Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia?

Abstract

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 -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 "25I-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. (J.

IGF2 and cancer

“…Surgical removal of the tumour can return the IGF2:IGFI ratio to normal, abolish the hypoglycaemia and restore normal GH and IGFBP3 concentrations (Zapf 1993, Perros et al 1996. In addition, mature IGF2 climbs following treatment, suggesting that big IGF2 has a suppressive effect on its concentrations (Zapf et al 1992).…”

High Molecular Weight Form Insulin-like Growth Factor II-producing Mesenteric Sarcoma Causing Hypoglycemia

“…IGF-II can only mediate its insulin-like effects when it is present as a free form unbound with this complex. The HMW form IGF-II produced by the tumors as in our case apts to form smaller binary complexes consisting of IGF-II bound to IGFBPs (mainly 1, 2 and 4) rather than ternary complexes (4)(5)(6)16). While ternary complexes for the most part do not cross capillary walls, binary complexes do (17).…”

“…Currently, most cases with NICTH are attributed to excessive production of IGF-II by the tumors based on the recent accumulating evidence that these tumors produce and secrete IGF-II (1)(2)(3)(4)(5)(6)(7)(8). The diagnosis of the present patient with NICTH was consistent with that of HMW form IGF-IIproducing tumor causing hypoglycemia for the following reasons: 1) preoperative high IGF-II levels; 2) hypoglycemia improved and serum IGF-II levels decreased to normal after tumor resection; 3) the presence of circulating HMW form IGF-II in patient's serum by Western blotting; 4) the expression of IGF-II mRNA and protein by the tumor as demonstrated by real-time quantitative RT-PCR and immunohistochemistry, respectively.…”

“…The present patient had elevated serum levels of IGF-II consisting predominantly of HMW (approximately 19.8 kDa) form. The HMW form IGF-II has been shown to mimic insulin's effects more effectively than a mature (7.5 kDa) form (1,2,(4)(5)(6)(7)(8). In normal subjects, about two-thirds of the circulating mature form IGF-II is present as a ternary 150 kD complex with IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS).…”

“…The hypoglycemia induced by these tumors can be reversed by tumor resection, but it relapses with recurrence of the tumor. Most of the non-islet cell tumors causing such hypoglycemic symptoms have been found to produce and secrete insulin-like growth factor-II (IGF-II) (1)(2)(3)(4)(5)(6)(7)(8).…”