Insulin resistance in genetically obese (fa/fa) rats: changes in the glycosyl-phosphatidylinositol signaling system in isolated hepatocytes.
In different types of mammalian cells, insulin has been shown to promote the release of an inositol phosphate glycan (InsP-glycan) through the hydrolysis of a glycosyl-phosphatidylinositol (glycosyl-PtdIns). This InsP-glycan, which has been demonstrated to be taken up by intact cells, may mediate some of the biological effects of insulin. We have investigated how the insulin resistance expressed in genetically obese (fa/fa) rats affects the glycosyl-PtdIns signaling system in isolated hepatocytes compared to what occurs in hepatocytes isolated from lean (Fa/-) rats. The hepatocyte content of glycosyl-PtdIns was reduced by about 30% in obese rats, with respect to that measured in lean rats (2553 +/- 138 vs. 3334 +/- 115 dpm/mg protein; P < 0.01; n = 5). This reduction was accompanied by a marked blockade of the insulin-mediated glycosyl-PtdIns hydrolysis as well as a decrease (approximately 30%) in the rate of InsP-glycan uptake by the isolated liver cells. Obese Zucker rat hepatocytes also showed a significant decrease in the effects of both insulin and InsP-glycan on the stimulation of glycogen synthesis and the activation of glycogen synthase compared to hepatocytes isolated from lean rats. Our results demonstrate that genetic obesity in Zucker (fa/fa) rats is associated with an impairment of the glycosyl-PtdIns-dependent insulin signaling system.
Sánchez-Gutiérrez
J C
JC
Servicio de Endocrinología Experimental, Hospital Puerta de Hierro, Universidad Autónoma de Madrid, Spain.
Sánchez-Arias
J A
JA
Valle
J C
JC
Guadaño
A
A
Samper
B
B
Mato
J M
JM
Felíu
J E
JE
D000818:Animals; D006003:Glycogen / Q000096:biosynthesis; D006006:Glycogen Synthase / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000032:analysis / Q000502:physiology*; D066298:In Vitro Techniques; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D017261:Glycosylphosphatidylinositols; D006003:Glycogen; D006006:Glycogen Synthase