What tests should be done for a patient experiencing morning hypoglycemia (low blood sugar) without a diagnosis of diabetes mellitus (DM)?

Diagnostic Workup for Morning Hypoglycemia in Non-Diabetic Patients

For a patient experiencing morning hypoglycemia without diabetes, the essential first step is to document Whipple's triad during a symptomatic episode: obtain simultaneous plasma glucose, insulin, C-peptide, pro-insulin, insulin antibodies, and screen for oral hypoglycemic agents when the patient is symptomatic with glucose <55 mg/dL. 1, 2

Initial Diagnostic Confirmation

The cornerstone of diagnosis requires fulfilling Whipple's triad during a symptomatic episode 1, 2:

• Low plasma glucose concentration (typically <55 mg/dL)
• Signs or symptoms consistent with hypoglycemia (neuroglycopenic symptoms like confusion, behavioral changes, or autonomic symptoms like sweating, palpitations)
• Resolution of symptoms when glucose is normalized

Critical point: Do not pursue extensive workup until you have biochemically confirmed hypoglycemia during symptoms—many patients self-diagnose hypoglycemia incorrectly, and studies show that symptoms often occur when glucose is normal 3.

Essential Laboratory Panel During Symptomatic Episode

When the patient experiences morning symptoms, obtain the following simultaneously 1, 2:

• Plasma glucose (must be <55 mg/dL to confirm true hypoglycemia)
• Serum insulin (elevated in endogenous hyperinsulinism)
• C-peptide (elevated with endogenous insulin production, suppressed with exogenous insulin)
• Pro-insulin (elevated in insulinoma)
• Insulin antibodies (positive in insulin autoimmune syndrome)
• Oral hypoglycemic agent screen (sulfonylureas, meglitinides)
• Beta-hydroxybutyrate (suppressed in insulin-mediated hypoglycemia)

Supervised Provocative Testing

If you cannot capture a spontaneous episode, proceed with supervised testing 1, 2:

72-Hour Supervised Fast

• This is the gold standard for diagnosing fasting hypoglycemia (which includes morning hypoglycemia) 1, 2
• Monitor plasma glucose every 4-6 hours initially, then hourly when glucose falls below 60 mg/dL 1
• Draw the complete hypoglycemic panel (insulin, C-peptide, pro-insulin, beta-hydroxybutyrate) when glucose drops below 55 mg/dL with symptoms 1, 2
• Most patients with insulinoma develop hypoglycemia within 48 hours 2

Mixed-Meal Test

• Consider this if symptoms occur specifically after evening meals (postprandial pattern extending into morning) 1
• Less useful for true fasting/morning hypoglycemia 1

Interpretation of Results

Endogenous Hyperinsulinism Pattern

If insulin ≥3 μU/mL, C-peptide ≥0.6 ng/mL, and pro-insulin elevated when glucose <55 mg/dL 2:

• Insulinoma: Order pancreatic imaging (CT or MRI with pancreatic protocol) 2
• Nesidioblastosis/Non-insulinoma pancreatogenous hypoglycemia: Consider if imaging negative 2
• Post-bariatric hypoglycemia: Relevant only if patient has history of gastric bypass surgery 1

Insulin Autoimmune Syndrome

If insulin antibodies positive with elevated insulin and C-peptide 2:

• Review medication history for drugs containing sulfhydryl groups
• This is more common in Asian populations 2

Exogenous Insulin/Sulfonylurea Use

If insulin elevated but C-peptide suppressed, or sulfonylurea screen positive 2:

• Consider factitious hypoglycemia or inadvertent medication exposure
• Insulin antibodies may be present with exogenous insulin use 2

Additional Evaluation for Non-Insulin-Mediated Causes

If insulin and C-peptide are appropriately suppressed during hypoglycemia 1, 2:

• Cortisol and ACTH (adrenal insufficiency)
• TSH and free T4 (hypothyroidism, though rarely causes hypoglycemia alone)
• IGF-II and IGF-I (non-islet cell tumor hypoglycemia from large mesenchymal tumors producing IGF-II)
• Comprehensive metabolic panel (hepatic or renal dysfunction)
• Medication review (quinolones, pentamidine, quinine)
• Alcohol use history (alcohol-induced hypoglycemia, especially with poor nutrition)

Common Pitfalls to Avoid

• Do not order a 5-hour oral glucose tolerance test—this is obsolete and generates false-positive results, as 10% of asymptomatic people have glucose nadirs ≤47 mg/dL during OGTT 3
• Do not rely on home glucose meter readings alone—confirm with laboratory plasma glucose, as meters can be inaccurate at low ranges 4
• Do not assume symptoms equal hypoglycemia—placebo testing shows patients often report "hypoglycemic symptoms" when glucose is normal 3
• Do not pursue extensive workup without first documenting Whipple's triad—this prevents unnecessary testing and misdiagnosis 1, 2

Clinical Context Considerations

Obtain detailed history regarding 1, 5:

• Timing: True fasting hypoglycemia (morning) versus postprandial (2-5 hours after meals)
• Medications: All prescription, over-the-counter, and herbal supplements
• Comorbidities: Chronic kidney disease, liver disease, heart failure, sepsis
• Recent illness: Critical illness is a common cause of hypoglycemia in hospitalized patients 5
• Alcohol intake: Particularly binge drinking with poor nutrition
• Weight loss or constitutional symptoms: Suggest possible malignancy causing non-islet cell tumor hypoglycemia

The key to diagnosis is capturing the biochemical profile during a documented symptomatic episode with confirmed low glucose—without this, you cannot definitively diagnose or exclude hypoglycemia. 1, 2, 3