Hypoglycemia in hepatocellular carcinoma: Failure of short-term growth hormone administration to reduce enhanced glucose requirements

Wing, Jeffrey; Panz, Vanessa R.; Joffe, B. I.; Kalk, W. J.; Seftel, H. C.; Zapf, J.; Kew, Michael C.

doi:10.1016/0026-0495(91)90232-l

Cited by 22 publications

(12 citation statements)

References 20 publications

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“…2 ml of normal or tumor serum was passed over a Sephadex G-200 (Pharmacia LKB Biotechnology Inc., Uppsala, Sweden) column (2.2 x 70 cm, flow rate 10 ml/h) in Dulbecco's buffer, pH 7.4, containing 20 mg/ 100 ml of NaN3. Fractions 51-64, 65-71, and 72-84 corresponding to the elution ranges of the 150-and 50-kD IGFBP complexes (as determined from the radiochromatographic pattern of normal and tumor serum preequilibrated with 125I-rhIGF II and gel filtered over the same Sephadex G-200 column) and fractions eluting before (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) and after (85-95 and 96-115) the two complexes (2 mg of HSA was added to fractions 80-115 to prevent adsorption of IGF to the tubes) were pooled, dialysed against 0.1 M NH4HCO3 in Spectrapor dialysis tubing (molecular weight cut-off, 3,500), lyophilized, and dissolved in 2 ml Krebs-Ringer-Hepes buffer, pH 7.4. The biological activity in each pool was determined in the presence of0.3 Ml of insulin antiserum (neutralizing capacity 0.4 mU) in the rat fat-cell assay (13).…”

Section: Methodsmentioning

confidence: 99%

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

Zapf¹,

Futo²,

Peter³

et al. 1992

J. Clin. Invest.

166

171

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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.

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Section: Methodsmentioning

confidence: 99%

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

Zapf¹,

Futo²,

Peter³

et al. 1992

J. Clin. Invest.

166

171

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“…Figure 4 also allows a therapeutic consideration: it should be possible to interrupt the vicious cycle and to reduce the glucose requirement in patients with EPTH by administering GH. Although Wing et al [13] have been unable to reduce enhanced glucose requirements in hypo glycemic patients with hepatocellular carcinoma by res toring GH levels towards normal during short-term GH infusion, glucose requirements were lowered by infusing higher doses of GH which raised serum GH levels into the acromegalic range [ 13], Altogether, EPTH can be classified as a paraneoplastic syndrome. In contrast to other paraneoplastic syndromes, oversecretion of the hormonal factor, big IGF II, by the tumor is masked in EPTH (1) by a 'negative feedback' obviously suppressing the production of normal IGF II by the body, and (2) by an altered distribution of the hor mone between its specific BP complexes in serum, which essentially enhances its bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Role of Insulin-Like Growth Factor II and IGF Binding Proteins in Extrapancreatic Tumor Hypoglycemia

Zapf

1994

Horm Res

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Serum from patients with extrapancreatic tumor hypoglycemia (EPTH) contains elevated levels of big (pro) IGF II which disappears after successful removal of the tumor. Nevertheless, total IGF II serum levels are mostly found in the normal range both before and after operation. Why then do these patients become hypoglycemic? Oversecretion of big IGF II leads to suppression of growth hormone (GH). As a consequence, formation of a GH-dependent 150-kD IGF binding protein (BP) complex is impaired which normally carries 70-80% of total serum IGF II and largely restricts its bioavailability. Impaired formation of the 150-kD complex leads to a shift of IGF II to a 50-kD IGFBP complex, resulting in a 30-fold shorter serum half-life of IGF II, increased turnover and enhanced bioavailability. Insulin target organs are thus exposed to an enormous insulin-like potential which is continuously provided by oversecreted big IGF II and causes increased glucose consumption by skeletal muscle, inhibition of hepatic glucose production, inhibition of lipid mobilisation from adipose tissue, and pronounced hypoglycemia.

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“…It was debated for many years whether this syn drome might be caused by tumor-derived IGFs (formerly known as somatomedins or nonsuppressible insulin-like activity, NSILA) [2][3][4][5]. In some individuals, increased serum total immunoreactive IGF-II levels have been found [6][7][8], free IGF-II is reported to be elevated [6], and the IGF-ILIGF-I ratio is generally elevated [7], There are many examples, however, where total immunoreactive IGF-II is reported to be normal or low [5,[8][9][10], often despite demonstrable overexpression of IGF-II mRNA by the tumor [11][12][13].…”

Section: Oversecretion Of Igf-ii Precursorsmentioning

confidence: 99%

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

Baxter¹

1996

Horm Res

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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.

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Hypoglycemia in hepatocellular carcinoma: Failure of short-term growth hormone administration to reduce enhanced glucose requirements

Cited by 22 publications

References 20 publications

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

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

Role of Insulin-Like Growth Factor II and IGF Binding Proteins in Extrapancreatic Tumor Hypoglycemia

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

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