Hepatic-dependent and -independent Insulin Actions Are Impaired in the Obese Zucker Rat Model

AFONSO, RICARDO A., ROGERIO T. RIBEIRO, ANA B. FERNANDES, RITA S. PATARRAO, AND M. PAULA MACEDO. Hepatic-dependent and -independent insulin actions are impaired in the obese Zucker rat model. Obesity. 2007;15:314-321. Objective: Whole-body insulin sensitivity (IS) depends on a hepatic pathway, involving parasympathetic activation and hepatic nitric oxide (NO) production. Both atropine and N-monomethyl-L-arginine (L-NMMA, NO synthase inhibi- tor) induce insulin resistance (IR). IR is associated with obesity. Because NO action was shown to be impaired in animal models of obesity, such as the obese Zucker rat (OZR), we tested the hypothesis that the hepatic-dependent pathway is diminished in OZR, resulting in IR. Research Methods and Procedures: Lean Zucker rats (LZRs) were used as OZR controls. IS was evaluated in terms of glucose disposal (milligrams of glucose per kilo- gram of body weight (bw)). Two groups were submitted to two protocols. First, a control clamp was followed by a post-atropine (3 mg/kg intravenously) clamp. Second, after the control clamp, L-NMMA (0.73 mg/kg intraportally) was given, and a second clamp was performed. Hepatic-depen- dent IS was assessed by subtracting the response after atropine or L-NMMA from the basal response. Results: In the first protocol, basal IS was lower in OZR than in LZR (OZR, 73.7 14.2; LZR, 289.2 24.7 mg glucose/kg bw; p 0.001), and atropine decreased IS in the same proportion for both groups (OZR, 41.3 8.0%; LZR, 40.1 6.5%). Equally, in the second protocol, OZR pre- sented lower IS (OZR, 79.3 1.6; LZR, 287.4 22.7 mg glucose/kg bw; p 0.001). L-NMMA induced IS inhibition in both groups (OZR, 48.3 6.6%; LZR, 46.4 4.1%), similar to that after atropine. Discussion: We show that the IR in OZR is due to similar impairment of both hepatic-dependent and -independent components of insulin action, suggesting the existence of a defect common to both pathways.