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Glucocorticoids Down-Regulate Glucose Uptake Capacity and Insulin-Signaling Proteins in Omental But Not Subcutaneous Human Adipocytes

Departments of Medicine (M.L., J.B., T.R., J.W.E.) and Surgery (T.M.), Umeå University Hospital, Umeå SE-901 85, Sweden

Address all correspondence and requests for reprints to: Dr. Jan W. Eriksson, Department of Medicine, Umeå University Hospital, SE-901 85 Umeå, Sweden. E-mail: jan.eriksson{at}medicin.umu.se.

Visceral adiposity is associated with insulin resistance and type 2 diabetes. This study explores the metabolic differences between sc and visceral fat depots with respect to effects in vitro of glucocorticoids and insulin on glucose uptake.

Adipocytes from human sc and omental fat depots were obtained during abdominal surgery in 18 nondiabetic subjects. Cells were isolated, and metabolic studies were performed directly after the biopsies and after a culture period of 24 h with or without dexamethasone. After washing, basal and insulin-stimulated [¹⁴C]glucose uptake as well as cellular content of insulin signaling proteins and glucose transporter 4 (GLUT4) was assessed.

Omental adipocytes had an approximately 2-fold higher rate of insulin-stimulated glucose uptake compared with sc adipocytes (P < 0.01). Dexamethasone treatment markedly inhibited (by 50%; P < 0.05) both basal and insulin-stimulated glucose uptake in omental adipocytes but had no consistent effect in sc adipocytes. The cellular content of insulin receptor substrate 1 and phosphatidylinositol 3-kinase did not differ significantly between the depots, but the expression of protein kinase B (PKB) tended to be increased in omental compared with sc adipocytes (P = 0.09). Dexamethasone treatment decreased the expression of insulin receptor substrate 1 (by 40%; P < 0.05) and PKB (by 20%; P < 0.05) in omental but not in sc adipocytes. In contrast, dexamethasone pretreatment had no effect on insulin-stimulated Ser⁴⁷³ phosphorylation of PKB. GLUT4 expression was approximately 4-fold higher in omental than sc adipocytes (P < 0.05). Dexamethasone treatment did not alter the expression of GLUT4.

In conclusion, human omental adipocytes display approximately 2-fold higher glucose uptake rate compared with sc adipocytes, and this could be explained by a higher GLUT4 expression. A marked suppression is exerted by glucocorticoids on glucose uptake and on the expression of insulin signaling proteins in omental but not in sc adipocytes. These findings may be of relevance for the interaction between endogenous glucocorticoids and visceral fat in the development of insulin resistance.

This work was supported by the Swedish Research Council (Medicine, Project 14287); the Swedish Diabetes Association; the Faculty of Medicine at Umeå University; and the Novo Nordisk, the Elsa and Folke Sahlberg, the Sigurd and Elsa Golje, and the Torsten and Ragnar Söderberg Foundations.

Abbreviations: ADA, Adenosine deaminase; BMI, body mass index; DBP, diastolic blood pressure; FFA, free fatty acid(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLUT4, glucose transporter 4; HOMA-IR, homeostasis model assessment insulin resistance index; HSL, hormone sensitive lipase; IRS1, insulin receptor substrate 1; MGU, maximal insulin effect (at 1000 µU/ml) on adipocyte glucose uptake; PIA, N⁶-(R-phenyl-isopropyl)adenosine; PI3-K, phosphatidylinositol 3-kinase; PKB, protein kinase B; SBP, systolic blood pressure; WHR, waist-to-hip ratio.

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