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Effects of diabetes, insulin, and vanadium on regulation of glycogen synthesis : roles of glycogen synthase kinase-3 and protein phosphatase-1 Semiz, Sabina

Abstract

Although the activation of muscle glycogen synthase by insulin was recognized 40 years ago (Villar-Palasi and Larner 1960), the molecular mechanisms of this insulin effect are still unclear. In the present study, we examined the in vivo effects of insulin and vanadium treatment on glycogen synthase (GS) activation in two animal models of diabetes. Wistar rats with streptozotocin (STZ)-induced (60 mg/kg i.v.) diabetes were used as an animal model of poorly controlled type 1 diabetes, while Zucker fatty rats were used as a model ofthe prediabetic state of type 2 diabetes. The GS fractional activity (GSFA), as well as the activity of its two proposed upstream regulating enzymes in the insulin-signaling cascade, glycogen synthase kinase-3 (GSK-3) and protein phosphatase-1 (PP1), were determined in control and STZ-diabetic rats with either short-term (4-week) or long-term (7- or 9-week) diabetes following vanadium treatment, which started one week after STZ-injection. Treated Wistar rats received either bis(maltolato)oxovanadium (IV) (BMOV) or bis(ethylmaltolato)oxovanadium (IV) (BEOV) at a final dose of 0.3-0.4 mmol/kg/day administered in drinking water. The Zucker rats were treated with the same dose of BMOV for 3 or 10 weeks. Treated animals were euglycemic at the time of termination. The skeletal muscle, liver and heart were removed quickly either before or following an insulin injection (5 U/kg i.v.), freeze-clamped, powdered using liquid nitrogen and homogenized. Neither diabetes, nor vanadium or insulin in vivo treatment affected GSK-3β activity in STZ-diabetic rats skeletal muscle, liver, and heart, nor in the Zucker fatty rat muscle as compared to controls. In skeletal muscle no difference in basal GSFA between either short- or long-term STZ-diabetic rats and their age-matched controls was shown. Following insulin stimulation in the short-term STZ-diabetic rats muscle GSFA was increased, while in the long-term diabetic rats it remained unchanged. Taken together with plasma glucose levels, these data suggest that STZ-diabetic rats become refractory to the effects of insulin on GS activity after a longer duration of diabetes. PP1 activity in skeletal muscle was increased by diabetes and returned to normal by vanadium treatment. However, this treatment did not stimulate GSFA in the skeletal muscle of STZ-diabetic animals. Interestingly, in the liver from long-term STZ-diabetic rats, the activities of both total and active GS were decreased compared to controls, and then restored by vanadium treatment, suggesting a tissue specific regulation of glycogen synthesis. Importantly, in the Zucker fatty rats vanadium treatment improved insulin sensitivity and mimicked insulin effects on GSFA and PP1 activity in skeletal muscle of fatty rats. Furthermore, insulin-stimulated PP1 activity in skeletal muscle of fatty rats was restored by vanadium treatment. In conclusion, the observed glucoregulatory effect of vanadium treatment in STZ-diabetic rats may be related, at least in part, to the regulation of hepatic glycogen synthesis. The discordance between GS and PP1 activity in skeletal muscle of two different animal models of diabetes may imply the involvement of alternative signaling pathways in the regulation of glycogen synthesis.

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