Pathophysiology of Diabetes Mellitus in Cushings Syndrome

Cushing’s syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing’s syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintePublished online: September 10, 2010 Rosario Pivonello Department of Molecular and Clinical Endocrinology and Oncology ‘Federico II’ University of Naples, Via Sergio Pansini, 5 IT–80131 Naples (Italy) Tel. +39 081 746 4737, Fax +39 081 546 5443, E-Mail rpivone @ tin.it © 2010 S. Karger AG, Basel 0028–3835/10/0925–0077$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 4: 30 :4 9 A M Pivonello/De Leo/Vitale/Cozzolino/ Simeoli/De Martino/Lombardi/Colao Neuroendocrinology 2010;92(suppl 1):77–81 78 ment of the impairment of glucose tolerance and diabetes mellitus in Cushing’s syndrome is represented by the stimulation of gluconeogenesis and the development of insulin resistance, in association with the occurrence of an impairment of insulin secretion by the endocrine pancreas [3] . The concomitant occurrence of different metabolic complications, including dyslipidemia and impairment of protein metabolism, as well as the ‘metabolic syndrome’ associated with the increase and predominance of visceral adipose tissue significantly participates in the pathogenesis of insulin resistance and, consequently, the development of diabetes mellitus [3] . Physiological Role of GCs on Glucose Metabolism GC hormones are secreted by the cortex of the adrenal gland under the control of the hypothalamus-pituitaryadrenal axis. In humans, the most important agent belonging to the GCs is represented by cortisol, whereas corticosterone is the main adrenal cortex hormone in rodents, generally used for experimental studies on the adrenal gland. GCs play an important role in glucose metabolism as well as in lipid and protein metabolism and significantly contribute to the energy homeostasis. The most important physiological role of GCs on metabolism is displayed during the postprandial period, when they behave as contra-insular hormones, providing substrates for oxidative metabolism by stimulating lipolysis and proteolysis, with consequent release of fatty acids and amino acids, and by inducing glucose production, through the stimulation of gluconeogenesis and the inhibition of glycogen synthesis. The metabolic effects of GCs, including the actions directed to the regulation of glucose metabolism, are mainly exerted not only in the liver, and in the skeletal muscle, which is responsible for the great majority of postprandial glucose uptake from the circulation and lodge the largest store of glycogen, but in the adipose tissue as well [4] . Pathological Role of GC Excess on Glucose