What causes hypoglycemia in healthy individuals with no history of diabetes?

Hypoglycemia in Healthy Non-Diabetic Adults

Primary Causes

In truly healthy individuals without diabetes, hypoglycemia is extremely rare and occurs only in extreme circumstances such as prolonged fasting during extreme sports or starvation. 1

The most common causes of hypoglycemia in non-diabetic adults include:

Medication and Substance-Related Causes

• Accidental or intentional ingestion of glucose-lowering medications (insulin, sulfonylureas, meglitinides) is a leading cause, particularly in individuals with access to diabetic medications through household members or healthcare settings 2, 3
• Alcohol consumption, especially on an empty stomach, inhibits gluconeogenesis and can cause severe hypoglycemia 3, 4
• Other medications including certain antibiotics (fluoroquinolones), beta-blockers, and salicylates can precipitate hypoglycemia 4

Critical Illness and Organ Dysfunction

• Severe systemic illness including sepsis, liver failure, and renal failure are major causes, as these conditions impair glucose production and clearance 3, 5
• Hepatic dysfunction reduces gluconeogenesis and glycogen storage capacity 4
• Chronic kidney disease or acute kidney injury increases hypoglycemia risk through impaired glucose production and altered drug metabolism 5
• Cortisol insufficiency and hypopituitarism eliminate critical counterregulatory hormone responses 4

Nutritional and Metabolic Causes

• Severe malnutrition and prolonged fasting deplete glycogen stores and impair gluconeogenesis 5
• Inherited metabolic disorders (glycogen storage diseases, fatty acid oxidation defects, gluconeogenesis disorders) can present in adulthood with fasting hypoglycemia, often accompanied by hepatomegaly, rhabdomyolysis, or cardiac involvement 4

Insulin-Mediated Causes

• Insulinoma (rare pancreatic tumor) causes fasting hypoglycemia with inappropriately elevated insulin and C-peptide levels 2, 3
• Post-bariatric surgery hypoglycemia occurs after gastric bypass procedures, typically 1-3 hours postprandially due to exaggerated insulin response 6, 4
• Autoimmune hypoglycemia from insulin autoantibodies (Hirata syndrome) or insulin receptor antibodies, particularly in patients with autoimmune thyroid disease 4
• Exercise-induced hyperinsulinism from SLC16A1 gene mutations causes hypoglycemia triggered by physical activity 4

Rare Paraneoplastic Causes

• Non-islet cell tumor hypoglycemia (NICTH) from large tumors secreting IGF-2, characterized by low insulin, C-peptide, and IGF-1 levels 4

Diagnostic Approach

Confirmation requires documenting Whipple's triad: plasma glucose ≤54 mg/dL during symptoms, neuroglycopenic symptoms (confusion, altered mental status, seizures), and symptom resolution with glucose normalization. 2, 6, 3

Critical Blood Samples During Hypoglycemia

When hypoglycemia is documented, obtain: 2, 3

• Laboratory plasma glucose (not fingerstick)
• Insulin level
• C-peptide
• Proinsulin
• Beta-hydroxybutyrate

These results classify hypoglycemia into three categories that direct further investigation: 3

• Non-ketotic hyperinsulinemia (elevated insulin/C-peptide, suppressed beta-hydroxybutyrate): suggests insulinoma, sulfonylurea use, or autoimmune hypoglycemia
• Non-ketotic hypoinsulinemia (low insulin/C-peptide, suppressed beta-hydroxybutyrate): suggests non-islet cell tumor or IGF-2 excess
• Ketotic hypoinsulinemia (low insulin/C-peptide, elevated beta-hydroxybutyrate): suggests cortisol deficiency, glycogen storage disease, or starvation

Essential History Elements

• Medication access and use, including over-the-counter supplements and others' medications 3
• Alcohol consumption patterns and timing relative to symptoms 3
• Timing of symptoms: fasting versus postprandial hypoglycemia narrows differential diagnosis significantly 4
• Comorbid conditions: liver disease, kidney disease, heart failure, malignancy 3, 5
• Family history of unexplained hypoglycemia or metabolic disorders 4
• Recent bariatric surgery or gastrointestinal procedures 6, 4

Important Caveats

Many individuals are incorrectly labeled as "hypoglycemic" based on symptoms alone without documented low glucose levels. 3 The threshold of 70 mg/dL (3.9 mmol/L) represents the counterregulatory response threshold in healthy individuals, but true neuroglycopenic symptoms typically don't occur until glucose falls below 54 mg/dL (3.0 mmol/L). 7

Pseudohypoglycemia from laboratory interference must be excluded, particularly in patients on peritoneal dialysis (icodextrin interference with GDH-PQQ meters), those with extreme triglycerides, or patients receiving certain intravenous solutions. 8 Always confirm fingerstick readings with laboratory plasma glucose when values seem discordant with clinical presentation.

In severely ill hospitalized patients, hypoglycemia awareness is critical for prevention, but extensive investigation is unnecessary unless another specific cause is suspected beyond critical illness itself. 3