Growth Hormone-Induced Alterations in the Insulin-Signaling System

Abstract

Growth hormone (GH) counteracts insulin action on lipid and glucose metabolism. However, the sequence of molecular events leading to these changes is poorly understood. Insulin action is initiated by binding of the hormone to its cell surface receptor (IR). This event activates the intrinsic tyrosine kinase activity residing in the β-subunit of the IR and leads to autophosphorylation of the cytoplasmic portion of the β-subunit and further activation of its tyrosine kinase towards several intermediate proteins, including the family of IR substrates (IRS) and the Shc proteins. When tyrosine phosphorylated, these cellular substrates connect the IR with several downstream signaling molecules. One of them is the enzyme phosphatidylinositol (PI) 3-kinase. The insulin antagonistic action of GH is not a consequence of a direct interaction with the IR. Instead, long-term exposure to GH is, in general, associated with hyperinsulinemia, which leads to a reduction of IR levels and an impairment of its tyrosine kinase activity. The signals of GH and insulin may converge at post-receptor levels. The signaling pathway leading to activation of PI 3-kinase appears to be an important site of convergence between the signals of these two hormones and seems to be mediated principally by IRS-1. Rodent models of chronic GH excess have been useful tools to investigate the mechanism by which GH induces insulin resistance. Decreased IR, IRS-1, and IRS-2 tyrosyl phosphorylation in response to insulin was found in skeletal muscle, whereas a chronic activation of the IRS-PI 3-kinase pathway was found in liver. The induction of the expression of proteins that inhibit IR signaling such as suppressors of cytokine signaling (SOCS)-1 and -6 may also be involved in this alteration. interestingly, the modulation of Insulin signaling and action observed in states of GH excess, deficiency, or resistance seems to be relevant to the changes in longevity associated with those States.

Nutritional Factors That Regulate Ovulation of the Dominant Follicle During the First Follicular Wave Postpartum in High-producing Dairy Cows

“…Plasma concentrations of growth hormone (GH) secreted from the pituitary increase from late gestation and an acute surge is observed at parturition [35]. GH acts on adipose tissue to stimulate lipolysis, namely, tissue mobilization is driven by increases in the rate of secretion of GH [36,37]. Furthermore, in the physiological states of undernutrition and early lactation, the liver becomes GH resistant [38,39].…”

Altered metabolism and resistance to obesity in long-lived mice producing reduced levels of IGF-I

“…GH can cause insulin resistance directly by altering the activity of insulin-stimulated phosphatidylinositol 3-kinase, thereby reducing insulin signaling (44). The elevated levels of GH present in IGF-I-deficient mice may then contribute to the insulin-resistant phenotype as a result of the interaction between GH receptor signaling and insulin signaling (16). GH can also elevate blood glucose levels by stimulating gluconeogenesis, further contributing to hyperglycemia (43).…”

“…Many possible downstream effectors have been proposed as primary mechanisms that underlie this relationship; however, several commonalities in the response to caloric restriction and reduced IGF-I signaling have led to the suggestion that a shift in metabolism toward improving insulin sensitivity may be a key determinant of mammalian longevity (1). In support of this, long-lived mice deficient in growth hormone (GH), the primary effector of circulating IGF-I levels in mammals, or long-lived mice deficient in the receptor of GH display both a general enhancement of insulin sensitivity and reduced circulating levels of glucose and insulin (5,15,16,28). However, this relationship has been less clearly defined in models in which IGF-I signaling has been targeted directly.…”

Diabetes in chronic liver disease: from old concepts to new evidence

“…Observations, at molecular level, have proven that GH does not directly interact with IR, whereas it modulates insulin activity at post-receptor levels. In other words, the binding of GH to its receptor affects the post-receptor signalling cascade by promoting the tyrosine phosphorylation of IRS-1 and IRS-2 through the activation of Janus Kinase (JAK)-2 [80]. This increased IRS phosphorylation leads to tissue insensitivity towards further insulin stimulation.…”