Traditional and novel aspects of the metabolic actions of growth hormone

Abstract

Growth hormone has been known to be diabetogenic for almost a century and it's diabetogenic properties fostered consideration of excessive and abnormal GH secretion as a cause of diabetes, as well as a role in the microvascular complications, especially retinopathy. However, besides inducing insulin resistance, GH also is lipolytic and a major anabolic hormone for nitrogen retention and protein synthesis. These actions are best illustrated at the extremes of GH secretion: Gigantism/acromegaly is characterized by excessive growth, CHO intolerance, hyperplasia of bone, little body fat and prominent muscle development, whereas total deficiency of GH secretion or action is associated with adiposity, poor growth, and poor muscle development. These actions also become apparent during puberty and pregnancy, times when GH secretion is increased and account for the characteristic changes in body composition and tendency to diabetes. More recently, tissue specific deletions of the GH receptor (GHR), have uncovered newer metabolic effects including it's essential role in triglyceride export from the liver when GHR is deleted in the liver, leading to hepatic steatosis and ultimately to hepatic adenoma formation, effects which may explain these findings in obesity, a state of diminished GH secretion and action. In addition deletion of GH action in muscle and fat is associated with specific patterns of disturbed phenotype and metabolic effects in CHO, fat, and protein metabolism affecting the specific tissue and whole body function. This chapter provides an overview of these classic and newer metabolic functions of GH, placing this hormone and its actions in a central role of body fuel economy in health and disease.

Introduction

A metabolic role for growth hormone (GH) has been postulated for over 80 years, one of the first being the Nobel laureate Bernardo Houssay, who showed in 1930 that hyperglycemia and other biochemical abnormalities improved after hypophysectomy in experimental-induced diabetes in dogs [1], [2]. By contrast, injections of pituitary extracts, and later purified GH, resulted in hyperglycemia and frank diabetes, younger dogs being more resistant to these effects than adult dogs; complications of diabetes such as retinopathy improved after pituitary infarction during labor and delivery in pregnancy (Sheehan's syndrome). In humans, acromegaly was associated with a greater prevalence of diabetes which could be provoked by several days of GH administration [2]. So strong were these associations that it was believed for some time that GH, or other hormonal abnormalities, might be the cause of diabetes and contribute to the complications. Indeed, until the advent of laser therapy in the mid-1970s, the standard therapy for proliferative retinopathy associated with diabetes was pituitary ablation via surgery or implantation of radioactive yttrium into the pituitary fossa [3].