Decreased insulin binding and antilipolytic response in adipocytes from patients with Cushing's syndrome

Abstract

Human adipocytes from patients with chronic endogenous hypercortisolism (Cushing's syndrome) showed a statistically significant decrease in insulin binding at low unlabelled-insulin concentrations but no change in receptor numbers (Cushing's 180,000 +/- 48,000 (3) receptors/cell and controls 189,000 +/- 30,000 (7)) together with a fourfold decrease in apparent receptor affinity (ED50: Cushing's 2.25 x 10(-9) M and controls 0.57 x 10(-9) M) and a decreased sensitivity to the antilipolytic effect of insulin. These events could represent the final situation of a chronic and endogenous regulation by high levels of cortisol of insulin receptors in human adipose tissue.

Insulin Receptor mRNA Levels are Modulated in a Tissue-Specific Manner in Cushing's Syndrome Patients

“…first evidence that human IR mRNA levels may be modulated "in vivo" by high levels of glucocorticoids. The absence of alterations in IR mRNA levels in the subcutaneous adipose tissue of the Cushing's patients is in agreement with our earlier results, indicating that there were no changes in the total number of (IR)s in adipocytes from patients with this pathology (Calle et al 1987). Nevertheless, these adipocytes exhibited decreased sensitivity to the antilipolytic effect of insulin {Calle et al 1987), suggesting the existence of a defect in some step in the signaling pathway between insulin binding and the antilipolytic response.…”

“…Cushing's syndrome is a pathological model of insulin resistance produced by chronically high Cortisol levels {Nosadini, Del Prato, Hengo, Valerio, Muggeo, Opocher, Mantero, Duner, Marescotti, Mollo and Belloni 1983;Karnieli, Cohen, Barzilai, Ish Salom, Armoni, Rafaelov and Barzilai 1985). In isolated adipocytes from patients with this syndrome we have previously observed a decreased sensitivity to the antilipolytic action of insulin without changes in the total number of insulin receptors (IR)s on the cell surface (Calle, Carranza, Simon, Torres and Mayor 1987). Other laboratories also failed to detect insulin receptor defects in erythrocytes and monocytes from hypercortisolemic patients, despite the presence in these patients of a clear situation of insulin resistance (Nosadini et al 1983;Muggeo, Saviolakis, Wachslicht-Rodbard and Roth 1983).…”

Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity

“…Hypercortisolism may also increase the appetite of patients, often resulting in positive caloric balance. Conversely, glucocorticoids are catabolic to muscle, causing muscle wasting and insulin resistance, and catabolic to adipose tissue, where lipolysis is modestly increased [1,24]. In peripheral, subcutaneous adipose tissue, exogenous corticosteroids may promote smaller adipocyte size, presumably due to catabolism and modest lipolytic activity [25].…”

Is insulin resistance caused by defects in insulin's target cells or by a stressed mind?

“…The clinical syndrome of glucocorticoid excess, Cushing's syndrome, is associated with insulin resistance, glucose intolerance, central obesity and hypertension. In vitro, adipocytes from patients with Cushing's syndrome are insulin-resistant [40]. Pharmacological treatment with high doses of glucocorticoids also leads to an impairment of insulin sensitivity.…”