How to investigate causes of hypoglycemia (low blood sugar) in a non-diabetic patient?

Investigation of Hypoglycemia in Non-Diabetic Patients

In non-diabetic patients presenting with hypoglycemia, immediately confirm Whipple's triad (low plasma glucose <55 mg/dL, neuroglycopenic symptoms, and symptom resolution with glucose normalization), then obtain critical blood samples during a documented hypoglycemic episode to measure insulin, C-peptide, proinsulin, and beta-hydroxybutyrate—these four tests will classify the hypoglycemia mechanism and direct all subsequent investigations. 1, 2

Initial Diagnostic Confirmation

Establish Whipple's Triad

• Document all three components: (1) plasma glucose <55 mg/dL (3.0 mmol/L), (2) neuroglycopenic and/or neurogenic symptoms, and (3) symptom resolution when glucose normalizes 1, 2, 3
• Laboratory glucose measurement is mandatory—never rely solely on point-of-care testing for diagnosis 2
• Many patients are asymptomatic and normoglycaemic at clinic visits, requiring provocation testing 2

Critical Blood Samples During Hypoglycemia

When hypoglycemia is documented, immediately obtain blood for:

• Insulin level 2, 4
• C-peptide 2, 4
• Proinsulin 2, 4
• Beta-hydroxybutyrate 2, 4

These four tests classify hypoglycemia into three mechanistic categories that direct further workup 2:

1. Non-ketotic hyperinsulinemia (elevated insulin/C-peptide, suppressed beta-hydroxybutyrate)
2. Non-ketotic hypoinsulinemia (low insulin/C-peptide, suppressed beta-hydroxybutyrate)
3. Ketotic hypoinsulinemia (low insulin/C-peptide, elevated beta-hydroxybutyrate)

Structured Clinical History

Medication and Substance Exposure

• All medications including over-the-counter drugs and supplements—sulfonylureas, meglitinides, and quinolones are common culprits 5, 6, 4, 3
• Alcohol consumption patterns—alcohol inhibits gluconeogenesis and is a frequent cause 4, 3
• Access to hypoglycemic agents (household members with diabetes, healthcare workers) 2
• Accidental or intentional medication ingestion (factitious hypoglycemia) 6, 4

Timing of Hypoglycemic Episodes

• Fasting hypoglycemia (>8 hours without food) suggests insulinoma, non-islet cell tumors, adrenal insufficiency, or glycogen storage disorders 2, 4
• Postprandial hypoglycemia (2-5 hours after meals) suggests post-bariatric surgery, insulin autoimmune syndrome, glucokinase-activating mutations, or hereditary fructose intolerance 1, 4
• Exercise-induced hypoglycemia suggests SLC16A1 gene mutations or metabolic disorders 4

Comorbid Conditions

• Critical illness (sepsis, severe infection, shock)—a common cause in hospitalized patients and may indicate illness severity 6, 3
• Organ failure: chronic kidney disease (impaired gluconeogenesis and insulin clearance), liver disease (impaired gluconeogenesis), heart failure 5, 6, 3
• Malignancy—particularly large tumors or insulinomas 6, 7
• Endocrine disorders: adrenal insufficiency, hypopituitarism 5, 4, 3
• Malnutrition or altered nutritional state 6, 3

Provocation Testing When Indicated

Supervised Fasting Test

• Indicated when: fasting hypoglycemia is suspected but not yet documented 2, 4
• Protocol: supervised 72-hour fast with glucose monitoring every 4-6 hours (more frequently if glucose <60 mg/dL) 2
• Obtain critical samples (insulin, C-peptide, proinsulin, beta-hydroxybutyrate) when glucose ≤55 mg/dL with symptoms 2, 4
• Terminate test when hypoglycemia is documented or 72 hours elapsed 2

Mixed-Meal Test

• Indicated when: postprandial hypoglycemia is suspected (post-bariatric surgery, reactive hypoglycemia) 1, 2
• Protocol: standardized meal followed by glucose monitoring every 30 minutes for 5 hours 2
• Obtain critical samples when hypoglycemia occurs 2

