Objectives: 

It was previously reported that the hepatic parasympathetic nervous system plays a role in insulin sensitivity. Here we want to elucidate the importance of both hepatic parasympathetic nervous system and its downstream effector nitric oxide synthase (NOS) as modulators of glucose excursions.

Materials: 

Male Wistar rats (12 weeks old) were studied in the fast and fed state; two experimental groups: sham and hepatic parasympathetic denervated were also studied. A Meal Tolerance Test (MTT) was performed, endogenous glucose production (EGP) was determined by a tracer administered as a continuous perfusion. To assess glucose appearance rate, glucose clearance and glucose disposal the meal was enriched with an additional tracer. Samples were evaluated by LC-MS (Liquid Chromatography – Mass Spectrometry). Insulin sensitivity was determined by a modified hyperinsulinemic euglycemic clamp. NOS isoforms gene expression was determined by RT-PCR, activity of the enzyme was determined using a commercially available kit, NO levels were determined using a chemiluminescence's method. Data are expressed as means ± SEM, values of p < 0.05 were considered statistically significant. A two-tailed t test was used to compare mean values in two-group comparisons.

Results: 

Hepatic NOS expression remains unchanged from the fast to the fed state; NOS activity and hepatic NO levels were increased in the fed state and this strongly correlates with an increase in insulin sensitivity. Hepatic parasympathetic denervation did not affect Insulin, c-peptide levels, insulin clearance and endogenous glucose production during the MTT. However, this group showed increased glucose excursions which were a direct result of decreased glucose clearance by 63% (p < 0.0001).

Conclusions: 

The results indicate that the integrity of the hepatic parasympathetic system is essential to maintain whole-body glucose homeostasis. Moreover, the hepatic NOS enzyme is determinant for proper peripheral insulin action.