Increased insulin-stimulated endothelin-1 release is a distinct vascular phenotype distinguishing Cushing's disease from metabolic syndrome.
OBJECTIVE
Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD).


METHODS
We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NO(x) (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers.


RESULTS
Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NO(x) release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NO(x) incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area.


CONCLUSIONS
In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers.
Setola
Emanuela
E
Diabetology, Endocrinology and Metabolic Disease Unit, Scientific Institute San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
Losa
Marco
M
Lanzi
Roberto
R
Lucotti
Pietro
P
Monti
Lucilla D
LD
Castrignanò
Tristana
T
Galluccio
Elena
E
Giovanelli
Massimo
M
Piatti
PierMarco
P
D000328:Adult; D000704:Analysis of Variance; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D006152:Cyclic GMP / Q000097:blood; D003937:Diagnosis, Differential; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016014:Linear Models; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000175:diagnosis*; D009569:Nitric Oxide / Q000378:metabolism; D047748:Pituitary ACTH Hypersecretion / Q000097:blood / Q000175:diagnosis*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D019332:Endothelin-1; D007328:Insulin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002097:C-Reactive Protein; D006152:Cyclic GMP