Endocrine Abstracts

Objective: In Cushing’s Syndrome, chronic glucocorticoid excess and their disrupted circadian rhythm lead to insulin-resistance, diabetes mellitus, dyslipidemia and cardiovascular comorbidities. As undifferentiated, self-renewing progenitors of adipocytes, mesenchymal stem cells may display the detrimental effects of glucocorticoid excess, thus revealing a promising model to study molecular mechanisms underlying metabolic complications of Cushing’s Syndrome.

Design and methods: mesenchymal stem cells isolated from the abdominal skin of healthy subjects were treated thrice daily with glucocorticoids according to two different regimens: lower, circadian-decreasing (Lower, Decreasing Exposure, LDE) vs persistently higher (Higher, Constant Exposure, HCE) doses, aimed at mimicking either the physiological condition or Cushing’s Syndrome, respectively. Subsequently, mesenchymal stem cells were stimulated with insulin and glucose thrice daily, resembling food uptake, and both glucose uptake/GLUT-4 translocation and the expression of LIPE, ATGL, IL-6 and TNF-α genes were analyzed at predefined timepoints (T1 to T7) over three days.

Results: A LDE to glucocorticoids did not impair glucose uptake by mesenchymal stem cells, whereas a HCE significantly decreased glucose uptake by mesenchymal stem cells only when prolonged. Persistent signs of insulin-resistance occurred after 30 hours of HCE to glucocorticoids (P<0.05 from T5 on). As compared to LDE, mesenchymal stem cells experiencing a HCE to glucocorticoids showed a significant down-regulation of lipolysis-related genes in the acute period (P<0.05 for LIPE, ATGLand TNF-α at T2), followed by a significant overexpression once insulin-resistance had established (P<0.05 for LIPE, ATGL, IL-6 and TNF-α at T7).

Conclusions: Preserving circadian glucocorticoid rhythmicity is crucial to prevent the occurrence of metabolic alterations. Like mature adipocytes, mesenchymal stem cells suffer from insulin-resistance and impaired lipolysis due to chronic glucocorticoid excess: mesenchymal stem cells could represent a reliable model to track the mechanisms involved in glucocorticoid-induced insulin-resistance throughout cellular differentiation.