Abstract
Spontaneous hypoglycaemia or fasting hypoglycaemia may be caused by inappropriate hyperinsulinaemia sometimes seen in exogenous insulin therapy. Endogenous causes of hyperinsulinaemia may occur, for example, due to autonomous production by an insulinoma, or from a compensatory increase in the rare insulin receptor defect or autoimmune insulin syndrome. 1 Insulin inhibits lipolysis and ketogenesis, and a lack of insulin is often commensurate with increased ketones. In the event of hypoglycaemia, hypoinsulinaemia and absence of ketones, increased activity of insulin-like growth factors (IGFs) should be considered. Some causes of adult hypoglycaemia are shown in Box 1. 2
Some causes of adult hypoglycaemia
glucocorticoid deficiency/adrenal insufficiency hypothyroidism hypopituitarism
severe liver disease established renal failure severe congestive cardiac failure
liver, kidney, lung/pleura, breast, head/neck mesenchymal, haemangiopericytomas leukaemias and lymphomas
insulinoma insulin receptor antibodies autoimmune insulin syndrome exogenous insulin, sulphonylureas, meglitinides
idiopathic postgastric surgery alcohol induced
von Gierke's disease (type 1 glycogen storage disease) drugs: e.g. salicylates, quinine, haloperidol, pentamidine, sulphonamides
In this issue of the Annals, Thabit et al. 3 present a case of non-islet cell tumour hypoglycaemia (NICTH) with hypoinsulinaemia in a patient with a large thoracic tumour. The overproduction of big-IGF2 was suggested by suppressed growth hormone (GH) and IGF1 concentrations, a raised IGF2:IGF1 ratio, and the resolution of symptoms on surgical removal of the tumour. Spindle cell tumour presenting with spontaneous hypoglycaemia was first reported over 80 y ago and subsequently various cases have been reported in the literature of the so-called Doege–Potter syndrome. 4 One must be mindful, however, that other tumours (see Box 1) may also be associated with hypoglycaemia, as are secondary lung metastases from some hepatic, biliary and pancreatic tumours. 4 Solitary fibrous tumours of the pleura represent 5% of all pleural tumours 5 and are associated with hypoglycaemia in 5% of cases, 4 attributed to big-IGF2 autonomous production. These tumours have characteristic pattern-less spindle cell arrangement with positive staining for CD34 and vimentin, and have been reported to also occur in the abdomen and the head and neck regions. 6,7
Mature IGF2 is cleaved from its prohormone pro-IGF2, which differs only by its 89 amino acid long E-domain. Pro-IGF2 can also be cleaved at position 21 of the E-domain yielding pro-IGF2-(E1–21), more commonly referred to as ‘big-IGF2’. 8 The latter is found in small quantities in normal sera but its biological function remains unclear. Normal big-IGF2 has a characteristic O-linked glycosylation of threonine at position 8 of the E-domain. In NICTH, big-IGF2 concentration is increased but it lacks normal O-glycosylation at the E-domain. The overproduction of aberrant big-IGF2 has been attributed to a loss of paternal allele imprinting or mutation in the responsible tumour suppressor genes. 6 Prohormone convertase 4, a candidate endoprotease responsible for the cleavage of pro-IGF2, has been shown to be under-expressed in NICTH. 9 Aberrant big-IGF2 in NICTH acts as a prohormone, which retains much of the action of its mature IGF2 form. As big-IGF2 has poor affinity binding to IGF binding protein 3 (IGFBP3), it mainly exists in its free form or binary complex formation with other IGFBPs, forms which confer increased bioavailability by virtue of their increased capillary permeability to reach target tissues. 6
Much of the action of big-IGF2 is mediated by its affinity to three structurally homologous receptors – the IGF type 1 receptor, IGF type 2 receptor and both the isoforms of the insulin receptor. The IGF1 receptor mediates cellular growth and proliferation and the IGF2 receptor regulates the circulating concentrations of big-IGF2 by endocytosis and subsequent intracellular degradation. The autonomous action of big-IGF2 suppresses the pituitary production of GH in a negative feedback loop and this in turn suppresses endogenous production of IGF1 and insulin. Thus, a low plasma IGF1 concentration with a raised IGF2:IGF1 ratio is often seen in NICTH, although the total mature IGF2 concentration may well remain in the reference range. This may be explained by the relatively higher proportion of free big-IGF2 now present as a result of its poor binding affinity to its carrier binding protein IGFBP3. 6 The increased activation of the IGF1 receptor by big-IGF2, instead of IGF1, leads to clinical manifestation of acromegalic features such as skin tags and oily skin in some reported cases of NICTH. 6 It is possible that the goitre, which the patient presented with in the case of Thabit et al., 3 was secondary to trophic actions via the IGF1 receptor on the thyroid as previously described. 10,11
Strictly speaking, the hypoglycaemia of NICTH is not the result of increased tumour consumption of circulating glucose. It is increasingly recognized that two separate and intertwined processes may contribute significantly to the occurrence of hypoglycaemia. The ability of big-IGF2 to bind to IGF1 receptor and insulin receptor (B-isoform) is known to promote peripheral tissue glucose uptake and reduce hepatic gluconeogenesis, respectively. The hybrid insulin/IGF1 receptor expressed in tissues with both IGF1 and insulin 12 may play a role here.
The coexistence of hypoglycaemia and glucose intolerance in the same patient presented by Thabit et al. 3 suggests simultaneous insulin action and resistance. In the presence of low circulating insulin concentrations, the pathogenic mechanism is likely to reside at the postreceptor level. It is possible that the continuous activation of insulin receptors by big-IGF2 induces a postreceptor negative feedback causing insulin resistance and glucose intolerance 13 as unmasked by the oral glucose tolerance test results in the presented case. This is akin to the insulin resistance observed in insulinoma patients.
In conclusion, the diagnosis of NICTH should be considered in chronic, spontaneous, fasting hypoglycaemia with hypoinsulinaemia, presenting with typical neuroglycopaenic symptoms such as personality changes and lethargy. Genuine hypoglycaemia should be confirmed with plasma glucose and concurrent plasma insulin and C-peptide measurements. A suppressed plasma GH and IGF1 concentration are helpful supportive findings, as is the IGF2:IGF1 ratio. 6 The demonstration of raised plasma big-IGF2 is desirable but not always necessary or possible due to the fact that few laboratories offer this assay. Both Western immunoblotting and size-exclusion acid chromatography have been employed to detect big-IGF2. Ultimately, the confirmatory diagnosis is made on the resolution of hypoglycaemia after the removal of the tumour.
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