Impaired insulin-like growth factor I-mediated stimulation of glucose incorporation into glycogen in vivo in the ob/ob mouse

Abstract

The ability of insulin to modulate glucose metabolism is impaired in insulin resistant ob/ob mice. It has been shown that insulin-like growth factor I stimulates the uptake and metabolism of glucose in muscle through the insulin-like growth factor receptor not the insulin receptor. Thus, we have compared the abilities of insulin-like growth factor I and insulin to stimulate the in vivo incorporation of [14C]-glucose into glycogen in the diaphragm of ob/ob mice and their lean littermates. The animals used in these studies were 12-14 weeks old and the serum insulin levels of the ob/ob mice were 16-fold higher than in their lean littermates. There were no differences in the serum levels of glucose or insulin-like growth factor I. Both insulin and insulin-like growth factor I stimulate the incorporation of [14C]-glucose into glycogen in lean mice. Significant stimulation occurs at doses as low as 1 μg/kg of either peptide. The effective doses of insulin and insulin-like growth factor I are quite similar, which indicates that the effect of insulin-like growth factor I is mediated by the insulin-like growth factor receptor and not the insulin receptor. In contrast, greater than 100 μg/kg of insulin-like growth factor I is required to stimulate [14C]-glucose incorporation into glycogen in the diaphragm of ob/ob mice. Thus, ob/ob mice are resistant to the action of both insulin and insulin-like growth factor I. In contrast to the decrease in the number of insulin receptors which occurs in ob/ob mice, there is no significant difference in the number of type 1 insulin-like growth factor receptors or in their affinity for insulin-like growth factor I in muscle membranes prepared from lean and ob/ob mice. In addition, the ability of insulin-like growth factor I to stimulate the catalysis of Val5-angiotensin II phosphorylation by the partially purified muscle type 1 insulin-like growth factor receptor is not decreased in ob/ob mice as compared with their lean littermates. These data indicate that the loss in sensitivity of the ob/ob mouse of both insulin and insulin-like growth factor I is most likely mediated by a post-receptor defect in metabolism and not by receptor down-regulation or desensitisation. © 1989 Springer-Verlag.