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

Zapf, J.

doi:10.1159/000184139

Cited by 54 publications

(48 citation statements)

References 25 publications

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“…Such an event does not occur for two reasons: 1) formation of 150 kDa (ALS-IGFBP-3/IGFBP-5-IGF) complexes that cannot cross the vascular endothelial cell barrier allow high concentrations of IGFs to accumulate in the blood without risk of hypoglycemia; 2) much of the IGF in the remaining 40-50 kDa complex is bound to inhibitory IGFBPs, and the IGFs in this complex are not bioavailable unless this complex is broken down (Rajaram et al 1997). The importance of IGFBPs in preventing the insulin-like effects of IGFs is evident from studies involving non-islet cell tumor hypoglycemia (NICTH), in which hypoglycemia is seen in the absence of detectable insulin because of the overproduction of partially processed biologically active IGF-II by mesenchymal tumors (Daughaday et al 1993, Zapf 1994. The state of hypoglycemia found in patients with NICTH is associated with an increase in the serum concentration of pro IGF-II, a decrease in the circulating concentration of the 150 kDa complex, and a corresponding increase in the circulating concentration of 50 kDa complex (Daughaday et al 1993, Zapf 1994, Rajaram et al 1997.…”

Section: Igfbps Prevent the Insulin-like Activity Of Igfsmentioning

confidence: 99%

IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

Mohan

Baylink²

2002

Journal of Endocrinology

387

300

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Traditionally, binding proteins are known to regulate the activity of ligands by prolonging their half-life, and insulin-like growth factor (IGF)-binding proteins (IGFBPs) are no exception to this. The IGFBP family contains six high-affinity members with variable functions and mechanisms of actions. In addition to functioning as simple carrier proteins, IGFBPs in serum function to regulate the endocrine actions of IGFs by regulating the amount of IGF available to bind to signaling IGF-I receptors, whereas locally produced IGFBPs act as autocrine/paracrine regulators of IGF action. Furthermore, recent in vitro and in vivo findings that IGFBPs function independently of the IGFs as growth modulators are particularly exciting. Regarding the role of IGFBPs as ligand-independent growth modulators, our recent data that IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs provide evidence that IGFBP-5 itself is a growth factor that can act independently of IGFs to regulate bone formation. In terms of the mechanism by which certain IGFBPs mediate their effects in a ligand-independent manner, the binding of IGFBP to its putative receptor on the cell membrane may stimulate the signaling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBPs may also exert IGF-independent effects by transcriptional activation of genes by IGFBPs transported into the nucleus via their nuclear localization signal. In conclusion, IGFBPs are unusually pleotrophic molecules with functions ranging from the traditional role of prolonging the half-life of the IGFs to functioning as growth factors independent of the IGFs. In this regard, it was surprising to find that the human genome contains only about 35 000 genes. One mechanism to account for such complexity with a relatively small number of genes is strikingly illustrated by the multifunctional IGFBP class of proteins.

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Section: Igfbps Prevent the Insulin-like Activity Of Igfsmentioning

confidence: 99%

IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

Mohan

Baylink²

2002

Journal of Endocrinology

387

300

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“…The remaining IGFs circulate almost exclusively as binary IGF:IGFBP complexes of about 30±50 kDa, leaving less than 1 % in the free form [11]. In NICTH, the secretion of GH is suppressed [3], and this results in a reduction in the levels of the GH dependent peptides ALS, IGFBP-3 and IGF-I, and thus ternary complex formation [4,12]. Levels of IGFBP-2, the second most abundant IGFBP, and IGFBP-1 are, on the other hand, increased [5,13].…”

Section: : 589±594]mentioning

confidence: 99%

“…These changes cause a shift in the molecular distribution of the IGFs, and in NICTH as much as 80 % of the circulating IGF-II is reported to be carried in the binary complexes and hence, to have access to the interstitial space [17]. It is likely that patients with NICTH have increased synthesis and turnover of IGF-II at the same time, and therefore only modest changes in the circulating levels of serum total IGF-II [2,3].…”

