HOW TO DIAGNOSE DIABETES MELLITUS AND DIFFERENTIATE BETWEEN TYPE 1 AND TYPE 2
Diagnostic Criteria for Diabetes Mellitus
Diagnose diabetes mellitus when any ONE of the following criteria is met: fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test, A1C ≥6.5%, or random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis. 1
Four Diagnostic Pathways:
Fasting Plasma Glucose (FPG): ≥126 mg/dL (7.0 mmol/L) after no caloric intake for at least 8 hours 1
2-Hour Plasma Glucose (2-h PG): ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT) 1
Hemoglobin A1C: ≥6.5% using a method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial (DCCT) assay 1
Random Plasma Glucose: ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms (polyuria, polydipsia, unexplained weight loss) or hyperglycemic crisis (diabetic ketoacidosis or hyperglycemic hyperosmolar state) 1
Confirmation Requirements:
- In the absence of unequivocal hyperglycemia (hyperglycemic crisis with classic symptoms), diagnosis requires confirmatory testing 1
- Obtain two abnormal results from the same sample or two separate test samples 1
- If using two different tests and both are above diagnostic thresholds, the diagnosis is confirmed 2
- If results are discordant from two different tests, repeat the test with results above the diagnostic threshold 2
- No confirmation is needed when a patient has classic symptoms of hyperglycemia or hyperglycemic crisis with random plasma glucose ≥200 mg/dL 2
Important A1C Testing Caveats:
Do NOT use A1C for diagnosis in conditions affecting red blood cell turnover: 1
- Hemoglobinopathies (sickle cell disease, thalassemia)
- Hemolytic anemias
- Pregnancy (second and third trimesters)
- Recent blood loss or transfusion
- Hemodialysis
- Erythropoietin therapy
In these conditions, use only plasma glucose criteria (FPG, 2-h PG, or random glucose). 1
- Marked discordance between measured A1C and plasma glucose levels should raise suspicion of hemoglobin variant interference with the assay 1
- Point-of-care A1C assays are not recommended for diagnostic purposes due to lack of mandated proficiency testing 1
Stepwise Approach to Differentiating Type 1 from Type 2 Diabetes
Classification of diabetes type is not always straightforward at presentation, and misdiagnosis occurs in up to 40% of adults with new type 1 diabetes who are misdiagnosed as having type 2 diabetes. 2 The diagnosis often becomes more obvious over time. 1
Step 1: Assess Clinical Presentation Features
Features Most Useful for Type 1 Diabetes: 1
- Younger age at diagnosis (<35 years)
- Lower BMI (<25 kg/m²)
- Unintentional weight loss
- Ketoacidosis at presentation
- Glucose >360 mg/dL (20 mmol/L) at presentation
- Classic symptoms: polyuria, polydipsia, rapid onset
- Approximately one-third to one-half present with diabetic ketoacidosis (DKA) 1
Features Suggesting Type 2 Diabetes: 1
- Increased BMI (≥25 kg/m²)
- Absence of weight loss
- Absence of ketoacidosis
- Less marked hyperglycemia at presentation
- Older age (though type 2 can occur in children and type 1 in adults) 1
- Non-White ethnicity
- Family history of type 2 diabetes
- Longer duration and milder severity of symptoms prior to presentation
- Features of metabolic syndrome (hypertension, dyslipidemia, central obesity) 1
Important caveat: Obesity does not preclude type 1 diabetes diagnosis, as obesity is increasingly common in the general population and may be a risk factor for type 1 diabetes. 1 Additionally, ethnic minorities with type 2 diabetes may occasionally present with DKA. 1
Step 2: Measure Islet Autoantibodies
Autoantibody testing helps distinguish type 1 from type 2 diabetes in ambiguous cases. 1
Testing Algorithm: 1
- Glutamic acid decarboxylase (GAD) antibodies should be the primary antibody measured 1
