The Role of Insulin-Like Growth Factors and Their Binding Proteins in Tumor Hypoglycemia

Abstract

Tumors of nonislet cell origin may overexpress insulin-like growth factor (IGF)-II leading to hypoglycemia with suppressed serum insulin levels (NICTH). Most of the serum IGF-II in NICTH patients is in precursor forms of 10-15 kD, and may be abnormally glycosylated. In NICTH, IGFs and IGF-binding protein-3 (IGFBP-3) are mainly found in binary complexes of 50-60 kD, instead of the normal ternary complex of about 140 kD with the acid-labile sub unit (ALS). Factors contributing to the defect are: (1) low ALS levels, secondary to suppressed growth hormone (GH); (2) defective IGFBP-3 binding to ALS; (3) reduced ability of pro-IGF-II forms to complex normally, and (4) very high levels of other IGFBPs, including IGFBP-2 and IGFBP-6, which might limit the formation of complexes with IGFBP-3. While both GH and glucocorticoids can restore normoglycemia and increase high-molecular-weight IGFBP-3 complexes, corticosteroid treatment suppresses tumor IGF-II, whereas GH can restore normoglycemia despite continuing high IGF-II levels. Both treatments increase serum ALS, IGFBP-3, and IGF-I levels, and decrease IGFBP-2, whereas IGFBP-6 is unaffected. The reversal of hypoglycemia, by surgery, GH, or glucocorticoid treatment, is always accompanied by improved ternary complex formation, emphasizing the importance of the components of this complex, in particular ALS, in normal blood sugar regulation.

Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.

“…These prohormones are then processed, by removal of the E-domain, into mature ‫ف‬ 7-kD peptides normally present in the circulation (17,18). IGF-II prohormone (IGF-IIE) appears to have biologic activity similar to IGF-II (19,20), and increased circulating levels of ‫ف‬ 10-20-kD IGF-IIE produced by certain mesenchymal and epithelial tumors have been im-plicated in the pathogenesis of nonislet cell tumor hypoglycemia (NICTH; [21][22][23][24].…”

Growth hormone therapy in non-islet cell tumor mediated hypoglycemia associated with metastatic lung adenocarcinoma

“…The IGF-2 levels may or may not be elevated [13], though have been consistently reported to be higher than the IGF-1 levels. And thus, reported IGF-2:IGF-1 ratios in cases of NICTH have been elevated, in some cases as high as 10:1 [11,14].…”

“…In a refractory setting, as was shown in this case, rhGH can be considered as well. GH suppresses peripheral glucose uptake [3] and leads to increased levels of IGF-1, IGFBP-3, and ALS, with resultant promotion of the normal ternary-complexed IGF-2 [13,17,20]. Drake et.…”

Recurrent Hypoglycaemia in a Case of Phyllodes Tumour of the Breast: A Rare Case Report

“…But several malignancies (like sarcomas) can produce large amounts of big IGF-2 [16] leading to a large amount of big IGF-2 at the level of target tissues. Mature IGF-2 has 47% sequence match with insulin, and also active biochemically, hence stimulates glucose metabolism pathways which leads to hypoglycaemia [15,17]. On the other hand, suppression of growth hormone occurs at pituitary gland by negative feedback mechanism which causes decrease in IGF-1level.…”