Section: : 589±594]mentioning

confidence: 99%

Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia

et al. 1998

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Non-islet cell tumour hypoglycaemia (NICTH) is a relatively rare syndrome defined by the presence of a solid tumour and severe recurrent fasting hypoglycaemia, which develops despite low or immeasurable levels of serum insulin [1±4]. The tumours are believed to cause hypoglycaemia by increasing the insulin-like activity of the circulating insulin-like growth factor (IGF) system. Firstly, almost all tumours involved in NICTH have increased expression of IGF-II mRNA and contain elevated protein levels of big IGF-II, i. e. partially processed proIGF-II [4,5]. Big IGF-II is present in small amounts in normal serum [6], but highly elevated in serum from most patients with NICTH [7±9], and big IGF-II has been reported to have relatively high insulin-like activity in vitro [9].Secondly, NICTH is characterised by major changes in the composition of the circulating IGF-binding proteins (IGFBPs), which are important regulators of IGF-bioavailability [10]. In NICTH, the levels of serum total IGF-II (including normal and big IGF-II) are often within the normal range, or only modestly elevated [2±4]. Therefore, it appears more likely that changes in the bioavailability rather than in the absolute levels of IGF-II are of importance in the induction of hypoglycaemia. Normally, about 80±90 % of the circulating IGF immunoreactivity is carried in a Diabetologia (1998) Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia

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“…The regulation and biological role of pro-IGF-II is unknown, but its insulin-like bioactivity has been shown to be 3-fold increased in the rat fatcell bioassay as compared with mature IGF-II (14). Increased serum pro-IGF-II has been a key finding in non-islet cell tumour hypoglycaemia (NICTH), where it is thought to play a pathogenetic role in the development of hypoglycaemia (15,16).…”

Section: Introductionmentioning

confidence: 99%

Pro- and mature IGF-II during diet-induced weight loss in obese subjects

Espelund¹,

Bruun²,

Richelsen³

et al. 2005

eur j endocrinol

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Background: In normal subjects up to 10% of circulating insulin-like growth factor II (IGF-II) consists of pro-IGF-II. However, its regulation and biological impact remains unknown. In obese subjects, serum free and total IGF-II are increased, and we therefore investigated the impact of obesity and diet on serum pro-IGF-II. Design: Non-diabetic, obese subjects (n ¼ 34) with a body mass index (BMI) of 38.9^0.5 kg/m 2 were subjected to 8 weeks with very low calorie diet (800 kcal/day) followed by 12 weeks with a weightstabilizing diet. Fasting serum was collected before the study, and after 8 and 20 weeks. Pro-IGF-II was determined after acid-gel chromatography using a novel, highly specific in-house assay, free and total IGFs were measured after ultrafiltration and acid-ethanol extraction, respectively, and IGF-binding proteins (IGFBPs) were measured with specific immunoassays. Results: Diet reduced BMI and fasting levels of insulin and glucose (P , 0.001). Serum pro-IGF-II was markedly reduced in obese subjects as compared with matched normal-weight controls (means and 95% confidence intervals: 93 mg/l (82 -104 mg/l) versus 171 mg/l (152 -192 mg/l), respectively; P , 0.001), and levels remained unchanged after the weight loss. In contrast, during the study period total and free IGF-II decreased (P , 0.05), whereas total IGF-I, IGFBP-1 and IGFBP-2 increased (P , 0.001). Serum free IGF-I remained unaltered. Cross-sectional and longitudinal correlation analyses showed that pro-IGF-II was closer and more consistently associated with IGF-I than IGF-II. Conclusion: This study demonstrates that pro-IGF-II is reduced in obesity, in contrast to mature IGF-II. This indicates a hitherto unrecognized link between nutrition and pro-IGF-II. In addition, our data indicate that pro-IGF-II is regulated independently of mature IGF-II.

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

Cited by 54 publications

References 25 publications

IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia

Pro- and mature IGF-II during diet-induced weight loss in obese subjects

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