Metabolic comorbidities in Cushing's syndrome

Abstract

Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome

“…According to its central role in physiology, disturbances in glucocorticoid secretion or prolonged glucocorticoid therapy have unwarranted clinical consequences. In fact, endogenous hypercortisolism also referred to as Cushing's syndrome (CS) is associated with increased mortality (2), due to impaired glucose metabolism, infectious and thrombotic complications, and musculoskeletal and cardiovascular co-morbidities (3). Even in patients with milder forms of hypercortisolism, who are not clinically evident as overt CS, metabolic and cardiovascular complications are well recognized (4,5,6).…”

Lack of association of the HSD11B1 gene polymorphisms with obesity and other traits of metabolic syndrome in children and adolescents

“…Of note, typical features, which define MetS are equally encountered in patients suffering from glucocorticoid excess, i.e. Cushing's syndrome, either of endogenous or exogenous origin [3,4]. These clinical observations prompted detailed studies of the hypothalamo-pituitary-adrenal (HPA) axis in patients with obesity and MetS.…”

Does pasireotide directly modulate skeletal muscle metabolism?

“…Besides a number of other metabolic comorbidities, such as hyperglycemia, dyslipidaemia, and obesity, protein metabolism is severely affected by GC excess via direct and indirect stimulation of protein degradation and inhibition of protein synthesis, which can lead to muscle tissue loss [2].…”

“…For this purpose, the Authors investigated the effects of pasireotide in the modulation of protein turnover and its interaction with the synthetic glucocorticoid dexamethasone (DEX) in differentiated rat myoblast-like cells (L6 cell line), a model of skeletal muscle cells [7]. More in detail, they focused on the effects of pasireotide on the mTOR-p70S6 kinase-S6 ribosomal protein signaling pathway, which plays a crucial role in the protein synthesis machinery [2]. From a clinical perspective, the demonstration of a direct anabolic effect of pasireotide on muscle cells could further strengthen the rationale for its use in CD treatment, and pave the way for pasireotide treatment in other diseases characterized by an excess of catabolism and loss of lean mass.…”

“…In their experimental setting, the Authors observed a positive effect of pasireotide on protein synthesis, and therefore they further investigated one of the main intracellular pathways related to this aspect. Indeed, during GC-mediated reduction of protein synthesis, GCs interfere with the stimulatory activity of hormones (e.g., insulin, IGF-1) and amino acids on Akt-mTOR pathway and, subsequently, on the phosphorylation of their substrates, such as the S6 ribosomal protein [2].…”