TY - JOUR
T1 - Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism
AU - Xue, Chengrui
AU - Aspelund, Gudrun
AU - Sritharan, Kumudesh C.
AU - Wang, Jin Ping
AU - Slezak, Lori A.
AU - Andersen, Dana K.
N1 - Funding Information:
1Supported by a grant from the National Institutes of Health (DK-39950). 2To whom correspondence should be addressed. Fax: (203) 737– 4067. E-mail: [email protected].
PY - 2000/5/1
Y1 - 2000/5/1
N2 - Background. Hepatic innervation plays an essential role in insulin extraction and glucose production, but the specific role of hepatic cholinergic innervation remains unclear. We sought to establish a model of isolated hepatic 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 vagotomy or sham operation. Liver tissue was stained for vesicular acetylcholine transporter (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-rain 12 ng/ml glucagon infusion was begun after equilibration, and after 10 min, a 200 μU/ml insulin infusion was added. Results. Uniform staining of PGP and absence of VAChT staining in hepatic vagotomized rats demonstrated the validity of our model. Glycogen content of sham-operated livers (n = 8) increased from 6.0 ± 1.7 in the tasting state 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). Perfusion with glucagon alone resulted in less HGP in IHCD livers (n = 12) compared with sham-operated livers (n = 10) (integrated HGP 3.3 ± 0.3 mg/g liver rain-1 vs 5.1 ± 0.5 mg/g liver rain-1, P < 0.05). Insulin infusion 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 initial 10 rain (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, possibly, to insulin. We conclude that hepatic cholinergic integrity is essential to normal hepatic glucose metabolism. (C) 2000 Academic Press.
AB - Background. Hepatic innervation plays an essential role in insulin extraction and glucose production, but the specific role of hepatic cholinergic innervation remains unclear. We sought to establish a model of isolated hepatic 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 vagotomy or sham operation. Liver tissue was stained for vesicular acetylcholine transporter (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-rain 12 ng/ml glucagon infusion was begun after equilibration, and after 10 min, a 200 μU/ml insulin infusion was added. Results. Uniform staining of PGP and absence of VAChT staining in hepatic vagotomized rats demonstrated the validity of our model. Glycogen content of sham-operated livers (n = 8) increased from 6.0 ± 1.7 in the tasting state 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). Perfusion with glucagon alone resulted in less HGP in IHCD livers (n = 12) compared with sham-operated livers (n = 10) (integrated HGP 3.3 ± 0.3 mg/g liver rain-1 vs 5.1 ± 0.5 mg/g liver rain-1, P < 0.05). Insulin infusion 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 initial 10 rain (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, possibly, to insulin. We conclude that hepatic cholinergic integrity is essential to normal hepatic glucose metabolism. (C) 2000 Academic Press.
KW - Animal
KW - Cholinergic denervation
KW - Glucose and glycogen metabolism
KW - Hepatic vagotomy
KW - Insulin and glucagon sensitivity
KW - Isolated liver per fusion
KW - Rat
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U2 - 10.1006/jsre.2000.5820
DO - 10.1006/jsre.2000.5820
M3 - Article
C2 - 10781370
AN - SCOPUS:0034193742
SN - 0022-4804
VL - 90
SP - 19
EP - 25
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -