Cortisol and metabolic syndrome
Prolonged elevation of cortisol can lead to hyperglycaemia and insulin resistance as observed in Type 2 diabetes and metabolic syndrome [164,170,171]. Glucocorticoids directly inhibit insulin release from the β pancreatic cells [172,173]. Cushing’s disease or hypercortisolism is a hormonal disorder that causes elevated cortisol levels. Adverse effects linked to upregulation of the HPA axis occur in patients with Cushing’s syndrome, causing outcomes such as osteoporosis, immunosuppression, hypertension, sleep disorders and glucose intolerance [174]. Other effects observed in women with high levels of cortisol include muscle wasting, striae, hirsuitism, acne, menstrual abnormalities and infertility [140]. Individuals who develop pathological states of glucocorticoid excess exhibit all the features of metabolic syndrome, however, Cushing’s syndrome is rare and the circulating levels of cortisol are normal in the majority of patients with obesity and Type 2 diabetes. One hypothesis is that tissue-specific deregulation of cortisol metabolism may be involved in the intricate pathophysiology of metabolic syndrome [175] and that changes in the expression of 11β-HSD1 increase tissue-specific levels of glucocorticoids [176,177]. Inhibitors of 11β-HSD1 are being evaluated in clinical trials for the treatment of Type 2 diabetes. The drugs work by decreasing the amount of cortisol generated in the liver and adipose tissue, thereby reducing gluconeogenesis and fatty-acid breakdown [178]. Ketoconazole is a steroid synthesis inhibitor that lowers cortisol in Cushing’s disease [179] by reducing plasma cortisol levels without affecting the CRH secretion in healthy adults [180].