Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia

Abstract

Hypoglycemia in patients with nonislet cell tumors is often secondary to overexpression of tumor insulin-like growth factor (IGF) II. In these patients the formation of serum complexes between IGFs, IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) is impaired. An 87-yr-old woman with nonislet cell tumor hypoglycemia resulting from a localized fibrous tumor of the pleura was treated for 97 days with graded doses of prednisolone (30, 10, and 5 mg/day) followed by GH (1, 4, 8, 4, and 2 U/day). Both prednisolone and GH alleviated the hypoglycemia, concomitantly with increases in IGF-I, IGFBP-3, and ALS levels. Pretreatment serum IGFBP-2 and IGFBP-6 levels were greatly elevated, but as glucose normalized with treatment, only IGFBP-2 decreased, showing an inverse correlation with glucose (r = 0.716). IGFBP-1 gave a variable pattern not clearly related to blood glucose. Both treatments caused a redistribution of serum IGFBP-3 from binary- to ternary-complexed forms. However, only prednisolone improved the ability of IGFBP-3 to bind ALS in vitro. Prednisolone also suppressed IGF-II, the effect being confined to pro-IGF-II forms. Compared with normal IGF-II, pro-IGF-II inhibited ALS binding to IGFBP-3 in vitro. Although prednisolone and GH reverse hypoglycemia by different mechanisms, with only prednisolone suppressing tumor IGF-II secretion, both increase the formation of ternary IGF-IGFBP-3 complexes. We conclude that the failure of serum IGFBP-3 and tumor IGF-II to complex with ALS is a primary cause of hypoglycemia in nonislet cell tumor hypoglycemia.

Free insulin-like growth factors – measurements and relationships to growth hormone secretion and glucose homeostasis

“…Taken together, these changes cause a shift in the molecular distribution of the IGFs from tissue inaccessible to tissue accessible forms, and this phenomenon was for a long time considered to be the primary cause of hypoglycemia in NICTH patients [280,313]. In accordance with this view, stimulation of ternary complex formation by GH treatment has been used to abolish/diminish hypoglycemia in NICTH patients [316].…”

“…In normal subjects up to about 80% of the circulating IGF-pool is bound in high-molecular 150 kDa GH-dependent ternary complexes composed of ALS, IGFBP-3 or -5 and IGF-I or -II in a 1:1:1 molar ratio. The ternary complex is, due to its size, confined to the bloodstream, and ternary complexed IGF is therefore unable to provoke hypoglycemia [223,316]. However, NICTH patients are virtually devoid of GH, most likely explained by an increased IGFmediated feedback inhibition, so that levels of IGF-I, IGFBP-3 and ALS are markedly suppressed.…”

“…However, NICTH patients are virtually devoid of GH, most likely explained by an increased IGFmediated feedback inhibition, so that levels of IGF-I, IGFBP-3 and ALS are markedly suppressed. Instead, an up-regulation of GH-independent peptides such as IGFBP-2, which become the main carriers of big IGF-II, as well as IGFBP-1, -4 and -6 have been noticed [223,313,316]. These IGFBPs do not form ternary complexes.…”

IGF2 and cancer

“…ALS, acid-labile subunit; IGF1, insulin-like growth factor 1; IGFBP3, IGF binding protein 3. Medical treatments include chemotherapy, glucocorticoids (Baxter et al 1995, diazoxide (Mitchell et al 1968), recombinant GH (Drake et al 1998), glucagon (Phillips & Robertson 1993), somatostatin analogues (Perros et al 1996) or combinations thereof. Of these, high-dose glucocorticoids are the most successful reducing both big IGF2 production and tumour size.…”

Severe hypoglycemia associated with insulin-like growth factor II-producing liver metastasis from gastric carcinoma treated with overnight total parenteral nutrition via a central vein catheter reserve port

“…Since our patient had multiple hepatic metastases, we selected best supportive care with the administration of glucocorticoid. Baxter et al [11] indicated that glucocorticoid therapies suppress peripheral glucose uptake and activate the IGF system. Moreover, glucocorticoids stimulate gluconeogenesis and might also normalize IGFBP profiles and reduce the serum level of big IGF-II [12].…”