Endocrine Abstracts

Humans have 10 insulin-like genes, the most closely related being insulin and the adjacent gene, insulin-like growth factor II (IGF-II). Despite insulin being at the vanguard of endocrinology, the role of IGF-II has remained an enigma. IGF-II was first discovered with the observation that after all detectable insulin was depleted from serum with very specific antibodies, the vast majority of insulin activity remained. While insulin is a very simple gene, the IGF-II gene is far more complex. The activation of target cells by insulin is also relatively simple, enabled via the insulin receptor (IR) which has two alternatively spliced forms, IR-A and IR-B. In contrast, IGF-II activates both the IGF-I receptor and the IR-A with comparable affinities but is also tightly regulated by a very high affinity decoy-receptor and by 6 specific binding proteins. As IGF-II is vastly more abundant than insulin within the body it will be the primary activator of IR-A, other than during the immediate post-prandial phase. While genetic variants and defects of the IGF-I gene are associated with alterations in body growth; those of IGF-II are associated with metabolic defects. Lower mammals maintain their activity via grazing-eating providing continuous metabolic fuels. Higher mammals have evolved to stay active for long periods between meals and developed specialised visceral adipose stores to maintain energy supplies throughout the prolonged periods of fasting. This evolutionary transition was accompanied by a dramatic change in the pattern of IGF-II expression. I suggest that this has important consequences for humans who now revert to grazing-eating patterns. The more stringent regulation of IGF-II than the other insulin-like genes implies an important role, but the research community has devoted the least interest in it. I will give a perspective of a career attempting to address this question and the problems of challenging dogmas.