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.