Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism

Background, Hepatic innervation plays an essential role in insulin extracti on and glucose production, but the specific role of hepatic cholinergic inn ervation remains unclear. We sought to establish a model of isolated hepati c cholinergic denervation (IHCD), and to assess whether glycogen storage or the control of net hepatic glucose production (HGP) was altered by IHCD. Materials and Methods. Sprague-Dawley rats underwent either hepatic vagotom y or sham operation. Liver tissue was stained for vesicular acetylcholine t ransporter (VAChT) and (nonspecific neural) protein gene product 9.5 (PGP) for verification of IHCD. Liver glycogen content was quantified in fed and fasted IHCD or sham-operated animals. HGP was determined after single-pass isolated liver perfusion, during which a 30-min 12 ng/ml glucagon infusion was begun after equilibration, and after 10 min, a 200 mu U/ml insulin infu sion was added. Results. Uniform staining of PGP and absence of VAChT staining in hepatic v agotomized rats demonstrated the validity of our model. Glycogen content of sham-operated livers (n = 8) increased from 6.0 +/- 1.7 in the fasting sta te to 10.6 +/- 1.8 mg/g liver, after feeding (P < 0.05). IHCD livers (n = 8 ) showed no comparable increase (3.5 +/- 0.6 to 4.0 +/- 0.7 mg/g liver). Pe rfusion with glucagon alone resulted in less HGP in IHCD livers (n = 12) co mpared with sham-operated livers (n = 10) (integrated HGP 3.3 +/- 0.3 mg/g liver min(-1) vs 5.1 +/- 0.5 mg/g liver min(-1), P < 0.05). Insulin infusio n revealed impaired responsiveness to insulin after IHCD; the ratio of HGP in the final 10 min of perfusion (glucagon and insulin) to HGP in the initi al 10 min (glucagon alone) was 90.3 +/- 2.4% for IHCD livers versus 68.1 +/ - 4.4% for sham-operated controls, respectively (P = 0.0002). Conclusions. Our study shows that IHCD results in significant impairment in liver glycogen storage and impaired hepatic sensitivity to glucagon and, p ossibly, to insulin, We conclude that hepatic cholinergic integrity is esse ntial to normal hepatic glucose metabolism. (C) 2000 Academic Press.