The pathogenesis of extrapancreatic
tumor hypoglycemia has been related to the secretion of big
insulin-like growth factor (
IGF) II by the
tumor. In 25 of 28 patients with this type of
hypoglycemia we found 1.5-8-fold elevated serum levels of immunoreactive big (15-25 kD), but decreased levels of normal
IGF II. After removal of the
tumor, big
IGF II disappeared and normal
IGF II increased.
Tumors contained elevated levels of
IGF II, 65-80% in the big form. The
insulin-like bioactivity of big
IGF II and its affinity towards
IGF-binding proteins (IGFBP)-2 and -3 are similar to those of normal
IGF II, but two- to threefold higher on a molar basis. Big
IGF II is mainly bound to the 50-kD
IGFBP complex. The latter contains approximately 10 times more of this
peptide than in normal serum and displays three- to fourfold increased
insulin-like bioactivity. The formation of the 150-kD
IGFBP complex with 125I-recombinant human
IGFBP-3 is impaired in
tumor serum. This results in sequestration of
IGFBP-3 and predominant association of big
IGF II with
IGFBP-2 and -3 in the 50-kD complex. Increased bioavailability of big
IGF II in this complex due to unrestricted capillary passage and enhanced
insulin bioactivity of this big
IGF II pool provide a continuous increased
insulin-like potential available to
insulin and type 1 IGF receptors of
insulin-sensitive tissues and thus may lead to sustained
hypoglycemia.