Diagnostic Algorithm Based on Biochemical Classification

Non-Ketotic Hyperinsulinemia (High Insulin/C-Peptide, Low Beta-Hydroxybutyrate)

Endogenous hyperinsulinism:

• Insulinoma: pancreatic imaging with MRI and endoscopic ultrasound 7, 4
• Post-bariatric hypoglycemia: history of gastric bypass or sleeve gastrectomy 1, 4
• Genetic causes: glucokinase-activating mutations (GCK gene), insulin receptor mutations, SLC16A1 mutations 4

Exogenous insulin or insulin secretagogue:

• Measure sulfonylurea/meglitinide screen in blood 2, 4
• Low C-peptide with high insulin suggests exogenous insulin administration 2, 4

Insulin autoimmune syndrome:

• Measure insulin antibodies—positive in Hirata syndrome 7, 4
• Associated with: methimazole, alpha-lipoic acid, Graves' disease 7, 4

Non-Ketotic Hypoinsulinemia (Low Insulin/C-Peptide, Low Beta-Hydroxybutyrate)

Non-islet cell tumor hypoglycemia (NICTH):

• Measure IGF-1 and IGF-2—low IGF-1 with elevated IGF-2:IGF-1 ratio suggests Big-IGF2 secretion 4, 3
• Imaging for large mesenchymal tumors (retroperitoneal, thoracic) 4, 3

Hormonal deficiencies:

• Cortisol and ACTH (adrenal insufficiency, hypopituitarism) 5, 4, 3
• Growth hormone (in appropriate clinical context) 4

Ketotic Hypoinsulinemia (Low Insulin/C-Peptide, High Beta-Hydroxybutyrate)

Inborn errors of metabolism:

• Glycogen storage disorders (types 0, I, III)—hepatomegaly, fasting hypoglycemia 4
• Fatty acid oxidation disorders—rhabdomyolysis after fasting/exercise, cardiomyopathy 4
• Gluconeogenesis defects 4
• Consider genetic testing when systemic involvement or family history present 4

Severe malnutrition or starvation 3

Additional Investigations Based on Clinical Context

Imaging Studies

• Pancreatic MRI and endoscopic ultrasound for suspected insulinoma 7
• CT chest/abdomen/pelvis for malignancy screening when NICTH suspected 7, 4
• Liver imaging when hepatic disease suspected 7

Laboratory Monitoring

• Renal function (creatinine, eGFR)—chronic kidney disease increases hypoglycemia risk 5
• Liver function tests—hepatic failure impairs gluconeogenesis 6, 3
• Complete blood count, albumin—markers of critical illness and malnutrition 6

Common Pitfalls to Avoid

• Never diagnose hypoglycemia without laboratory-confirmed glucose <55 mg/dL—point-of-care meters can be inaccurate 2
• Do not obtain critical samples when glucose is normal—they are uninterpretable and lead to misdiagnosis 2
• Avoid mislabeling healthy individuals as "hypoglycemic" based on symptoms alone without documented low glucose 2
• Do not pursue extensive workup in critically ill patients unless another specific cause is suspected—hypoglycemia in severe illness is multifactorial and investigation is unnecessary 6, 2, 3
• Never overlook medication review—drug-induced hypoglycemia is the most common cause overall 4, 3
• Do not miss factitious hypoglycemia—consider in healthcare workers or those with access to insulin/sulfonylureas 2, 4

Immediate Management During Investigation

• Administer glucagon 1 mg IM/SC/IV (or 3 mg intranasal) for persistent hypoglycemia while investigating the cause 6
• Establish continuous glucose monitoring or frequent bedside checks (every 1-2 hours initially) 6
• Initiate continuous IV dextrose infusion (D10 preferred over repeated D50 boluses) to prevent rebound hyperglycemia 6
• Review and discontinue potentially causative medications 6