Insulin-induced activation of glycerol-3-phosphate acyltransferase by a chiro-inositol-containing insulin mediator is defective in adipocytes of insulin-resistant, type II diabetic, Goto-Kakizaki rats.
Type II diabetic Goto-Kakizaki (GK) rats were insulin-resistant in euglycemic-hyperinsulinemic clamp studies. We therefore examined insulin signaling systems in control Wistar and diabetic GK rats. Glycerol-3-phosphate acyltransferase (G3PAT), which is activated by headgroup mediators released from glycosyl-phosphatidylinositol (GPI), was activated by insulin in intact and cell-free adipocyte preparations of control, but not diabetic, rats. A specific chiro-inositol-containing inositol phosphoglycan (IPG) mediator, prepared from beef liver, bypassed this defect and comparably activated G3PAT in cell-free adipocyte preparations of both diabetic GK and control rats. A myo-inositol-containing IPG mediator did not activate G3PAT. Relative to control adipocytes, labeling of GPI by [3H]glucosamine was diminished by 50% and insulin failed to stimulate GPI hydrolysis in GK adipocytes. In contrast to GPI-dependent G3PAT activation, insulin-stimulated hexose transport was intact in adipocytes and soleus and gastrocnemius muscles of the GK rat, as was insulin-induced activation of mitogen-activated protein kinase and protein kinase C. We conclude that (i) chiro-inositol-containing IPG mediator activates G3PAT during insulin action, (ii) diabetic GK rats have a defect in synthesizing or releasing functional chiro-inositol-containing IPG, and (iii) defective IPG-regulated intracellular glucose metabolism contributes importantly to insulin resistance in diabetic GK rats.
Farese
R V
RV
J. A. Haley Veterans' Hospital, Tampa, FL 33612.
Standaert
M L
ML
Yamada
K
K
Huang
L C
LC
Zhang
C
C
Cooper
D R
DR
Wang
Z
Z
Yang
Y
Y
Suzuki
S
S
Toyota
T
T
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004789:Enzyme Activation; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D007295:Inositol Phosphates / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar
D007295:Inositol Phosphates; D007328:Insulin; D010716:Phosphatidylinositols; D011134:Polysaccharides; C028039:inositol phosphate glycan; D003847:Deoxyglucose; D005992:Glycerol-3-Phosphate O-Acyltransferase