Calorie restriction reduces pinealectomy‐induced insulin resistance by improving GLUT4 gene expression and its translocation to the plasma membrane

Abstract

The present study aimed to investigate insulin sensitivity and GLUT4 expression protein in pinealectomized rats, as well as to determining the effects of melatonin and calorie restriction on the changes induced by pinealectomy. Wistar rats were pinealectomized (Pinx) or sham operated (Sham), and studied 30 days later. Melatonin replacement treatment (50 g/100 g body weight) was continued for 30 days after pinealectomy. Calorie restriction was performed by offering 60% of the standard food intake. In vivo insulin sensitivity was evaluated using the glucose disappearance constant (kITT) during an insulin tolerance test, and GLUT4 mRNA and protein were assessed by Northern and Western blotting, respectively. The in vitro effect of melatonin on GLUT4 protein content in plasma membrane was investigated in adipocytes isolated from intact rats. Compared with Sham rats, Pinx rats showed decreased kITT (40%), GLUT4 expression in white adipose tissue (WAT, approximately 70%), and unchanged GLUT4 expression in skeletal muscle. Melatonin treatment in Pinx rats restored the kITT and GLUT4 protein to control values. No in vitro effects of melatonin (10-9 m) upon GLUT4 protein were observed. Calorie restriction of Pinx rats increased their kITT value ( approximately 40%), total GLUT4 protein content ( approximately 240%) and its translocation to the plasma membrane ( approximately 80%) in WAT. The results show that pinealectomy, for lack of melatonin, decreased insulin sensitivity as well as GLUT4 gene expression. Calorie restriction improved insulin sensitivity in Pinx rats, and this was related to increased GLUT4 gene expression and insulin-induced GLUT4 translocation to the plasma membrane in WAT.

Alterations in adipocyte glucose transporter GLUT4 and circulating adiponectin and visfatin in rat adjuvant induced arthritis

“…For example, 40% caloric restriction reversed insulin resistance in pinealectomized rats by enhancing GLUT4 content in adipocytes and its translocation to the plasma membranes (Zanquetta et al 2003). Similarly in fatty rats caloric restriction improved glucose utilization by upreguletion of adipocyte GLUT4 expression (Park et al 2005).…”

Role of melatonin on diabetes-related metabolic disorders

“…On the other hand, an inappropriate time schedule for the administration of melatonin may induce supraphysiological concentrations of melatonin, thus resulting on a desensitization of melatonin receptors. Lengthy exposure to melatonin might mimic 'artificial darkness', thereby causing physiological disturbances, e.g., to glucose metabolism [51] , whereas pinealectomy, which leads to melatonin depletion, appears to decrease insulin sensitivity, as well as GLUT4 gene expression [52] .…”

Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8)

“…Data obtained from experimental animal models in vivo and studies in vitro suggest that melatonin might regulate glucose homeostasis (Zanquetta et al 2003;Lima et al 1998;Ha et al 2006). In normal rats, pinealectomy induces insulin resistance and glucose intolerance (Zanquetta et al 2003;Lima et al 1998). In obese insulinresistant rats, parenteral melatonin administration was able to decrease body weight and to lower plasma glucose (Prunet-Marcassus et al 2003) and insulin (Hussein et al 2007) levels, but the underlying mechanisms are not known.…”

“…Melatonin is a highly phylogenetically conserved molecule that exerts many regulatory functions, modulating cellular metabolism through its binding to specific membrane and nuclear receptors (Zanquetta et al 2003;Lima et al 1998). Data obtained from experimental animal models in vivo and studies in vitro suggest that melatonin might regulate glucose homeostasis (Zanquetta et al 2003;Lima et al 1998;Ha et al 2006).…”