1 Department of Molecular Physiology and Biophysics, 3 Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615; and 2 Department of Neuroscience, Pro-Neuron, Gaithersburg, Maryland 20877
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ABSTRACT |
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We determined if blocking transmission
in the fibers of the vagus nerves would affect basal hepatic glucose
metabolism in the 18-h-fasted conscious dog. A pancreatic clamp
(somatostatin, basal portal insulin, and glucagon) was employed. A
40-min control period was followed by a 90-min test period. In one
group, stainless steel cooling coils (Sham, n = 5) were
perfused with a 37°C solution, while in the other (Cool,
n = 6), the coils were perfused with 20°C solution.
Vagal blockade was verified by heart rate change (80 ± 9 to
84 ± 14 beats/min in Sham; 98 ± 12 to 193 ± 22 beats/min in Cool). The arterial glucose level was kept euglycemic by
glucose infusion. No change in tracer-determined glucose production
occurred in Sham, whereas in Cool it dropped significantly (2.4 ± 0.4 to 1.9 ± 0.4 mg · kg
1 · min
1). Net
hepatic glucose output did not change in Sham but decreased from
1.9 ± 0.3 to 1.3 ± 0.3 mg · kg
1 · min
1 in the Cool
group. Hepatic gluconeogenesis did not change in either group. These
data suggest that vagal blockade acutely modulates hepatic glucose
production by inhibiting glycogenolysis.
vagal cooling; liver nerves; parasympathetic blockade; gluconeogenesis; glycogenolysis
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INTRODUCTION |
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THE AUTONOMIC NERVOUS SYSTEM is involved in the regulation of hepatic glucose metabolism. It has been demonstrated, for example, that electrical stimulation of the vagus nerves induces activation of the liver enzyme glycogen synthase, which in turn increases glycogen synthesis and reduces glucose output (19). Conversely, electrical stimulation of the splanchnic nerve induces activation of the liver enzyme glycogen phosphorylase, which in turn increases glycogenolysis and glucose output (20). Taken together, these data have been interpreted to suggest that activation of the parasympathetic nervous system promotes glucose uptake and hepatic glycogen deposition while activation of the sympathetic nervous system promotes glycogenolysis and glucose output.
It is also known that glucosensors within the hepatoportal region have the ability to sense glucose and inform the brain of its concentration via afferent fibers traveling, at least in part, along the hepatic vagus nerves (16). It has been hypothesized that the brain uses this information to minimize fluctuations in the plasma glucose level after feeding (18). The efferent responses of this feedback loop involve the pancreas, adrenal glands, adipocytes, skeletal muscles, and the liver (2). Although it is known that the autonomic nervous system is vital to the regulation of glucose metabolism in times of stress, evidence is accumulating to support a role for it in the postprandial state. Nevertheless, its role in regulating hepatic glucose metabolism after an overnight fast is not clear.
Our aim, therefore, was to cool the vagus nerves, in the presence of a pancreatic clamp, to study the involvement of the parasympathetic nervous system in the control of hepatic glucose output in the 18-h-fasted dog.
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MATERIALS AND METHODS |
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Animal care. Experiments were conducted on 11 conscious, mongrel dogs (22 ± 2 kg) of either sex. The animals were fed one time daily with a meat (KalKan, Vernon, CA) and chow (Lab Canine Diet No. 5006; Purina, St. Louis, MO) diet (34% protein, 46% carbohydrate, 14.5% fat, and 5.5% fiber based on dry weight). Before the study, the dogs were deprived of food for 18 h. The animals were housed in a facility that met the standards of the American Association for the Accreditation of Laboratory Animal Care International, and the protocols were approved by the Vanderbilt University Medical School Animal Care Committee.
Surgical procedures. Two weeks before the experiment, the dogs underwent surgery for placement of splenic and jejunal vein infusion catheters, hepatic and portal vein sampling catheters, and a femoral artery sampling catheter, as previous described (4). Each dog was used for an experiment only if it had a leukocyte count <18,000/mm3, a hematocrit >35%, a good appetite, and normal stools. The position of the catheter tips was confirmed upon necropsy at the end of each experiment.
Stainless steel cooling coils, with Silastic extension tubing attached, were placed around the vagus nerves in the neck in all dogs, as described previously (1, 10). The effectiveness of the cooling-induced blockade of parasympathetic signaling was verified by measuring the heart rate (which is under vagal control). On the day of the study, the abdominal and femoral artery catheters, as well as the Silastic tubes connected to the cooling coils, were exteriorized from their subcutaneous pockets under local anesthesia (2% lidocaine; Astra Pharmaceutical Products, Worcester, MA). The ends of the Silastic tubes connected to the vagal cooling coils were joined to inflowing lines (ID 0.125 in.; OD 0.25 in.) from the cooling bath and to outflowing lines linking them to the collection reservoir. Angiocaths (18 gauge; Becton-Dickinson, Sandy, UT) were inserted percutaneously in the left cephalic vein for somatostatin infusion, in the right cephalic vein for peripheral glucose infusion (20% dextrose) as needed, and in the saphenous vein for tracers and indocyanine green infusion. After coil preparation, each dog was allowed to stand calmly in a Pavlov harness for 30 min before the start of the experiment.Experimental design.
