PMID- 7895667
OWN - NLM
STAT- MEDLINE
DCOM- 19950425
LR  - 20131121
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 136
IP  - 4
DP  - 1995 Apr
TI  - Insulin and dexamethasone regulate insulin receptors, insulin receptor 
      substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells.
PG  - 1579-88
AB  - Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in 
      phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), 
      which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus 
      activating the enzyme. In the present study we have examined these three early 
      postreceptor components of the insulin action pathway in rat hepatoma (Fao) cells 
      and have determined the effects of two hormones that can induce insulin 
      resistance, dexamethasone and insulin. Dexamethasone (1 microM) induced a time- 
      and dose-dependent increase in insulin receptor levels in Fao cells, reaching 135 
      +/- 3% of basal levels after 24 h (P < 0.05). There was a simultaneous increase 
      in IRS-1 protein to 255 +/- 66% of the control value (P < 0.05) and a parallel 
      increase in IRS-1 phosphorylation. Insulin stimulation of IRS-1-associated PI 
      3-kinase was also increased by 70% in cells treated with dexamethasone despite 
      only a minimal increase in PI 3-kinase protein, as determined by immunoblotting. 
      Prolonged insulin treatment induced a time- and dose-dependent decrease in 
      insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 
      0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 
      100 nM insulin. There was also a decrease in the phosphorylation of insulin 
      receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 
      3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without 
      a significant change in PI 3-kinase protein levels. When cells were exposed to 
      both insulin and dexamethasone, the effect of insulin to reduce insulin receptor 
      and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. These 
      data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase 
      contributes significantly to the insulin resistance induced by chronic 
      hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located 
      beyond these early steps in insulin action.
FAU - Saad, M J
AU  - Saad MJ
AD  - Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215.
FAU - Folli, F
AU  - Folli F
FAU - Kahn, C R
AU  - Kahn CR
LA  - eng
GR  - DK-33201/DK/NIDDK NIH HHS/United States
GR  - DK-36836/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, rat)
RN  - 0 (Phosphoproteins)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Animals
MH  - Dexamethasone/*pharmacology
MH  - Immunoblotting
MH  - Immunosorbent Techniques
MH  - Insulin/*pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Insulin Resistance
MH  - Kinetics
MH  - Liver Neoplasms, Experimental/*metabolism
MH  - Phosphatidylinositol 3-Kinases
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - Rats
MH  - Receptor, Insulin/*metabolism
MH  - Tumor Cells, Cultured
EDAT- 1995/04/01 00:00
MHDA- 1995/04/01 00:01
CRDT- 1995/04/01 00:00
PHST- 1995/04/01 00:00 [pubmed]
PHST- 1995/04/01 00:01 [medline]
PHST- 1995/04/01 00:00 [entrez]
AID - 10.1210/endo.136.4.7895667 [doi]
PST - ppublish
SO  - Endocrinology. 1995 Apr;136(4):1579-88. doi: 10.1210/endo.136.4.7895667.