What are the causes of glycosuria with normal blood glucose and hemoglobin A1c (HbA1c) levels?

Causes of Glycosuria with Normal Blood Glucose and HbA1c

The most common cause of glycosuria with normal blood glucose and HbA1c levels is renal glycosuria, a benign condition resulting from a reduced renal threshold for glucose reabsorption in the kidneys. 1

Primary Causes

1. Renal Glycosuria

• Results from defects in the sodium-glucose cotransporters (SGLT) in the proximal renal tubules
• Characterized by persistent glycosuria despite normal blood glucose levels
• May be caused by:
  • Genetic mutations in SGLT2 transporters 2
  • Familial renal glycosuria (inherited in autosomal dominant pattern)
  • Acquired tubular dysfunction

2. Pregnancy-Related

• Lower renal threshold for glucose during pregnancy
• Second and third trimesters commonly associated with glycosuria
• A1C is also less reliable during pregnancy 3

3. Fanconi Syndrome

• Generalized proximal tubular dysfunction
• Features include:
  • Glycosuria
  • Phosphaturia
  • Aminoaciduria
  • Bicarbonaturia
  • Normal blood glucose levels

Secondary Causes

1. Medications

• Drugs that affect renal glucose handling:
  • SGLT2 inhibitors (mimic renal glycosuria)
  • Some antibiotics (especially some anti-tuberculosis medications) 4
  • Certain antihypertensives

2. Hemoglobinopathies and Red Blood Cell Disorders

• These conditions may cause discordance between A1C and actual glycemic status:
  • Sickle cell trait/disease 3
  • Glucose-6-phosphate dehydrogenase deficiency 3
  • Hemolytic anemia 3
  • Iron deficiency anemia (falsely elevated A1C) 3

3. Increased Red Blood Cell Turnover

• Conditions that shorten red blood cell lifespan:
  • Recent blood transfusion
  • Erythropoietin therapy
  • Hemolysis
  • These can lead to falsely low A1C despite hyperglycemia 3

4. Ethnic/Racial Variations

• African Americans may have different A1C values for a given level of glycemia 3
• Certain genetic variants affect A1C independently of glucose levels:
  • HbS variant in African Americans can lower A1C by about 0.3% 3
  • X-linked glucose-6-phosphate dehydrogenase G202A can decrease A1C by 0.7-0.8% 3

5. Early-Stage Diabetes

• Early development of type 1 diabetes, especially in children
• Rapidly evolving diabetes may show glycosuria before significant elevation in A1C 3
• Patients with MODY (Maturity Onset Diabetes of the Young) may initially present with glycosuria and mild hyperglycemia 5

Diagnostic Approach

When glycosuria is detected with normal blood glucose and A1C:

1. Confirm findings with repeat testing
2. Perform oral glucose tolerance test with timed urine collections
3. Rule out other causes of tubular dysfunction
4. Consider genetic testing for SGLT2 mutations in appropriate cases
5. Monitor patients over time, as some may develop diabetes later 6, 5

Clinical Pitfalls

• Mistaking renal glycosuria for diabetes can lead to inappropriate treatment and dangerous hypoglycemia 1
• Not all glucosuria requires treatment; renal glycosuria is generally benign
• When A1C and glucose measurements are discordant, consider factors that may affect A1C reliability 3
• Sequential A1C values within 0.5% may not represent true changes in glycemic control due to laboratory variation 3
• Point-of-care A1C testing may introduce additional sources of error 3

Understanding these various causes of glycosuria with normal blood glucose and A1C is essential for proper diagnosis and to avoid unnecessary treatment that could lead to adverse outcomes.