What is the significance of high proinsulin levels with low glucose levels and normal insulin and C-peptide (Connecting Peptide) levels?

High Proinsulin with Low Glucose and Normal Insulin/C-peptide: Diagnostic Significance

The most likely explanation for high proinsulin with low glucose levels and normal insulin and C-peptide levels is an islet cell tumor (insulinoma) or nesidioblastosis, which causes inappropriate proinsulin secretion leading to hypoglycemia. 1

Pathophysiology and Diagnostic Significance

• The persistence of inappropriately increased plasma insulin concentrations with low glucose concentration strongly suggests the presence of an islet cell tumor 1
• An increase in the ratio of fasting proinsulin to insulin in an individual with hypoglycemia is particularly suggestive of an islet cell tumor 1
• Proinsulin levels above 5 pmol/L with blood glucose levels below 2.5 mmol/L during a 72-hour fast test represent the best criterion for diagnosing endogenous hyperinsulinism, with 100% diagnostic specificity and sensitivity 2
• Normal C-peptide levels with elevated proinsulin may indicate a defect in the conversion of proinsulin to insulin, which can occur in certain islet cell tumors 1

Differential Diagnosis

1. Insulinoma

• Insulinomas are characterized by inappropriate insulin secretion with elevated proinsulin levels 3
• The diagnostic triad (Whipple's triad) includes:
  • Symptomatic hypoglycemia
  • Low blood glucose (<55 mg/dL)
  • Resolution of symptoms after glucose administration 3
• Insulinomas typically show elevated C-peptide levels (>0.2 nmol/L) with blood glucose below 2.5 mmol/L 2

2. Nesidioblastosis

• Adult-onset nesidioblastosis presents with hyperinsulinemic hypoglycemia without a discrete tumor 4
• Unlike insulinomas, C-peptide levels may not be consistently elevated in nesidioblastosis when glucose is below 2.5 mmol/L 2
• Diagnosis is challenging and often requires extensive testing to rule out insulinoma 4

3. Genetic Disorders

• Genetic abnormalities that result in the inability to convert proinsulin to insulin can be inherited in an autosomal dominant pattern 1
• These conditions typically present with mild glucose intolerance rather than hypoglycemia 1
• Mutations in proinsulin processing enzymes can lead to high proinsulin with normal insulin levels 1

4. Surreptitious Insulin Administration

• This can be ruled out by measuring C-peptide, which would be low or suppressed with exogenous insulin administration 1, 5
• Normal C-peptide levels in this case indicate endogenous insulin production 5

Diagnostic Approach

1. Confirm Hypoglycemia with Inappropriate Insulin/Proinsulin Secretion

   • Perform a 72-hour supervised fast with measurements of:
     • Blood glucose
     • Insulin
     • C-peptide
     • Proinsulin 3, 2
   • Test for sulfonylureas in the urine to rule out factitious hypoglycemia 3

2. Imaging Studies

   • If endogenous hyperinsulinism is confirmed, proceed with pancreatic imaging:
     • CT or MRI scans
     • Consider endoscopic ultrasound (82% sensitivity for localizing insulinomas) 3

3. Additional Testing

   • Measure the proinsulin-to-insulin ratio, which is typically elevated in insulinomas 1
   • Consider selective arterial calcium stimulation with hepatic venous sampling if conventional imaging is negative 3

Management Considerations

• Surgical treatment is recommended for localized insulinomas, with a cure rate of approximately 90% 3
• Preoperative stabilization of blood glucose through dietary measures and/or diazoxide may be necessary 3
• For nesidioblastosis or unresectable tumors, diazoxide therapy can be an effective and safe alternative 4
• Caution is advised when using somatostatin analogs due to potential worsening of hypoglycemia 3

Important Clinical Pearls

• The absence of changes in glucose, insulin, and proinsulin concentrations in an individual with fasting hypoglycemia makes the diagnosis of an islet cell tumor unlikely 1
• Measurement of C-peptide is essential in investigating nondiabetic hypoglycemia to rule out hypoglycemia due to surreptitious insulin administration 1, 5
• Hyperinsulinemia of insulinoma and selected cases of functional hypoglycemia are associated with a greater percentage of proinsulin compared to normal 6