Hypoglycemic Effect of Insulin-like Growth Factor II (IGF-II) Is Mediated Mainly through Insulin and/or IGF-I Receptor but not IGF-II Receptor

Abstract

Insulin-like growth factor-II (IGF-II) has an insulin-like effect in vitro and in vivo. Recently, mutants of IGF-II have been synthesized by the site-directed mutagenesis technique, and the structure determinants for the function of IGF-II have been studied. With the availability of the biosynthetic IGF-II and IGF-II mutants, we have investigated the hypoglycemic effect of IGFnormal rats and insulin resistant mice. When the IGF-II mutants with markedly decreased affinities for both insulin and IGF-I receptors were injected in normal rats, the blood glucose levels slightly decreased. However, when IGF-II mutant with slightly decreased affinities for both insulin and IGF-I receptors was injected, the blood glucose decreased to the same extent as with IGF-II. In insulin resistant mice, insulin did not decrease the blood glucose levels, but, the blood glucose levels decreased after IGF-I and IGF-II injection. The hypoglycemic effect of IGF-II was greater than that of IGF-I. The IGF-II mutant without affinity for IGF-II receptor but with affinities for both IGF-I and insulin receptors the same as IGF-II, caused hypoglycemia the same as IGF-I. However, the IGF-II mutant with markedly decreased affinities for both insulin and IGF-I receptors did not decrease blood glucose levels, and the IGF-II mutant with slightly decreased affinities for both insulin and IGF-II receptors slightly decreased blood glucose levels. These data indicate that the hypoglycemic effect of IGF-II is mediated mainly through insulin and/or IGF-I receptor but not IGF-II receptor. Furthermore, the data suggest that IGF-II might also be useful for the treatment of the insulin resistant status.

Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia

“…In 1988, Daughaday et al reported a case of leiomyosarcoma producing insulin-like growth factor (IGF)-II associated with recurrent hypoglycemia [2]. As IGF-II has a hypoglycemic effect in animal studies [3] and an amino acid sequence homologous to that of proinsulin, these investigators concluded that IGF-II produced and secreted by the tumor was the cause of the hypoglycemia in this patient [2]. Since that report there have been many similar cases described in the literature [4][5][6], with IGF-II producing non-islet-cell tumor hypoglycemia (NICTH) now recognized as a major cause of fasting hypoglycemia [7].…”