Large tumours, usually of mesodermal origin, can cause severe and often intractable hypoglycaemia in the presence of undetectable levels of insulin. This phenomenon, referred to as non-islet-cell tumour hypoglycaemia (NICTH), is now generally thought to be due to secretion by the tumour of insulin-like growth factor-2 (IGF-2). Various interactions of IGF-2 with different receptors have been described,1 but most of the biological actions of IGF-2 are thought to be mediated via the IGF-1 receptor (IGF-1R), the binding of which results in differentiation, malignant transformation and the regulation of cell–cell adhesion. Interaction with the IGF-2 receptor (IGF2-R) promotes endocytosis and degradation of extra-cellular IGF-2 and may play a role in the transport of lysosomal enzymes, but is unlikely to be pathologically important. However, IGF-2 has also been shown to have high affinity binding with the insulin receptor; binding to the A isoform predominantly leads to mitogenic effects, but it also has (low) affinity with the B isoform that is principally concerned with its metabolic effects, including hypoglycaemia. Usually, IGF-2 is extensively bound to its binding-protein BP-3, and thus very little has access to the extravascular space. In NICTH the secretory product is principally the precursor pro-IGF-2, which is unable to bind BP-3 and thus can access extra-vascular receptors such as the insulin receptor isoforms. Thus, it has been thought that the hypoglycaemia in this condition relates to IGF-2 occupation of the insulin receptor. Downstream signalling form the insulin receptor involves the mammalian target of rapamycin (mTOR) pathway, and several recent case reports have suggested that blockade of the mTOR pathway with everolimus can effectively treat the severe hypoglycaemia associated with …