Growth hormone receptor deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice

Growth hormone (GH), acting through its receptor (GHR), is essential for somatic growth and development and maintaining metabolic homeostasis. GHR gene deficient (GHR) mice exhibit drastically diminished IGF-I levels, proportional growth retardation, elevated insulin sensitivity and reduced islet β-cell mass. Unlike the liver which is mostly unaffected by changes in the IGF-I level, skeletal muscles express high levels of IGF-I receptor (IGF-IR). The net result of a concurrent deficiency in the actions of both GH and IGF-I, which exert opposite influences on insulin responsiveness, has not been evaluated. Here we have studied insulin-stimulated early responses in the insulin receptor (IR), IRS-1 and p85 subunit of PI3K. Upon in vivo insulin stimulation, the skeletal muscles of GHR mice exhibit transient delayed responses in IR and IRS-1 phosphorylation, but normal level of p85 association with IRS-1. This is in contrast to normal/elevated insulin responses in hepatocytes and indicates tissue-specific effects of GHR gene deficiency. In addition to stimulating normal islet cell growth, GH might participate in islet cell overgrowth, which compensates for insulin resistance induced by obesity. To study whether the islet cell overgrowth is dependent on GH signaling, we have studied the response of male GHR mice to high-fat diet (HFD)-induced obesity. After 17 weeks on a HFD, GHR mice became more significantly obese than the wild-type mice and exhibited increased β-cell mass to a slightly higher extent. This data demonstrates that GH signaling is not required for compensatory islet growth. Thus, in both muscle insulin responsiveness and islet growth compensation, normal levels of GH signals do not seem to play a dominant role.