Growth Hormone and Diabetes mellitus

Abstract

The diabetogenic action of pituitary extracts containing growth hormone has been recognised for more than 60 years and the importance of growth hormone in the development and progression of diabetic retinopathy for more than 30 years. Hypophysectomy was the first effective treatment for retinopathy but was discontinued because of the risk of severe hypoglycaemia that it produced and the development of an alternative, less dangerous therapy -photocoagulation. The precise role and significance of growth hormone in diabetes care, however, remains to this day a mystery. The fact that modern, highly purified biosynthetic preparations of growth hormone still retain full diabetogenic potency and the fact that diabetes develops in up to 25% of patients with acromegaly indicate growth hormone’s potential for involvement in the aetiology of diabetes mellitus, although most will agree that this is not likely to be an important factor in the large majority of ‘idiopathic’ cases. There is strong evidence to indicate a substantial hypersecretion of growth hormone in ‘idiopathic’ diabetes mellitus (particularly insulin-dependent cases and those with retinopathy), which appears to be more related to residual pancreatic insulin secretion than to metabolic control. Since the advent of biosynthetic growth hormone in sufficient quantity to perform trials in adults, we are more aware of growth hormone’s considerable potency in the regulation of body composition, growth factor production and intermediary metabolism. In this article, we review the literature and, from this and our own work, propose a new hypothesis which links the hypersecretion of growth hormone to reduced hepatic secretion of insulin-like growth-factor I (IGF-I) as a direct result of reduced portal insulin levels in diabetes mellitus. The hypersecretion of growth hormone exposes peripheral organs such as the retina and kidney to conditions favouring the expression of growth-hormone-dependent growth factors such as IGF-I which may contribute to the development of diabetic microvascular disease by autocrine and/or paracrine effects. If this hypothesis proves to be true, it offers new opportunities for the prevention of diabetic microvascular complications through suppression of growth hormone secretion which in turn will increase insulin sensitivity and facilitate good glycaemic control.

Low Serum IGF-I/GH Ratio Is Associated with Abnormal Glucose Tolerance in Acromegaly

“…Previous reports have indicated that insulin deficiency led to impaired hepatic IGF-I synthesis [27], and serum IGF-I levels were positively associated with the dose of insulin administration in type 1 DM patients [28]. Also, Sonksen’s group[29,30,31] have reported that insulin increased hepatic IGF-I expression and secretion. These data suggested that plasma insulin level was one of the positive regulators for serum IGF-I levels.…”

Recruitment of a Repressosome Complex at the Growth Hormone Receptor Promoter and Its Potential Role in Diabetic Nephropathy

“…One paradox of the role of GH/IGF-1 in the genesis of on May 10, 2018 by guest http://mcb.asm.org/ microvascular complication of DM is that the liver is resistant to GH while GH action is required for the genesis of retinopathy and nephropathy (1,19,21,23,30). Tissue-specific differences in the expression of the GHR may play a role in this differential sensitivity of organs to the effects of DM (21).…”

“…For humans, acquired hypopituitarism ameliorated retinopathy and iatrogenic hypopituitarism was the standard care for proliferative retinopathy until the advent of laser coagulation therapy (24). In contrast there is resistance to GH's actions in promoting linear growth and IGF-1 generation in poorly controlled IDDM (30); animal and human studies indicate that decreased hepatic expression of GHR contributes to this resistance to GH's actions (1,19,21). However, the molecular mechanisms underlying the paradox of the liver becoming resistant but the kidney and retina retaining sensitivity to GH in DM is not known.…”

The Glomerular Podocyte as a Target of Growth Hormone Action: Implications for the Pathogenesis of Diabetic Nephropathy

“…Paradoxically, despite the increase in the concentrations of circulating GH in patients with poor glycemic control, the concentrations of circulating IGF-1 are decreased, suggesting a state of GH resistance/insensitivity in Type 1 DM [24–26], Thus GH hypersecretion in Type 1 DM is the result of negative feedback on the hypothalamus and pituitary from reduced levels of circulating IGF-1 and decreased action of IGF-1 at the cellular level. The decrease in circulating levels of IGF-1 reflects a state of GH resistance secondary to decreased hepatic GHR mRNA and protein expression and abnormalities in GHR signaling pathways in the liver in uncontrolled diabetes.…”

“…However, on continuing the administration of Samatuline the differences between treated and placebo group failed to maintain statistical significance. In patients with acromegaly, surgical ablation of pituitary adenoma resulted in decreased GH levels and GFR followed by decrease in kidney size to normal values [26]. …”