Workup for Hypoglycemia in Non-Diabetic Individuals
The recommended workup for hypoglycemia in non-diabetic individuals should first establish Whipple's triad (symptoms consistent with hypoglycemia, low plasma glucose, and resolution of symptoms with glucose administration) before proceeding with a systematic evaluation to determine the underlying cause 1.
Initial Assessment
Document Whipple's Triad
- Confirm hypoglycemia exists by documenting:
- Symptoms consistent with hypoglycemia (neuroglycopenic or adrenergic)
- Measured low blood glucose (<70 mg/dL)
- Resolution of symptoms when blood glucose is raised
Critical Laboratory Tests During Hypoglycemic Episode
- Obtain the following when blood glucose is <70 mg/dL:
- Plasma glucose
- Insulin
- C-peptide
- Proinsulin
- β-hydroxybutyrate
- Sulfonylurea screen
- Insulin antibodies
- IGF-1 and IGF-2
Diagnostic Testing Based on Timing of Symptoms
For Fasting Hypoglycemia
- 72-hour supervised fast (gold standard test)
- Monitor blood glucose every 4-6 hours while awake
- When glucose falls <60 mg/dL or symptoms develop:
- Collect critical samples listed above
- Administer glucose to resolve symptoms
- Test can be terminated early if diagnostic criteria are met
For Postprandial Hypoglycemia
- Mixed meal tolerance test
- Administer standardized meal
- Check glucose, insulin, and C-peptide at baseline and every 30 minutes for 5 hours
- Collect critical samples if hypoglycemia occurs
Evaluation for Specific Causes
Endogenous Hyperinsulinism
- If insulin and C-peptide elevated during hypoglycemia:
- Abdominal CT/MRI to locate insulinoma
- Consider endoscopic ultrasound if CT/MRI negative
- 68Ga-DOTATATE PET scan for occult insulinoma
Non-Islet Cell Tumor Hypoglycemia
- If IGF-2:IGF-1 ratio elevated:
- Whole-body imaging to locate tumor
Medication-Related Causes
- Comprehensive medication review for:
- Accidental/surreptitious insulin or sulfonylurea use
- Non-diabetes medications (quinine, salicylates, pentamidine)
- Alcohol consumption
Hormonal Deficiencies
- Morning cortisol and ACTH
- TSH and free T4
- Growth hormone and IGF-1
Critical Illness
- Liver function tests
- Renal function tests
- Nutritional assessment
Autoimmune Causes
- Anti-insulin antibodies
- Anti-insulin receptor antibodies
- Screen for autoimmune disorders (particularly if Graves' disease present)
Risk Assessment
Major Risk Factors for Hypoglycemia
- Recent episodes of severe hypoglycemia
- End-stage kidney disease
- Cognitive impairment or dementia
- Food insecurity
- Low-income status
- Homelessness
Management During Workup
- For conscious patients with hypoglycemia: Administer 15-20g of oral glucose, recheck in 15 minutes, repeat if still hypoglycemic 2
- For severe hypoglycemia with altered consciousness: Administer glucagon or IV glucose
- Prescribe glucagon for all individuals at risk for severe hypoglycemia 3
- Train family members/caregivers on glucagon administration
Follow-Up
- Schedule follow-up within 1-2 weeks to review results
- Refer to endocrinology if cause remains unclear after initial workup
- Consider rare genetic causes if standard workup is negative
By systematically following this approach, clinicians can effectively diagnose the underlying cause of hypoglycemia in non-diabetic individuals and implement appropriate treatment strategies to prevent recurrent episodes.