- If GAD is negative, follow with islet tyrosine phosphatase 2 (IA-2) and/or zinc transporter 8 (ZnT8) antibodies where available 1
- In individuals not yet treated with insulin, insulin autoantibodies may also be useful 1
Interpretation:
- Presence of two or more islet autoantibodies is an almost certain predictor of type 1 diabetes 1
- Multiple autoantibodies indicate autoimmune beta cell destruction characteristic of type 1 diabetes 1
- In individuals diagnosed at <35 years of age with no clinical features of type 2 diabetes or monogenic diabetes, a negative antibody result does not change the diagnosis of type 1 diabetes, since 5-10% of people with type 1 diabetes do not have detectable antibodies 1
Step 3: Measure C-Peptide (If Needed for Ambiguous Cases)
C-peptide measurements help distinguish type 1 from type 2 diabetes in ambiguous cases, such as individuals who have a type 2 phenotype but present in ketoacidosis. 1
When to Measure C-Peptide: 1
- Only indicated in people receiving insulin treatment
- Can help assess residual beta cell function
- Useful when antibody testing is negative or unavailable
Testing Protocol: 1
- A random sample (with concurrent glucose) within 5 hours of eating can replace a formal C-peptide stimulation test
- If result is >600 pmol/L (>1.8 ng/mL), the circumstances of testing do not matter—this suggests preserved beta cell function consistent with type 2 diabetes
- If result is <600 pmol/L (<1.8 ng/mL) and concurrent glucose is <4 mmol/L (<70 mg/dL) or the person may have been fasting, consider repeating the test
- Very low levels (e.g., <80 pmol/L [<0.24 ng/mL]) do not need to be repeated and indicate severe insulin deficiency consistent with type 1 diabetes
- Do not test C-peptide within 2 weeks of a hyperglycemic emergency 1
- C-peptide values 200-600 pmol/L (0.6-1.8 ng/mL) are usually consistent with type 1 diabetes or maturity-onset diabetes of the young (MODY) 1
Step 4: Consider Monogenic Diabetes in Specific Scenarios
Monogenic diabetes (such as MODY) is suggested by: 1
- A1C <58 mmol/mol (<7.5%) at diagnosis
- One parent with diabetes
- Specific features: renal cysts, partial lipodystrophy, maternally inherited deafness
- Severe insulin resistance in the absence of obesity
- Positive monogenic diabetes prediction model probability
If monogenic diabetes is suspected, genetic testing should be considered. 1
Step 5: Recognize Special Diabetes Types
Other specific types to consider: 1
- Latent autoimmune diabetes in adults (LADA): Phenotypically similar to type 2 diabetes but with autoantibodies present 1
- Drug- or chemical-induced diabetes: Glucocorticoids, HIV/AIDS treatment, post-organ transplantation medications 1
- Diseases of the exocrine pancreas: Cystic fibrosis, pancreatitis 1
- Idiopathic type 1 diabetes: Permanent insulinopenia and prone to DKA but no evidence of autoimmunity; more common in individuals of African or Asian ancestry 1
Practical Clinical Algorithm
For a newly diagnosed patient with diabetes:
Assess age, BMI, presentation severity, and symptoms 1
- Age <35, BMI <25, DKA, glucose >360 mg/dL → likely Type 1
- Age >35, BMI ≥25, no ketoacidosis, gradual onset → likely Type 2
If classification is unclear, measure GAD antibodies 1
- Positive → Type 1 diabetes
- Negative → Measure IA-2 and/or ZnT8 antibodies
If antibodies are negative or unavailable and patient is on insulin, measure C-peptide 1
- <80 pmol/L → Type 1 diabetes (severe insulin deficiency)
600 pmol/L → Type 2 diabetes (preserved beta cell function)
- 200-600 pmol/L → Consider Type 1 or MODY
If features suggest monogenic diabetes, consider genetic testing 1
Monitor clinical course over time—the diagnosis often becomes more obvious with disease progression 1