Eighteen-hour-fasted dogs underwent an experiment consisting of a
100-min tracer equilibration period (140 to
40 min), a 40-min
control period (
40 min to 0 min), and a 90-min experimental period
(0-90 min). A priming dose (55 µCi) of
[3-3H]glucose (NEN, Boston, MA) was administered at
140
min followed by a continuous infusion of 0.47 µCi/min
[3-3H]glucose, 0.42 µCi/min
[14C]alanine (NEN), and indocyanine green (0.07 mg/min). At time
130 min, a peripheral somatostatin
infusion (0.8 µg · kg
1 · min
1), an
intraportal porcine insulin infusion (0.3 mU · kg
1 · min
1; Eli Lilly,
Indianapolis, IN), and an intraportal glucagon infusion (0.65 ng · kg
1 · min
1; GlucaGen;
Bedford Laboratories, Bedford, OH) were started and continued for the
entirety of the experiment in both protocols. Plasma glucose samples
were taken every 5 min, and the insulin infusion rate was adjusted as
necessary to maintain glucose at basal levels. The last change was made
at least 30 min before the start of the control period, and the insulin
infusion rates (192 and 214 µU · kg
1 · min
1 in the
Sham and Cool groups, respectively) remained unchanged after that. To
maintain a euglycemic clamp (
100 mg/dl), glucose (20% dextrose;
Baxter, Deerfield, IL) was infused through a leg vein as needed during
the experimental period. The dogs were randomly assigned to the Sham
(n = 5) or Cool (n = 6) groups. During
Sham experiments, the coils were perfused for the entire experimental period (90 min) with 37°C fluid. In contrast, in the Cool group, a
20°C fluid was perfused for the entire experimental period (90 min). In a previous experiment, we have shown that perfusing the coils
at this temperature maximally blocked the parasympathetic input to the
heart and that atropine did not further increase the heart rate,
demonstrating the efficacy of the procedure (10). Small
blood samples were taken every 5 min to measure the glucose concentration so that exogenous glucose could be administered as needed
to maintain the glucose clamp. Arterial, portal, and hepatic blood was
sampled every 10 min during the basal period and every 15 min
thereafter. The collection and processing of blood samples have been
described previously (21). Approximately 8% of the dog's
total blood volume was removed during each study.
Hormone and metabolic assays.
Plasma glucose levels were assayed using the glucose oxidase method
with a Beckman glucose analyzer. Plasma insulin and glucagon were
measured using double-antibody RIAs described previously (15) with interassay coefficients of variation (CV) of 7 and 5%, respectively. Plasma samples used for glucagon determination contained 100,000 kallikrein inhibitor units aprotinin (Trasylol; Miles; Kankakee, IL) added at collection. Catecholamines were assayed using HPLC as previously described (13). The
interassay CV for epinephrine and norepinephrine were 7 and 5%,
respectively. The samples for catecholamine analysis contained 60 µl
glutathione/EGTA added at collection. Plasma cortisol was assayed using
the Clinical Assays Gamma Coat RIA kit with an interassay CV of 6%
(7). Whole blood levels of lactate, glycerol, alanine, and
-hydroxybutyrate were determined using perchloric acid-treated (3%)
blood samples according to the method of Lloyd et al.
(11), as adapted to the Monarch 2000 centrifugal analyzer
(Lexington, MA). Plasma [3-3H]- and
[14C]glucose were determined by liquid scintillation
counting after Somogyi-Nelson deproteinization and an
3H2O exclusion procedure (21).
Calculations.
The total rate of glucose production was determined by means of a
primed tracer infusion. The data were calculated according to the
method of Wall et al. (25), as simplified by DeBodo et al.
(5), and also according to a two-compartment model
described by Mari (12) using parameters for the dog as
determined by Dobbins et al. (6). The results obtained
with the two methods were not significantly different, and we therefore
chose to display the data from the two-compartment model in Figs.
