Early events involved in the development of insulin resistance in Zucker fatty rat

Abstract

AIM: To clarify the mechanism by which insulin resistance develops in obesity, Zucker fatty rats (ZFR) and lean litter mates (ZLR) were temporally subjected to oral glucose tolerance tests (OGTT) at 6 and 15 weeks of age. METHOD: As candidates for causative factors of insulin resistance, plasma leptin, free fatty acids (FFA) and tumor necrosis factor (TNF)-a levels were evaluated. RESULTS: There was no difference in the body weight between the two groups at 6 weeks of age, but ZFR were significantly heavier than ZLR at 15 weeks of age. At 6 weeks of age, blood glucose levels and area under the curve of glucose (AUCg) during OGTT were not significantly different between the two groups, while plasma insulin levels and area under the curve of insulin (AUCi) in the ZFR group were significantly higher than those in the ZLR group. At 15 weeks of age, the blood glucose levels and AUCg as well as plasma insulin levels and AUCi in the ZFR group during OGTT were significantly higher than those in the ZLR group. The ratio of fasting insulin to glucose in the ZFR group was significantly higher than that in the ZLR group at 6 and 15 weeks of age. Peripheral and portal plasma leptin and FFA levels were significantly higher in ZFR than ZLR both at 6 weeks and 15 weeks of age. Meanwhile, at 6 weeks, plasma TNF-a levels and expression of TNF-a protein in subcutaneous and visceral fat tissues were similar in both groups; however at 15 weeks, these were significantly higher in the ZFR group than the ZLR group. CONCLUSION: These results suggest that FFA rather than TNF-a may play an important role in early events involved in the development of insulin resistance and TNF-a accelerates insulin resistance together with FFA in the later stage.

Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease

“…Specifically, downregulation of Mrp2 mRNA during endotoxemia has been demonstrated to be dependent on TNF-␣ (Geier et al, 2003). In contrast, in obese Zucker rats, which develop elevated plasma levels of TNF-␣, abrogation of TNF-␣ activity with etanercept has no effect on Mrp2 protein levels (Liu et al, 2002;Pizarro et al, 2004). Although there are limited data on the hepatic and serum levels of proinflammatory cytokines in rat models of NAFLD, it seems reasonable to propose that cytokines may be important in transporter regulation in the MCD model of NASH.…”

Insulin-Mediated Hemodynamic Changes Are Impaired in Muscle of Zucker Obese Rats

“…Raised plasma levels of TNF␣ have been reported in obese Zucker rats (38) and the blunted hemodynamic effects observed in these rats may be a consequence of this (18). However, elevated plasma free fatty acids may be more important (39) and responsible for the insulin resistance of the Zucker rat. Recent data from our laboratory support this view and show that acutely elevated free fatty acids in a nonobese strain markedly impair insulin-mediated capillary recruitment and muscle glucose uptake in vivo (40).…”

Altered cardiac bradykinin metabolism in experimental diabetes caused by the variations of angiotensin-converting enzyme and other peptidases

“…In a previous study, tissue TNFconcentration was not increased in 6-week old fat Zucker rats, but became elevated at 15 weeks (Liu et al, 2002). In a different model of type II diabetes, the db/db mice, heart ACE was normal but renal ACE was decreased at 8 weeks of age, raising the possibility of complex timedependent transitions of peptidase expression (Ye et al, 2004).…”

“…These animals are characterized by marked insulin resistance. Initially, they are both normoglycemic and hyperinsulinemic but, with time, they develop type II diabetes which becomes evident after 12 weeks (Bray, 1977;Liu et al, 2002). In Zucker fa/fa rats and their lean controls, BK t 1/2 at 8 weeks of age was significantly lower than in control Sprague-Dawley animals.…”