Hypoglycemia of Malignancy is Caused by IGF-2
Hypoglycemia of malignancy is caused by insulin-like growth factor 2 (IGF-2), not IGF-1. This paraneoplastic syndrome, also known as non-islet cell tumor hypoglycemia (NICTH), results from tumors producing an abnormal high molecular weight form of IGF-2 (often called "big IGF-2") that mimics insulin's effects 1, 2, 3.
Pathophysiology
IGF-2 overproduction by mesenchymal tumors (most commonly fibromas, fibrosarcomas, and hepatomas) and epithelial tumors causes severe fasting hypoglycemia by activating insulin receptors and IGF-1 receptors 3.
The characteristic biochemical profile includes elevated IGF-2 levels with suppressed insulin, IGF-1, and growth hormone 3, 4.
An IGF-2/IGF-1 ratio above 10 is highly suggestive of IGF-2-mediated hypoglycemia when IGF-2 is normal or elevated 2.
The abnormal "big IGF-2" form has altered binding to IGF binding proteins, allowing increased bioavailability and enhanced hypoglycemic effects 1, 5.
Clinical Context
Tumors associated with this syndrome include malignant fibrous histiocytoma, solitary fibrous tumors of the pleura, hemangiopericytomas, and various mesenchymal malignancies 1, 4, 5.
Patients present with fasting hypoglycemia and early morning symptoms, often years after initial tumor diagnosis 1.
IGF-1 is mentioned in neuroendocrine contexts (such as acromegaly from ectopic GHRH secretion in pulmonary carcinoids), but this is unrelated to hypoglycemia of malignancy 6.
Diagnostic Workup
During a hypoglycemic episode, measure:
- Serum glucose, C-peptide, insulin, and insulin antibodies (all will be low/suppressed) 2
- Beta-hydroxybutyrate (suppressed due to insulin-like effects) 2
- IGF-2, IGF-1, and calculate the IGF-2/IGF-1 ratio 2, 3
- Sulphonylurea screen to exclude factitious causes 2
Treatment Approach
Surgical resection of the tumor is curative and the definitive treatment 2, 3, 4, 5.
For unresectable disease, medical management options include:
- Moderate-dose glucocorticoids (e.g., dexamethasone) to increase hepatic glucose production 1, 2
- Low-dose glucocorticoids combined with recombinant growth hormone to counteract IGF-2 effects 2
- Glucagon administration for acute management 1
- Pasireotide has shown promise in refractory cases 2
- Frequent meals and continuous dextrose infusion provide only temporary relief 2
Important Caveats
False positives can occur with sepsis and cachexia (both IGF-2 and IGF-1 are subnormal), or with low IGF binding protein 3 levels as seen in renal failure 2.
Do not confuse this with insulinomas, where insulin and C-peptide are elevated rather than suppressed 6.
The term "non-islet cell tumor hypoglycemia" is being replaced with "IGF-2-oma" to better reflect the pathophysiology 3.