What is Insulin-like Growth Factor (IGF)-induced hypoglycemia?

IGF-Induced Hypoglycemia: Causes, Mechanisms, and Management

IGF-induced hypoglycemia is a rare paraneoplastic syndrome caused by excessive production of insulin-like growth factor (primarily IGF-II) from non-islet cell tumors, leading to severe hypoglycemia with suppressed insulin levels. 1

Pathophysiology

• IGF-induced hypoglycemia occurs when tumors (typically of mesenchymal or epithelial origin) overproduce IGF-II, often in a precursor form called "big IGF-II" (10-15 kD) 2
• Unlike normal IGF-II, this "big IGF-II" fails to properly form the typical 140 kD ternary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) 2
• Instead, IGFs circulate in smaller binary complexes of 50-60 kD, which can more easily leave the circulation and bind to insulin and IGF receptors, causing hypoglycemia 2, 3
• The hypoglycemic effect occurs because IGF-II can bind to insulin receptors, mimicking insulin's glucose-lowering effects 4

Clinical Presentation

• Patients typically present with fasting hypoglycemia and neuroglycopenic symptoms (confusion, altered consciousness, seizures) 1
• Hypoglycemic episodes are often more severe during the early morning hours 5
• Laboratory findings show:
  • Low blood glucose levels
  • Suppressed insulin levels
  • Low C-peptide levels
  • Elevated total IGF-II or normal IGF-II with elevated IGF-II/IGF-I ratio (>10) 1

Risk Factors and Associated Conditions

• Presence of mesenchymal tumors, particularly:
  • Malignant fibrous histiocytoma 5
  • Other mesenchymal or epithelial tumors 1
• Advanced or metastatic disease with large tumor burden 1
• Fasting states that deplete glycogen stores 6

Diagnostic Approach

• During a hypoglycemic episode, measure:
  • Serum glucose
  • Insulin levels (will be suppressed)
  • C-peptide (will be low)
  • IGF-I and IGF-II levels
  • IGF-II/IGF-I ratio (ratio >10 is highly suggestive of IGF-II-mediated hypoglycemia) 1
• Imaging to identify the underlying tumor (CT, MRI) 5

Management

• The definitive treatment is surgical resection of the tumor when possible 1
• For unresectable disease, medical management includes:
  • Glucocorticoids (e.g., dexamethasone) - first-line therapy that reduces tumor IGF-II production 5, 1
  • Recombinant growth hormone - increases ALS and IGFBP-3 levels, improving ternary complex formation 1, 2
  • Frequent small meals and complex carbohydrates to maintain glucose levels 6
  • Glucagon administration can be effective in acute settings 5
  • Pasireotide has shown promise in some cases 1

Pathophysiological Mechanisms Contributing to Hypoglycemia

• Low acid-labile subunit (ALS) levels due to suppressed growth hormone 2
• Defective binding of IGFBP-3 to ALS 2
• Reduced ability of pro-IGF-II forms to form normal complexes 2
• High levels of other IGFBPs (including IGFBP-2 and IGFBP-6) that may interfere with normal complex formation 2

Prognosis and Monitoring

• Hypoglycemia severity often correlates with tumor burden 1
• Successful treatment of the underlying tumor typically resolves hypoglycemia 1
• For patients on medical therapy, blood glucose monitoring is essential to assess treatment efficacy 5
• Monitoring IGF-II/IGF-I ratio can help assess response to treatment 1

Clinical Pitfalls to Avoid

• Don't mistake IGF-induced hypoglycemia for insulinoma (check insulin and C-peptide levels, which will be low in IGF-induced hypoglycemia) 1
• Be aware that false positives in IGF-II/IGF-I ratio can occur in sepsis and cachexia 1
• Low IGFBP3 (as seen in renal failure) may result in falsely normal or low IGF-II/IGF-I ratio 1
• Don't rely solely on IGF-II levels, as they may be normal in some cases; the IGF-II/IGF-I ratio is more reliable 1