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Hyperinsulinemia Induces Insulin Resistance on Glucose and Lipid Metabolism in a Human Adipocytic Cell Line: Paracrine Interaction with Myocytes

Department of Biochemistry and Molecular Biology II (S.F.-V., I.N.-V., M.L.), Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain; Department of Biochemistry and Molecular Biology (J.d.C., M.P.R.), Faculty of Pharmacy, San Pablo-CEU University, 28668 Madrid, Spain; and Department of Pathology (S.B., P.M.), University of Ulm, 89081 Ulm, Germany

Address all correspondence and requests for reprints to: M. Lorenzo, Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain. E-mail: mlorenzo{at}farm.ucm.es.

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: The objective of the study was 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 signaling, and secretion pattern at different days of adipocyte differentiation in the presence of insulin.

Results: Adipocytes differentiated for 14 d gain insulin sensitivity on glucose uptake and inhibition of lipolysis, but prolonged cultures develop an insulin-resistant state characterized by an increase in phosphatase and tensin homolog-deleted on chromosome 10 expression and defects in insulin signaling at the insulin receptor substrate-1/AKT level. The secretion pattern of nonesterified fatty acids, IL-6, adiponectin, leptin, and monocyte chemotactic protein-1 was in keeping with the changes in insulin sensitivity during differentiation. An inverse biphasic response was also observed in human myocytes when they were cultured with various adipocyte-conditioned media, although insulin resistance was detected earlier than in adipocytes. This behavior mimics hyperinsulinemia because insulin action was restored when adipocytes were cultured in the absence of the hormone. Pharmacological treatment of adipocytes with a liver X receptor agonist reestablishes insulin-stimulated glucose uptake, whereas treatment with a peroxisome proliferator-activated receptor- 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.

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