What causes glucose in urine apart from diabetes?

Non-Diabetic Causes of Glucosuria

Glucose in the urine without diabetes most commonly results from renal glycosuria (a benign inherited tubular defect), medications like SGLT2 inhibitors, pregnancy, or acute stress states—not from hyperglycemia exceeding the renal threshold.

Primary Renal Causes

Familial Renal Glycosuria

• This is the most important non-diabetic cause of persistent glucosuria. It results from a genetic defect in the sodium-glucose co-transporter 2 (SGLT2), encoded by the SLC5A2 gene, causing impaired glucose reabsorption in the proximal tubule despite normal blood glucose levels 1.
• Patients present with persistently high urine glucose levels in the complete absence of hyperglycemia, distinguishing this from diabetes 1.
• This condition is benign and requires no treatment, but must be recognized to avoid unnecessary diabetes workup 1.

Acquired Tubular Dysfunction

• Any condition affecting proximal tubular function can impair glucose reabsorption, leading to glucosuria at normal plasma glucose levels 2.
• The proximal tubule normally reabsorbs virtually all of the approximately 180g of glucose filtered daily by the kidneys 2, 3.

Medication-Induced Glucosuria

SGLT2 Inhibitors

• These diabetes medications intentionally block SGLT2 in the proximal tubule, reducing renal glucose reabsorptive capacity from ~450 g/day to ~80 g/day, causing therapeutic glucosuria even in non-diabetic ranges 2.
• SGLT2 inhibitors open the "safety valve" at a lower threshold, making glucosuria occur at near-normal glucose levels 2.

Physiologic States

Pregnancy

• Pregnancy can lower the renal threshold for glucose, causing glucosuria at normal or mildly elevated blood glucose levels 4.
• This occurs due to increased glomerular filtration rate and altered tubular glucose handling during pregnancy 4.

Stress and Acute Illness

• Acute stress states, infections, and critical illness can cause transient hyperglycemia through counter-regulatory hormone release (glucagon, catecholamines, cortisol, growth hormone), leading to glucosuria 5, 6.
• This stress-induced hyperglycemia may occur in individuals without underlying diabetes 5.

Chronic Kidney Disease Considerations

Advanced CKD Paradox

• In advanced CKD, patients may have increased renal glucose reabsorption despite hyperglycemia, resulting in less glucosuria than expected for a given plasma glucose level 7.
• Type 2 diabetes patients specifically show increased expression of SGLT2 and GLUT2 transporters, enhancing glucose reabsorption and raising the threshold for glucosuria 8, 3.
• This means glucosuria may be absent even with significant hyperglycemia in CKD patients 7.

Critical Diagnostic Approach

Essential First Steps

• Always check simultaneous blood glucose when glucosuria is detected to determine if hyperglycemia is present 5.
• If blood glucose is normal with persistent glucosuria, consider familial renal glycosuria and obtain genetic testing for SLC5A2 mutations 1.
• Review medication list for SGLT2 inhibitors or other drugs affecting renal glucose handling 2.

Common Pitfalls to Avoid

• Do not assume all glucosuria indicates diabetes—renal glycosuria is a benign condition that mimics diabetes on urine testing but has completely normal blood glucose 1.
• Do not rely on urine glucose alone for diabetes screening; blood glucose or HbA1c testing is mandatory 5.
• In CKD patients, absence of glucosuria does not exclude hyperglycemia due to enhanced tubular reabsorption 7, 8.

When Glucosuria Indicates Pathology

• Glucosuria with normal blood glucose warrants evaluation for tubular dysfunction or inherited disorders 1.
• Glucosuria with hyperglycemia requires assessment for diabetes, stress hyperglycemia, or medication effects 5, 3.
• New-onset glucosuria in pregnancy requires glucose tolerance testing to exclude gestational diabetes 4.