Context: Adipocytes release a variety of factors which deregulation could provide the basis for complications such as insulin resistance, an early defect on the onset of type 2 diabetes. Such insulin resistance can initially be overcome by compensatory hyperinsulinemia, but the prolonged presence of the hormone can be detrimental for insulin sensitivity.

Objective: To dissect the molecular mechanisms that may regulate hyperinsulinemia-induced insulin resistance in a human liposarcoma cell line and its paracrine interactions with a human rhabdomyosarcoma cell line.

Designs: We studied glucose uptake, lipolysis, insulin signalling and secretion pattern at different days of adipocyte differentiation in the presence of insulin.

Results: Adipocytes differentiated for 14-day gain insulin sensitivity on glucose uptake and inhibition of lipolysis, but prolonged-cultures develop an insulin-resistant state characterized by an increase in PTEN expression and defects in insulin signalling at the IRS1/AKT level. The secretion pattern of NEFA, IL-6, adiponectin, leptin and MCP-1 was in keeping with the changes in insulin sensitivity during differentiation. An inverse biphasic-response was also observed in human myocytes when were cultured with various adipocyte-conditioned media, although insulin resistance was detected earlier than in adipocytes. This behaviour mimics hyperinsulinemia because insulin action was restored when adipocytes were cultured in the absence of the hormone. Pharmacological treatment of adipocytes with a LXR-agonist re-establish insulin-stimulated glucose uptake, whereas treatment with a PPAR-agonist restored the antilipolytic action of insulin.

Conclusions: Hyperinsulinemia deregulates adipocyte secretion pattern, producing insulin resistance in adipocytes and myocytes, a situation that can be ameliorated with nuclear receptor agonists.