Inappropriately Elevated Plasma Insulin‐like Growth Factor Ii in Relation to Suppressed Insulin‐like Growth Factor I in the Diagnosis of Non‐islet Cell Tumour Hypoglycaemia

Abstract

The diagnosis of non-islet cell tumour (hypoinsulinaemic) hypoglycamia has been complicated by contradictory biochemical evidence. Although insulin-like growth factor II (IGF-II) has been identified as the hypoglycaemic agent, plasma levels are often not elevated. In this study specific radioimmunoassay procedures for the measurement of IGF-I and IGF-II are described. Reference data on plasma IGF-II concentrations in relation to a wide range of IGF-I levels have been accumulated using plasma samples from acromegalic, hypopituitary and insulinoma (i.e. hyperinsulinaemic hypoglycaemia) patients as well as normal subjects from all age groups. The reference data indicate that a low plasma IGF-I value is normally associated with a relatively low plasma IGF-II level. Within a group of hypoinsulinaemic hypoglycaemia patients, a small number, invariably with evidence of a neoplasm, had low plasma IGF-I concentrations but apparently normal IGF-II levels. We propose that, in such cases, an apparently normal plasma IGF-II value is inappropriately high for the low plasma IGF-I level and, in association with non-ketotic hypoinsulinaemia and suppressed plasma growth hormone (GH), is diagnostic of a non-islet cell tumour as the cause of hypoglycaemia.

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

“…Glycosylation may therefore be a targeting signal for cleavage of the E-domain peptide and contribute to the size heterogeneity observed in 'big'-IGF-II. It seems likely that in many neoplastic cells the levels of the various enzymes involved in post-translational processing are not sufficient to handle the relatively high amounts of pro-IGF-II produced adequately (Megyesi et al 1974, Gorden et al 1981, Axelrod & Ron 1988, Daughaday et al 1988, Lowe et al 1989, Ron et al 1989, Shapiro et al 1990, Teale & Marks 1990, Daughaday & Trivedi 1992b, Zapf 1993, van Doorn et al 2002.…”

A 67-year-old woman with recurrent hypoglycemia: non-islet cell tumour hypoglycemia

“…A total IGF-II/IGF-I ratio of greater than 10 is felt to be diagnostic. 2 A description of how "big" IGF-II levels are measured is included in an online appendix (www.cmaj.ca/cgi/content/full /173/359/DC1).…”

Tumours producing hypoglycaemia

“…It was, however, only after radioimmunoassays for circulating IGF-I, IGF-II, and latterly, the E-domain of the 'large' or aberrant form of IGF-II, became available (Perdue et al 1991) that the key role of IGF-II in the pathogenesis of NICTH has been proved. Indeed the presence, in plasma, of increased concentration of IGF-II, mostly of the 'big' but also the normal variety (Daughaday et al 1988(Daughaday et al , 1990, coupled with a gross reduction in the amount of IGF-I is so characteristic of NICTH that it is diagnostically useful (Teale & Marks 1990).…”

“…This is analogous to the disproportionate ratio of proinsulin to insulin in the blood of most patients with insulinomas. Teale & Marks (1990) were the first to draw attention to the distortion of the IGF-II:IGF-I ratio in patients with NICTH and suggest that it might prove useful in its diagnosis, especially in cases in which IGF-II levels themselves were 'normal' or only slightly elevated. Their early conclusions have been confirmed repeatedly and a molar ratio of total plasma IGF-II:IGF-I of more than 10 is virtually pathognomonic of NICTH.…”

“…It is now recognised that in most cases it is a consequence of overproduction of an aberrant form of IGF-II (Megyesi et al 1974, Gorden et al 1981, Axelrod & Ron 1988, Ron et al 1989, Lowe et al 1989, Shapiro et al 1990, Teale & Marks 1990, Daughaday & Trivedi 1992. Other, even rarer causes, are sometimes encountered, however, and these will be discussed later.…”