Persistent Islet Hyperplasia (NonInsulinoma Pancreatogenous Hypoglycemia Syndrome)

In a very small number of patients with organic hyperinsulinism, islet hyperplasia rather than an adenoma is present. These patients typically have documented hyperinsulinemic hypoglycemia after meals but not with fasting up to 72 hours.

The patients have a positive response to calcium-stimulated angiography. A gradient-guided partial pancreatectomy leads to clinical remission, and the pathology of the pancreas shows evidence of islet hyperplasia and nesidioblastosis.

These patients do not have mutations in the Kir 6.2 and SUR1 genes, which has been reported in children with familial hyperinsulinemic hypoglycemia.

Hypoglycemia Due to Extrapancreatic Tumors

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.

The expression and release of an incompletely processed insulin-like growth factor-2 (IGF-2) has provided the best explanation for the clinical manifestations of hypoglycemia in these cases. A larger immature form of the IGF-2 molecule is released which binds to a carrier protein but not to an acid-labile component of serum which inactivates normal IGF-2. This immature IGF-2 complex therefore 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. Serum 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 only be detected by special laboratory techniques. Laboratory diagnosis depends on documenting fasting hypoglycemia associated with undetectable serum insulin levels.

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.

Le Roith D: Tumor-induced hypoglycemia. N Engl J Med 1999; 341:757. [PMID: 10471466]

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