The mechanism of non‐islet cell hypoglycaemia caused by tumour‐produced IGF‐II

Zachariah, Sunil; Brackenridge, Anna; Shojaee‐Moradie, Fariba; Camuncho-Hubner, C.; Umpleby, A. Margot; Russell‐Jones, David

doi:10.1111/j.1365-2265.2007.02938.x

Cited by 10 publications

(8 citation statements)

References 6 publications

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“…Also, in the single human sample run for IGF-II on a Western blot by Qiu et al, "big" IGF-II was present but pro-IGF-II was not seen (19). In addition, the single human sample run by Zachariah et al showed bands that did not appear to be separated enough to determine whether both pro-IGF-II and "big" IGF-II were present (20). Thus, it had been speculated that pro-IGF-II was not present in human plasma.…”

Section: Discussionmentioning

confidence: 92%

“…This same study also showed that this technique could be used on human plasma to achieve the same separation, suggesting that Western blotting could be an alternative to immunoassays that would distinguish between "big" IGF-II and pro-IGF-II. Another report from the same year also demonstrated successful separation of the forms of IGF-II in a single human sample, although the separation was not sufficient to individually distinguish "big" and pro-IGF-II (20).…”

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confidence: 90%

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Plasma Distribution and Signaling Activities of IGF-II Precursors

et al. 2011

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IGF-II is thought to function through activation of the IGF-I receptor (IGF-IR) and the A isoform of the IR, with the IGF-IR being relevant to tumorigenesis and the IR to both tumorigenesis and metabolic control. In the paraneoplastic syndrome of nonislet cell tumor hypoglycemia, tumor-derived IGF-II has been proposed to exert both proliferative and metabolic effects, exemplifying this dual mode of action. Increased levels of IGF-II precursors ("big" and pro-IGF-II) have been reported in the circulation of nonislet cell tumor patients and have been proposed to exert greater or different effects than mature IGF-II. However, most studies have not defined which version is being investigated, and the relative activation of the IR and IGF-IR by IGF-II precursors has not been delineated. In this study, we determined the distribution of IGF-II isoforms in normal human plasma and their ability to activate the alternative versions of the IR. The majority (71%) of total IGF-II in human plasma was the mature form, while "big" and pro-IGF-II comprised 16% and 13%, respectively, with more variation seen in the levels of mature IGF-II. In IGF-IR-deficient cells expressing similar levels of human IR-A or IR-B, mature and "big" IGF-II exhibited similar activation of IR signaling, while pro-IGF-II exhibited significantly less activation. Downstream activation of Akt by mature and "big" IGF-II was greater in IR-A cells, consistent with previous reports of the greater affinity of IR-A for IGF-II. Thus, both IGF-II precursor forms are present in human plasma but do not preferentially activate the IR.

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Section: Discussionmentioning

confidence: 92%

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confidence: 90%

Plasma Distribution and Signaling Activities of IGF-II Precursors

et al. 2011

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“…Several studies on NICTH indicate that a major part of the glucose intake is rapidly disposed into peripheral tissues, especially skeletal muscle, rather than consumed by the tumour. Suppression of hepatic glucose production or fat oxidation does occur but seems to play a minor role in the development of hypoglycaemia (Eastman et al 1992, Chung & Henry 1996, Zachariah et al 2007. Indeed, in contrast to the liver, skeletal muscle contains large numbers of both the IGF1R and insulin receptors (Daughaday & Rotwein 1989) and the effect of 'big'-IGF-II on peripheral tissue was greater than its effect on the liver (Zachariah et al 2007).…”

Section: J W B De Groot Et Al: Non-islet Cell Tumour-induced Hypoglymentioning

confidence: 99%

Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases

Groot¹,

Rikhof²,

Doorn³

et al. 2007

Endocrine Related Cancer

202

326

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This review focuses on the tumour types and symptoms associated with non-islet cell tumourinduced hypoglycaemia (NICTH) as well as the pathogenesis, diagnosis and treatment of this rare paraneoplastic phenomenon. In addition, we report two illustrative cases of patients suffering from NICTH caused by a solid fibrous tumour and a haemangiopericytoma respectively. In the first case, NICTH resolved following complete resection of the tumour, but in the second case the patient needed long-term treatment aimed at controlling hypoglycaemia because of nonresectable metastases. Many tumour types have been associated with NICTH. The crucial event in the development of NICTH seems to be overexpression of the IGF-II gene by the tumour. NICTH is characterised by recurrent fasting hypoglycaemia and is associated with the secretion of incompletely processed precursors of IGF-II ('big'-IGF-II) by the tumour. This induces dramatic secondary changes in the circulating levels of insulin, GH, IGF-I and IGF-binding proteins, resulting in an insulin-like hypoglycaemic activity of 'big'-IGF-II.

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“…Theoretically, both IGF-I and IGF-II are capable of decreasing glucose levels, but, they fail to do so because they are normally trapped within the vascular vessel in a high molecular weight protein complex with IGFBP3 and acid-labile subunit (ALS). 12 – 14 The big IGF-II reside in the binary complex with IGFBP3 which was considered to be capable of crossing the endothelial barrier, resulting in a persistent insulin-like activity and leading to severe hypoglycemia. 15 , 16 …”

Section: Discussionmentioning

confidence: 99%

Severe Hypoglycemia Caused by Recurrent Sarcomatoid Carcinoma in the Pelvic Cavity

Fang

Fan

et al. 2015

Medicine

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Nonislet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia in different tumor types of mesochymal or epithelial origin; however, NICTH is infrequently induced by sarcomatoid carcinoma (SC). Despite some sarcomatoid and epithelioid characteristics in few cases of malignancies from epithelium, NICTH induced by recurrent SC in pelvic cavity in this report is extremely rare.We report a case in which NICTH caused by recurrence and pulmonary metastases from SC in the pelvic cavity, and the computed tomography scan revealed multiple pelvic masses and multiple large masses in the pulmonary fields. During the treatment of intestinal obstruction, the patient presented paroxysmal loss of consciousness and sweating. Her glucose even reached 1.22 mmol/L while the serum glycosylated hemoglobin was normal and previous history of diabetes or use of oral hypoglycemic agents and insulin denied.The laboratory examination showed that the low level of insulin, C-peptide, and growth hormone levels in the course of hypoglycemic episodes suggesting to the diagnosis of hypoglycemia induced by nonislet cell tumor, and the decreased levels of insulin-like growth factor (IGF)-I and IGFBP3 and the high expression of big IGF-II in the serum further confirmed the diagnosis of NICTH. Because of the widely pelvic recurrence and pulmonary metastases were unresected, the patient was discharged from the hospital after 2 weeks treatment with dexamethasone and glucose and unfortunately died 1 week later.NICTH caused by SC in the pelvic cavity is extremely rare case in clinical. The aim of this report was to present the importance to examine big IGF-II expression in patient's serum in order to reach the diagnosis of NICTH in cases of intractable cancer-associated hypoglycemia.

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The mechanism of non‐islet cell hypoglycaemia caused by tumour‐produced IGF‐II

Cited by 10 publications

References 6 publications

Plasma Distribution and Signaling Activities of IGF-II Precursors

Plasma Distribution and Signaling Activities of IGF-II Precursors

Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases

Severe Hypoglycemia Caused by Recurrent Sarcomatoid Carcinoma in the Pelvic Cavity

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