title: Glucocorticoid modulation of insulin signaling in human subcutaneous adipose tissue.
abstract: BACKGROUND
  Glucocorticoid (GC) excess is characterized by central obesity, insulin resistance, and in some cases, type 2 diabetes. However, the impact of GC upon insulin signaling in human adipose tissue has not been fully explored.
  
  
  OBJECTIVE
  We have examined the effect of GC upon insulin signaling in both human sc primary preadipocyte cultures and a novel human immortalized sc adipocyte cell line (Chub-S7) and contrasted this with observations in primary cultures of human skeletal muscle.
  
  
  METHODS
  This is an in vitro study characterizing the impact of GC upon insulin signaling in human tissues.
  
  
  METHODS
  Biopsy specimens were from healthy volunteers who gave their full and informed written consent.
  
  
  METHODS
  Combinations of treatments, including GC, RU38486, and wortmannin, were used.
  
  
  METHODS
  Insulin signaling cascade gene and protein expression and insulin-stimulated glucose uptake were determined.
  
  
  RESULTS
  In human adipocytes, pretreatment with GC induced a dose-dependent [1.0 (control); 1.2 +/- 0.1 (50 nm); 2.2 +/- 0.2 (250 nm), P < 0.01 vs. control; 3.4 +/- 0.2 (1000 nm), P < 0.001 vs. control] and time-dependent [1.0 (1 h); 3.2 +/- 2.0 (6 h); 9.1 +/- 5.9 (24 h), P < 0.05 vs. 1 h; 4.5 +/- 2.2 (48 h)] increase in insulin-stimulated protein kinase B/akt phosphorylation. In addition, whereas insulin receptor substrate (IRS)-1 protein expression did not change, IRS-1 tyrosine phosphorylation increased. Furthermore, GC induced IRS-2 mRNA expression (2.8-fold; P < 0.05) and increased insulin-stimulated glucose uptake [1.0 (control) 1.8 +/- 0.1 (insulin) vs. 2.8 +/- 0.2 (insulin + GC); P < 0.05]. In contrast, in primary cultures of human muscle, GC decreased insulin-stimulated glucose uptake [1.0 (control) 1.9 +/- 0.2 (insulin) vs. GC 1.3 +/- 0.1 (insulin + GC); P < 0.05].
  
  
  CONCLUSIONS
  We have demonstrated tissue-specific regulation of insulin signaling by GC. Within sc adipose tissue, GCs augment insulin signaling, yet in muscle GCs cause insulin resistance. We propose that enhanced insulin action in adipose tissue increases adipocyte differentiation, thereby contributing to GC-induced obesity.
authors: Institute of Biomedical Research, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom.
authors: Laura L
authors: LL
authors: Gathercole
authors: Iwona J
authors: IJ
authors: Bujalska
authors: Paul M
authors: PM
authors: Stewart
authors: Jeremy W
authors: JW
authors: Tomlinson
mesh_terms: D017667:Adipocytes / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D050151:Subcutaneous Fat / Q000166:cytology / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D005947:Glucose
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