Would pulling an insulin level be helpful in a patient with dropping blood sugar and normal lab results, who is likely taking insulin or other diabetes medications?

Measuring Insulin Levels in Hypoglycemia with Normal Labs

Yes, measuring insulin levels is critically important in this clinical scenario and should be obtained during the next hypoglycemic episode, along with C-peptide, to differentiate between endogenous and exogenous causes of hypoglycemia. This diagnostic approach is essential for determining whether the patient has factitious hypoglycemia from surreptitious insulin administration, insulinoma, or other causes of hyperinsulinemic hypoglycemia.

Diagnostic Approach to Unexplained Hypoglycemia

When to Measure Insulin Levels

The most important diagnostic tool for detecting the cause of fasting hypoglycemia is the simultaneous determination of glucose and insulin in plasma during a hypoglycemic episode 1. For patients with dropping blood sugar despite normal routine labs, this becomes the cornerstone of diagnosis.

• Obtain blood samples during documented hypoglycemia (glucose <70 mg/dL or 3.9 mmol/L) for insulin, C-peptide, and glucose levels 2, 3
• The timing is critical—samples must be drawn when the patient is actually hypoglycemic, not during normoglycemia 1
• If the patient is on insulin therapy, measuring insulin levels can still reveal factitious hypoglycemia patterns 4

Critical Interpretation Patterns

An elevated insulin level during hypoglycemia with low C-peptide confirms exogenous insulin administration (factitious hypoglycemia), while elevated insulin with elevated C-peptide suggests insulinoma or other endogenous hyperinsulinism 4, 1.

• In insulinoma, there is an inappropriate fall in blood glucose relative to plasma insulin concentration, resulting in an increased insulin-glucose ratio 1
• Raised fasting proinsulin levels are pathognomonic for insulinoma 1
• For diabetic patients on insulin analogues, use multiple insulin assays with different cross-reactivity profiles, as standard assays may miss exogenous insulin administration 4

Special Considerations for Patients on Diabetes Medications

If Patient is Taking Insulin

Recurrent unexplained hypoglycemia in insulin-treated patients requires measurement of insulin levels using assays that account for insulin analogue cross-reactivity 4. Two pediatric cases demonstrated that initial insulin measurements showing "low" levels were misleading due to assay limitations, and repeat testing with different assays revealed hyperinsulinemic hypoglycemia confirming factitious administration 4.

• Surreptitious insulin administration should not be excluded based on a single negative insulin assay 4
• The rate of cross-reactivity of insulin analogues with the specific insulin assay used must be considered 4
• Document the specific insulin formulation the patient is prescribed (e.g., regular, aspart, glargine) to guide assay selection 5

If Patient is on Oral Hypoglycemic Agents

Sulfonylureas and meglitinides cause endogenous insulin secretion and will show elevated insulin AND C-peptide levels during hypoglycemia 5, 3. This pattern differs from exogenous insulin administration.

• Metformin alone carries minimal hypoglycemia risk and would not explain dropping blood sugars 2
• Sulfonylureas (particularly chlorpropamide) carry high risk of prolonged and unpredictable hypoglycemia 2
• Other medications that can cause hypoglycemia include salicylates, sulfa antibiotics, certain antidepressants, and alcohol 5

Comprehensive Hypoglycemia Workup

Essential Laboratory Tests During Hypoglycemia

Beyond insulin levels, obtain:

• Simultaneous glucose, insulin, C-peptide, and proinsulin during documented hypoglycemia (<50 mg/dL or 2.8 mmol/L) 1
• Consider sulfonylurea/meglitinide screen if patient denies taking these medications 3
• Beta-hydroxybutyrate and free fatty acids (should be suppressed if insulin excess is present) 3

Clinical Context Matters

Hypoglycemia in the context of insulin-deficient diabetes (type 1 or advanced type 2) typically results from the interplay of absolute or relative insulin excess and compromised glucose counterregulation 3.

• In established diabetes, insulin levels do not decrease appropriately as glucose falls 3
• Deficient glucagon and epinephrine responses cause defective glucose counterregulation 3
• Recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness, creating a vicious cycle 3, 6

Common Pitfalls to Avoid

Assay Selection Errors

The single most important pitfall is using an insulin assay with inappropriate cross-reactivity for the patient's insulin type 4. Standard immunoassays may not detect or may underestimate insulin analogue concentrations.

• Always specify which insulin formulation the patient uses when ordering the test 4
• If initial results are inconsistent with clinical presentation, repeat with a different assay methodology 4

Timing Errors

Never draw insulin levels when the patient is normoglycemic or hyperglycemic—the diagnostic value is only during documented hypoglycemia 1. Elevated insulin during euglycemia has different diagnostic implications than during hypoglycemia.

Medication Interference

Beta-blockers, clonidine, guanethidine, and reserpine can mask hypoglycemia symptoms, leading to delayed recognition and more severe episodes 5. These medications do not cause hypoglycemia but prevent the patient from recognizing it early.

Immediate Management While Awaiting Results

Implement frequent blood glucose monitoring (6-10 times daily for insulin-treated patients) to capture hypoglycemic episodes and document patterns 7.

• Provide immediate access to glucose tablets (15-20g) for treatment of documented hypoglycemia 2
• For unconscious patients or those unable to take oral carbohydrates, glucagon administration is indicated 2
• Any episode of severe hypoglycemia or recurrent episodes mandates immediate reevaluation of the treatment regimen 2, 8