microvascular complications (3.5% absolute risk reduction) and mortality (2.7-4.9% absolute risk reduction) over 20 years 3

Add GLP-1 receptor agonist or SGLT2 inhibitor early if 3:

• Established cardiovascular disease (12-26% cardiovascular risk reduction)
• Heart failure (18-25% risk reduction)
• Chronic kidney disease (24-39% kidney disease risk reduction)
• High cardiovascular risk (10-year risk >10%)

Type 1 Diabetes: Insulin Therapy

Initiate insulin immediately upon diagnosis of type 1 diabetes 1:

• Type 1 diabetes results from autoimmune β-cell destruction leading to absolute insulin deficiency 1
• Approximately half of children with type 1 diabetes present with DKA; adults may have more variable onset 1
• Do not delay insulin in antibody-positive patients or those with classic type 1 features 1, 5

Antibody-Negative Patients with Unclear Classification

For patients <35 years with type 1 phenotype but negative antibodies 5:

• Treat as type 1 diabetes with insulin therapy
• Monitor closely—51% of antibody-negative patients require insulin within 3 years 5

For patients >35 years with unclear phenotype 1, 5:

• Trial of non-insulin therapy may be appropriate with careful monitoring
• Rapidly initiate insulin if glycemic deterioration occurs
• Consider C-peptide testing after >3 years if on insulin to reassess classification 1

Baseline Screening for Complications

At Diagnosis of Type 2 Diabetes

• Comprehensive dilated eye examination by ophthalmologist or optometrist 1
• Quantitative urine albumin excretion (annual screening thereafter) 1
• Fasting lipid profile (total cholesterol, HDL, LDL, triglycerides) 1
• Serum creatinine to calculate eGFR 1
• Comprehensive foot examination 1

At 5 Years After Diagnosis of Type 1 Diabetes

• Dilated eye examination within 5 years of onset 1
• Annual urine albumin excretion starting at 5 years duration 1

Cardiovascular Risk Reduction

Initiate statin therapy regardless of baseline lipid levels in patients with diabetes who are 1:

• Age ≥40 years with any additional cardiovascular risk factor
• Any age with established cardiovascular disease

Consider aspirin 75-162 mg/day for primary prevention in patients with 10-year cardiovascular risk >10% (most men >50 years or women >60 years with ≥1 additional risk factor) 1