What are the possible medical causes of hypoglycemia in a non‑diabetic patient and how should it be evaluated and treated?

Medical Causes of Hypoglycemia in Non-Diabetic Patients

In non-diabetic adults, hypoglycemia is most commonly caused by critical illness (sepsis, renal failure, liver disease), malignancy, alcohol use, medications (especially corticosteroid withdrawal), and nutritional interruptions, with insulin-mediated causes like insulinoma being rare. 1

Critical Illness and Organ Dysfunction

The most frequent causes of spontaneous hypoglycemia in hospitalized non-diabetic patients are:

• Sepsis causes dysregulated glucose metabolism and is a major predictive marker of hypoglycemia 1
• Renal insufficiency produces hypoglycemia through decreased renal gluconeogenesis (which normally accounts for 20-40% of glucose production) and impaired insulin clearance 1
• Liver disease impairs gluconeogenesis and glycogen storage, leading to fasting hypoglycemia 2
• Heart failure is independently associated with hypoglycemia risk in hospitalized patients 1
• Malignancy can cause hypoglycemia through multiple mechanisms, including non-islet cell tumors producing IGF-II (NICTH syndrome) 1, 2

Endocrine Disorders

• Adrenal insufficiency (including hypopituitarism) impairs counterregulatory responses through cortisol deficiency 3, 2
• Sudden corticosteroid dose reduction precipitates hypoglycemia by removing cortisol's counterregulatory effect 1
• Insulinoma presents with fasting hypoglycemia and elevated insulin, C-peptide, and proinsulin levels during documented hypoglycemia 2, 4
• Non-islet cell tumors (NICTH) typically occur in older patients with large tumors secreting "Big-IGF2," characterized by low insulin, C-peptide, and IGF-1 levels 3, 2

Nutritional and Metabolic Causes

• Alcohol-induced hypoglycemia typically develops 6-24 hours after moderate-to-heavy intake in individuals with insufficient food intake for 1-2 days, as alcohol inhibits gluconeogenesis 1, 5
• Malnutrition is particularly common in elderly hospitalized patients and increases hypoglycemia risk 1
• Food insecurity with irregular access to adequate nutrition 1
• Prolonged fasting for religious or cultural reasons 1
• Interruptions in nutritional intake during hospitalization (NPO status, delayed meals, emesis, interrupted enteral/parenteral feedings) 1

Medication-Related Causes (Non-Diabetes Medications)

• Fluoroquinolones (especially in combination with other medications) 6
• Pentamidine can cause hypoglycemia through direct beta-cell toxicity 6
• Quinine used for malaria treatment 2
• Beta-blockers may mask hypoglycemic symptoms and impair counterregulatory responses 6

Post-Surgical and Autoimmune Causes

• Post-bariatric surgery hypoglycemia presents with postprandial symptoms due to exaggerated insulin response 3, 4
• Noninsulinoma pancreatogenous hypoglycemia (NIPH) causes postprandial hypoglycemia from nesidioblastosis 4
• Autoimmune hypoglycemia from insulin autoantibodies (Hirata syndrome, especially with Graves' disease) or insulin receptor antibodies 3, 2

Rare Genetic Causes

• Glucokinase-activating mutations cause postprandial hypoglycemia with marked hyperinsulinism 3
• Glycogen storage disorders (types 0, I, III) present with fasting hypoglycemia 3
• Fatty acid oxidation disorders cause fasting or exercise-induced hypoglycemia 3
• Inherited fructose intolerance causes postprandial hypoglycemia 3

Diagnostic Approach

Confirm true hypoglycemia using Whipple's triad before pursuing extensive workup: 6, 4

1. Low plasma glucose concentration (typically <55 mg/dL)
2. Neurogenic symptoms (sweating, tremor, palpitations, hunger) and/or neuroglycopenic symptoms (confusion, weakness, blurred vision, slurred speech) 5
3. Resolution of symptoms with glucose normalization

Key Laboratory Evaluation During Symptomatic Episode

Obtain these critical labs during documented hypoglycemia (not at other times): 4

• Plasma glucose (confirm <55 mg/dL)
• Insulin level (elevated in insulinoma, suppressed in NICTH and most other causes)
• C-peptide (elevated in endogenous hyperinsulinism, suppressed in exogenous insulin)
• Proinsulin (elevated in insulinoma)
• Beta-hydroxybutyrate (suppressed in hyperinsulinism, elevated in other causes)
• Cortisol and growth hormone (assess counterregulatory response)
• IGF-1 and IGF-2 (elevated IGF-2:IGF-1 ratio in NICTH) 2

Timing-Based Diagnostic Algorithm

Fasting hypoglycemia (>8 hours after eating): 3, 4

• Consider insulinoma, NICTH, adrenal insufficiency, liver disease, renal failure, alcohol, glycogen storage disorders
• Perform supervised 72-hour fast if needed to reproduce symptoms 4

Postprandial hypoglycemia (1-4 hours after eating): 3, 4

• Consider post-bariatric hypoglycemia, NIPH, autoimmune hypoglycemia, glucokinase mutations, inherited fructose intolerance
• Perform mixed-meal test to reproduce symptoms 4

Critical Pitfalls to Avoid

• Do not pursue extensive workup without first documenting Whipple's triad during a spontaneous episode—many patients have symptoms without true hypoglycemia 4
• Recognize that mortality is higher in patients with spontaneous hypoglycemia, which may reflect underlying disease severity rather than direct hypoglycemia effects 1
• In elderly patients, hypoglycemia risk is compounded by multiple comorbidities, impaired counterregulatory mechanisms, and inability to perceive symptoms 1
• Low albumin levels predict hypoglycemia risk through altered drug pharmacokinetics 1
• Acute kidney injury is an important and often overlooked risk factor for hospital-acquired hypoglycemia 1