1-5. For calculation of hepatic glucose uptake, the net
[3H]glucose uptake was divided by the arterial
[3H]glucose specific activity. The net hepatic balances
of unlabeled glucose and [3H]glucose were calculated
using the formula (H [0.28 × A + 0.72 × P]) × HF where H, A, and P were the substrate concentrations in
hepatic vein, femoral artery, and portal vein blood or plasma, respectively. HF represents the total hepatic blood flow estimated from
indocyanine green, and 0.28 and 0.72 are the approximate contributions
of the hepatic artery and the portal vein, respectively, to the total
hepatic blood flow during a pancreatic clamp. We have shown in a
previous study (Cardin and Cherrington, unpublished observation) that
vagal cooling did not alter the flow distribution. With this
calculation, a positive value represents net production by the liver,
whereas a negative value represents net hepatic uptake. Plasma glucose
and [3H]glucose values in the calculations were
multiplied by 0.73 to convert them to blood glucose values, as
validated elsewhere (14). To obtain endogenous glucose
production, the amount of glucose infused was subtracted from total
glucose production. Gluconeogenesis was assessed by determining
gluconeogenic efficiency, as previously described (3). In
addition, the total net hepatic uptake of the gluconeogenic precursors
was determined and divided by two to convert the rate to glucose
equivalents
(mg · kg
1 · min
1). This
provides an estimate of hepatic gluconeogenic flux to glucose
6-phosphate as previously described (4). Net hepatic glycogenolysis was estimated using the following equation
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Statistical analysis. Data are expressed as means ± SE. Statistical comparisons among groups and between groups were made using ANOVA with repeated measures. Post hoc analysis was performed using universal F-tests. Significance was presumed at P < 0.05.
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RESULTS |
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Glucose and heart rate.
Arterial plasma glucose levels were stable during the experiment
(100 ± 5 and 97 ± 5 mg/dl in the Sham and 98 ± 2 and
94 ± 3 mg/dl in the Cool groups for the control and experimental
periods, respectively, Fig. 1,
top). The heart rate did not increase significantly in the
Sham group when the coils were perfused (Fig. 1, bottom). On
the other hand, perfusion of the coils with a cold solution resulted in
a marked increase (P < 0.05) in the heart rate of 63 ± 13 beats/min within 15 min and 102 ± 22 beats/min by
the end of the experimental period (Fig. 1, bottom). This
increase attested to the effectiveness of cooling in producing
parasympathetic blockade. The hepatic blood flow was similar in the
basal period (25.6 ± 3.4 and 25.1 ± 3.2 ml · kg1 · min
1) and the
experimental period (26.9 ± 3.6 and 28.7 ± 3.1 ml · kg
1 · min
1) in both
protocols and did not change in response to vagal cooling.
Insulin and glucagon. The average arterial plasma insulin concentrations were 4 ± 1 and 5 ± 1 µU/ml in the basal period and 4 ± 1 and 6 ± 1 µU/ml in the experimental period for the Sham and Cool groups, respectively (Fig. 2, top). Similarly, the average arterial plasma glucagon concentrations were 46 ± 4 and 53 ± 6 pg/ml in the basal period and 44 ± 4 and 51 ± 5 pg/ml in the experimental period for the Sham and Cool groups, respectively (Fig. 2, bottom). In the presence of a pancreatic clamp, vagal cooling had no effect on plasma insulin or glucagon levels.
Cortisol.
Basal arterial plasma cortisol levels (Fig.
3) were similar in the two groups (Sham
2.0 ± 0.4 and Cool 2.1 ± 0.4 µg/dl). Perfusing the coils
with a 37°C solution did not significantly affect the arterial plasma
cortisol level. On the other hand, perfusing the coils with a 20°C
solution caused a rapid small increase in the plasma cortisol level of
~3 µg/dl (Fig. 3). The rise was sustained over the 90-min test period.
Epinephrine and norepinephrine. Although the arterial plasma epinephrine levels tended to rise slightly in the Cool group compared with the Sham group, no significant difference between the groups was found at any time point (Sham 56 ± 26 to 73 ± 25 and Cool 99 ± 45 to 145 ± 67 pg/ml for basal and experimental periods, respectively; Fig. 4, top). Similarly, the arterial plasma norepinephrine levels (Fig. 4, bottom) were stable in the Sham (81 ± 11 to 93 ± 20) and in the Cool (84 ± 12 to 76 ± 14 pg/ml) groups.
Gluconeogenic precursors and lipolysis.
Arterial blood lactate levels remained at basal values throughout the
experiment (Table 1) regardless of
treatment. Average basal values for net hepatic lactate output were
8.20 ± 3.06 in the Sham and 8.59 ± 3.26 µmol · kg1 · min
1 in the
Cool groups (Table 2). These values
showed a tendency to decrease over time to an average of 5.60 ± 2.40 and 4.78 ± 2.94 µmol · kg
1 · min
1 in Sham
and Cool groups, respectively. There were no significant differences
between the two groups.
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Glucose metabolism.
Net hepatic glucose output did not change over time in the Sham group
(2.10 ± 0.15 and 2.17 ± 0.25 for the average basal and experimental period values, respectively; Fig.
