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These rare causes of hypoglycemia include mesenchymal tumors such as retroperitoneal sarcomas, hepatocellular carcinomas, adrenocortical carcinomas, and miscellaneous epithelial-type tumors. The tumors are frequently large and readily palpated or visualized on CT scans or MRI.

In many cases the hypoglycemia is due to the expression and release of an incompletely processed insulin-like growth factor 2 (IGF-2) by the tumor. This immature form of the IGF-II molecule (pro-IGF-2 or "big IGF-2") binds IGF-binding protein-3 (IGFBP-3) but not to the acid-labile subunit. As a consequence, this pro-IGF-II remains active and binds to insulin receptors in muscle to promote glucose transport and to insulin receptors in liver and kidney to reduce glucose output. It also binds to receptors for IGF-1 in the pancreatic B cell to inhibit insulin secretion and in the pituitary to suppress growth hormone release. With the reduction of growth hormone, there is a consequent lowering of IGF-1 levels as well as IGFBP-3 and acid-labile subunit.

The diagnosis is supported by laboratory documentation of serum insulin levels below 5 microunit/mL with plasma glucose levels of 45 mg/dL (2.5 mmol/L) or lower. Values for growth hormone and IGF-1 are also decreased. Levels of IGF-2 may be increased but often are “normal” in quantity, despite the presence of the immature, higher-molecular-weight form of IGF-2, which can be detected only by special laboratory techniques.

Not all the patients with nonislet cell tumor hypoglycemia have elevated pro-IGF-2. Ectopic insulin production has been described in bronchial carcinoma, ovarian carcinoma, and small cell carcinoma of the cervix. Hypoglycemia due to IgF-1 released from a metastatic large cell carcinoma of the lung has also been reported. GLP-1–secreting tumors (ovarian and pNETs) can also cause hypoglycemia by stimulating insulin release from normal pancreatic islets.

The prognosis for these tumors is generally poor, and surgical removal should be attempted when feasible. Dietary management of the hypoglycemia is the mainstay of medical treatment, since diazoxide is usually ineffective.

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Bodnar  TW  et al. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab. 2014 Mar;99(3):713–22.
[PubMed: 24423303]

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