Mitogenic and metabolic effects of type IIGF receptor overexpression in insulin receptor-deficient hepatocytes

We have previously shown that hepatocytes lacking insulin receptors (Ir-/-) fail to mediate metabolic responses, such as stimulation of glycogen synth esis, while retaining the ability to proliferate in response to IGFs. In th is study we have asked whether overexpression. of type I IGF receptors woul d rescue the metabolic response of Ir-/- hepatocytes. After IGF-I stimulati on, insulin receptor substrate-1 and -2 phosphorylation and PI3K activity w ere restored to levels similar to or greater than those seen in wild-type c ells. Rates of cell proliferation in response to IGF-I increased approximat ely 2-fold, whereas glycogen synthesis was restored to wild-type levels, bu t was comparatively smaller than that elicited by overexpression of insulin receptors. In summary, overexpression of IGF-I receptors in Ir-/- hepatocy tes normalized insulin receptor substrate-2 phosphorylation and glycogen sy nthesis to wild-type levels, whereas it increased cell proliferation above wild-type levels. Moreover, stimulation of glycogen synthesis was submaxima l compared with the effect of insulin receptor overexpression. We conclude that IGF-I receptors are more efficiently coupled to cell proliferation tha n insulin receptors, but are less potent than insulin receptors in stimulat ing glycogen synthesis. The data are consistent with the possibility that t here exist intrinsic signaling differences between insulin and IGF-I recept ors.