Pathophysiology of Diabetes Mellitus in Cushing’s Syndrome

Abstract

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 maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing’s syndrome.

Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: a large cross-sectional study

“…However, this association was not confirmed in IP patients, suggesting that alterations of glucose metabolism may be related to the degree of cortisol hypersecretion, which may indeed play an independent negative role. In fact, as also demonstrated in patients with Cushing's syndrome (35), cortisol excess has been shown to: inhibit insulin secretion (36,37), glucose uptake, and glycogen synthesis (38,39); worsen insulin sensitivity; and increase gluconeogenesis.…”

Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome

“…GC excess increases the expression of several key enzymes involved in liver gluconeogenesis and thus increased production of glucose; they also play an important role in the development of both insulin resistance and impaired b-cell function (7,37,38).…”

Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy

“…To determine which miRNAs might play a role in the dicer-KO phenotype, we examined the mRNAs upregulated in dicer-KO preadipocytes (GEO GSE24683) and asked whether there were enriched miRNA targets among them. Using gene set enrichment anal- partial lipodystrophy, especially in patients with HIV-related lipodystrophy (36)(37)(38)(39)(44)(45)(46)(47). To determine whether the latter might be linked to dicer downregulation, we analyzed biopsies of subcutaneous fat depots from the dorsocervical and abdominal regions of 2 independent cohorts of controls and HIV patients undergoing antiretroviral treatment (Supplemental Tables 6 and 7).…”