What are the clinical markers of diabetes?

Clinical Markers of Diabetes

Diabetes is diagnosed using four equally valid laboratory criteria: fasting plasma glucose ≥126 mg/dL, 2-hour plasma glucose ≥200 mg/dL during oral glucose tolerance test, hemoglobin A1C ≥6.5%, or random plasma glucose ≥200 mg/dL in patients with classic hyperglycemic symptoms. 1

Primary Diagnostic Tests

Glucose-Based Criteria

• Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) confirms diabetes, with fasting defined as no caloric intake for at least 8 hours 1, 2
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-gram oral glucose tolerance test (OGTT) is diagnostic 1, 2
• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in patients presenting with classic symptoms of hyperglycemia (polyuria, polydipsia, unexplained weight loss) or hyperglycemic crisis confirms diabetes 1

Hemoglobin A1C Criteria

• A1C ≥6.5% (48 mmol/mol) is diagnostic when performed in a laboratory using a method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial (DCCT) assay 1
• A1C reflects average blood glucose levels over the preceding 2-3 months and offers greater convenience than glucose testing since fasting is not required 1
• A1C has superior preanalytical stability compared to glucose measurements, which are subject to glycolysis if not processed immediately 3

Confirmation Requirements

Unless there is unequivocal hyperglycemia with acute metabolic decompensation, diagnosis requires two abnormal test results from either the same sample or two separate samples. 1

• If using two separate samples, the second test (either repeat of the initial test or a different test) should be performed without delay 1
• For example, if A1C is 7.0% and repeat result is 6.8%, diabetes is confirmed 1
• If two different tests (such as A1C and FPG) are both above diagnostic thresholds when analyzed from the same sample, diabetes is confirmed 1
• In patients with classic symptoms and random glucose ≥200 mg/dL, a single test is sufficient for diagnosis 1

Type-Specific Markers

Type 1 Diabetes Autoimmune Markers

• Islet cell autoantibodies indicate autoimmune destruction of pancreatic β-cells 1
• Glutamic acid decarboxylase (GAD65) autoantibodies are present in immune-mediated diabetes 1
• Insulin autoantibodies (IAA) serve as markers of autoimmune β-cell destruction 1, 2
• Tyrosine phosphatase autoantibodies (IA-2 and IA-2β) indicate type 1 diabetes 1
• Zinc transporter 8 (ZnT8) autoantibodies are additional markers of autoimmune diabetes 1
• Stage 1 type 1 diabetes is defined by the presence of two or more autoantibodies with normoglycemia 1
• Low or undetectable C-peptide levels indicate little or no insulin secretion, characteristic of advanced type 1 diabetes 1, 2

Genetic Markers

• Strong HLA associations exist with linkage to DQB1 and DRB1 haplotypes 1
• Specific alleles can be predisposing (e.g., DRB10301-DQB10201 [DR3-DQ2] and DRB10401-DQB10302 [DR4-DQ8]) or protective (e.g., DRB11501 and DQA10102-DQB1*0602) 1

Critical Testing Considerations and Pitfalls

When A1C Should NOT Be Used

In conditions with altered red blood cell turnover, only plasma glucose criteria should be used for diagnosis. 1

• Hemoglobinopathies including sickle cell disease 1
• Pregnancy (second and third trimesters and postpartum period) 1
• Glucose-6-phosphate dehydrogenase deficiency 1
• HIV infection, particularly those treated with certain protease inhibitors and nucleoside reverse transcriptase inhibitors 1
• Hemodialysis 1
• Recent blood loss or transfusion 1
• Erythropoietin therapy 1
• Iron-deficient anemia 1

Hemoglobin Variant Interference

• Marked discordance between measured A1C and plasma glucose levels should prompt consideration of A1C assay interference due to hemoglobin variants 1
• African American individuals heterozygous for HbS may have A1C levels approximately 0.3% lower than those without the trait for any given level of mean glycemia 1
• An updated list of A1C assays with interferences is available at ngsp.org/interf.asp 1
• For individuals with hemoglobin variants but normal red blood cell turnover (such as sickle cell trait), use an A1C assay without interference from hemoglobin variants 1

Race and Ethnicity Considerations

• African Americans may have higher A1C levels than non-Hispanic Whites with similar fasting and postglucose load glucose levels 1
• Despite these differences, the association of A1C with risk for complications appears similar across racial groups 1

Pre-analytical Glucose Sample Handling

• Plasma should be separated immediately or samples should be kept on ice to prevent glycolysis, which causes falsely low glucose concentrations 3, 2
• For OGTT, adequate carbohydrate intake (at least 150 grams per day) should be ensured for 3 days prior to testing 1, 3

Prediabetes Markers

Prediabetes is identified by A1C 5.7-6.4%, fasting plasma glucose 100-125 mg/dL, or 2-hour OGTT glucose 140-199 mg/dL. 1, 3

• A1C between 5.7-6.4% (39-47 mmol/mol) indicates increased diabetes risk 1, 3
• Impaired fasting glucose (IFG): FPG 100-125 mg/dL (5.6-6.9 mmol/L), though WHO defines IFG cutoff at 110 mg/dL 1
• Impaired glucose tolerance (IGT): 2-hour plasma glucose 140-199 mg/dL (7.8-11.0 mmol/L) during 75-gram OGTT 1
• Risk is continuous across all three tests, extending below the lower limit and becoming disproportionately greater at the higher end 1
• Those with A1C 6.0-6.5% have a 5-year risk of developing diabetes between 25-50% 1

Point-of-Care Testing Limitations

• Point-of-care A1C assays may be used for assessment of glycemic stability in the clinic but must be FDA-approved and performed in CLIA-certified settings 1
• These settings require specified personnel requirements including documented annual competency assessments and participation in approved proficiency testing programs three times per year 1