What is the best course of action for a patient with asymptomatic hypoglycemia, normal C (connecting) peptide levels, and normal morning cortisol levels?

Management of Asymptomatic Hypoglycemia with Normal C-Peptide and Normal Morning Cortisol

For a patient with asymptomatic hypoglycemia, normal C-peptide, and normal morning cortisol, you should first confirm true hypoglycemia with documented blood glucose ≤70 mg/dL during symptoms (Whipple's triad), then conduct a systematic evaluation for exogenous causes (medications, alcohol, surreptitious insulin use) and non-insulin-mediated hypoglycemia, as the normal C-peptide excludes endogenous hyperinsulinism. 1

Immediate Diagnostic Approach

Confirm True Hypoglycemia

• Document Whipple's triad: low blood glucose (≤70 mg/dL), symptoms of neuroglycopenia (even if mild or "asymptomatic"), and resolution with glucose normalization 1
• Obtain laboratory glucose measurement during symptomatic episodes, not just point-of-care testing, as this is essential to verify true hypoglycemia 1
• Critical caveat: Many patients labeled as "asymptomatic" actually have subtle neuroglycopenic symptoms they don't recognize—ask specifically about confusion, difficulty concentrating, weakness, or behavioral changes 1

Interpret the Normal C-Peptide

The normal C-peptide is your most important clue and excludes endogenous hyperinsulinism (insulinoma, insulin autoimmune syndrome, sulfonylurea use) 2:

• Normal C-peptide (<200 pmol/L) during documented hypoglycemia rules out insulin-mediated causes 2
• If C-peptide were elevated (≥200 pmol/L), you would need to measure insulin (≥6 microU/mL), proinsulin (≥5 pmol/L), beta-hydroxybutyrate (≤2.7 mmol/L), and screen for sulfonylureas 2
• The normal C-peptide pattern indicates non-ketotic hypoinsulinemia or ketotic hypoinsulinemia as the mechanism 1

Evaluate for Exogenous and Iatrogenic Causes

Medication review is paramount 3, 1:

• Screen for surreptitious insulin use (would show high insulin with LOW C-peptide, not normal) 2
• Check for sulfonylureas or meglitinides in plasma, even if patient denies use 2
• Assess alcohol consumption—alcohol inhibits hepatic glucose release and is a common cause of hypoglycemia in otherwise healthy individuals 4
• Review all medications including beta-blockers (which mask hypoglycemia symptoms), quinolones, pentamidine 1

Assess for Critical Illness and Organ Dysfunction

Normal morning cortisol does not exclude adrenal insufficiency under stress 5:

• A single morning cortisol is insufficient—consider ACTH stimulation testing if clinical suspicion exists 5
• Evaluate for hepatic failure (impaired gluconeogenesis), renal failure (impaired insulin clearance, reduced gluconeogenesis), or sepsis 6, 1
• Severely ill patients commonly develop hypoglycemia—if this is the context, further investigation is unnecessary unless another specific cause is suspected 1

Classification and Further Workup

Obtain Critical Blood Samples During Hypoglycemia

If hypoglycemia recurs and remains unexplained, obtain the following during a documented hypoglycemic episode 1, 2:

• Laboratory glucose (confirm <70 mg/dL)
• Insulin level
• C-peptide
• Proinsulin
• Beta-hydroxybutyrate
• Sulfonylurea screen
• Cortisol (to reassess adrenal function during stress)

Provocation Testing if Needed

• 72-hour supervised fast if fasting hypoglycemia is suspected but not yet documented 1
• Mixed-meal tolerance test if postprandial (reactive) hypoglycemia is suspected based on symptom timing 1

Management Strategy

If No Clear Cause Identified

Dietary modifications are first-line 4, 7:

• Small, frequent meals with complex carbohydrates and protein
• Avoid simple sugars that provoke reactive hypoglycemia
• Limit or eliminate alcohol 4

Patient Education and Monitoring

• Educate on recognizing early hypoglycemia symptoms (tremor, palpitations, sweating, confusion) 8, 4
• Prescribe glucose tablets or gel to carry at all times 8, 4
• Recommend medical identification indicating hypoglycemia risk 8
• Increased frequency of blood glucose monitoring is essential in patients with recurrent or unexplained hypoglycemia 6

When to Escalate Care

Any episode of severe hypoglycemia or recurrent episodes requires reevaluation of the management plan 8, 4:

• Consider admission for observation if hypoglycemia is unexplained, recurrent, or severe 8
• Arrange endocrinology consultation for persistent cases without identified cause 1

Common Pitfalls to Avoid

• Don't rely on point-of-care glucose meters alone—they can mislabel healthy individuals as hypoglycemic; always confirm with laboratory measurement 1
• Don't assume asymptomatic means benign—subtle neuroglycopenia may be present and dangerous (impaired driving, falls) 6
• Don't stop at a single normal cortisol—adrenal insufficiency may only manifest during metabolic stress 5
• Don't overlook insulin autoimmune syndrome (IAS)—if insulin levels are disproportionately high relative to C-peptide, measure insulin autoantibodies, though this typically presents with elevated C-peptide 9, 7
• Don't miss surreptitious insulin use—this would show high insulin with suppressed C-peptide, but factitious disorder patients may also inject small amounts intermittently 2