5, top). Conversely, net
hepatic glucose output in the Cool group significantly decreased from
an average basal value of 1.95 ± 0.34 to 1.32 ± 0.22 by 30 min and remained significantly reduced for the rest of the perfusion period (Fig. 5, top). The average values for the last 45 min
of the experiment were significantly (P < 0.05) lower
in the Cool compared with the Sham group (1.51 ± 0.18 and
2.18 ± 0.27 mg · kg1 · min
1, respectively).
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DISCUSSION |
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This study investigates the effect of acute blockade of the vagus nerves on hepatic metabolism in the conscious dog. The fact that a maximal increase in heart rate was observed in response to vagal cooling demonstrates the effectiveness of vagal blockade. To prevent changes in pancreatic hormonal and glucose levels that could themselves affect hepatic glucose production, insulin, glucagon, and glucose were fixed at basal levels for the duration of the experiment using a euglycemic pancreatic clamp. Our data indicate that interrupting vagal transmission using the vagal cooling technique decreased net hepatic glucose output resulting from a decrease in glycogenolysis.
The main finding of the present study was that vagal blockade decreased glucose production. This was evident from three independent pieces of data. First, a decrease in net hepatic glucose output was seen by 30 min during vagal blockade, whereas no significant change was seen in net hepatic glucose output in the Sham group. Second, tracer-determined endogenous glucose production also decreased in the Cool group without any change occurring in the Sham group. Third, the rate of glucose infusion required to maintain euglycemia in the Cool group was significantly greater than in the Sham group despite equivalent glucose utilization rates. These three independent measures attest to the veracity of the observation. Because neither gluconeogenic efficiency nor gluconeogenic flux was altered by vagal blockade, it seems likely that a decrease in glycogenolysis was responsible for the decrease in glucose output by the liver.
Our finding of reduced net hepatic glucose output is somewhat surprising in view of the literature that would have predicted a possible increase in net hepatic glucose output when the inhibitory effects of ACh were removed. Indeed an activation of the parasympathetic nervous system promotes glucose uptake by the liver (19, 23). In the absence of parasympathetic input, we would therefore have expected a net increase in hepatic glucose output. It must be remembered, however, that the vagus nerves carry both afferent and efferent fibers. It is possible, therefore, that, by blocking the afferent fibers traveling along the vagus nerves, we reflexively decreased sympathetic inflow to the liver. Thus, by cooling the vagus nerve, we created a situation that reproduced a feeding signal, which has been shown to decrease efferent sympathetic outflow (17). To the extent that basal sympathetic tone is important to glucose production by the liver, this would decrease glycogen phosphorylase activity, glycogenolysis, and eventually glucose production (20). The fact that acutely interrupting vagal transmission decreased hepatic glucose production is in contrast to other studies that have shown that hepatic vagotomy does not change basal hepatic glucose production (24). It should be kept in mind, however, that, when one uses chronic surgical denervation, the organism can adapt to the change, thus potentially obscuring the acute effects of denervation.
The arterial blood glycerol levels remained basal throughout the experiments, and no significant differences were found between the groups. This suggests that lipolysis was not affected by the vagal blockade. Thus one can assume that sympathetic input to the adipocytes did not change. This suggests that, if the decrease in net hepatic glucose output was because of decreased sympathetic input, this was a selective decrease to the liver.
A significant increase in arterial plasma cortisol of 3 µg/dl
occurred 15 min after the beginning of the cooling procedure. This
increase appears to be a specific response to vagal cooling, since we
observed a similar increase in our previous experiments using the vagal
cooling technique and since it did not occur in the Sham group. This
increase in cortisol cannot, however, explain the fall in glucose
production, because if anything a rise in cortisol would be expected to
increase glucose production (8, 9). In fact, however, we
have previously shown that an acute change of this magnitude would have
little effect on glucose production over a 3-h period (9).
Likewise, the small nonsignificant rise in epinephrine, even if real,
would have done little to alter hepatic glucose production based on our
earlier dose-response studies with the catecholamine (22).
In summary, vagal blockade decreased hepatic glucose production without altering hepatic glucose uptake or gluconeogenesis. These data suggest that hepatic vagus nerves play a role in maintaining hepatic glycogenolysis during the basal state in conscious 18-h-fasted dogs. We postulate that they do so by altering the vagosympathetic reflex, to maintain sympathetic input to the liver, which in turn stimulates glucose production to a modest extent.
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ACKNOWLEDGEMENTS |
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We acknowledge the excellent technical assistance of Jon Hastings.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants 2RO1 DK-18243 and 5PO60 DK-20593 and Juvenile Diabetes Foundation International Grant JDFI no. 397008.
Address for reprint requests and other correspondence: A. D. Cherrington, Dept. of Molecular Physiology and Biophysics, Vanderbilt Univ. School of Medicine, 702 Light Hall, Nashville, TN 37232-0615.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00566.2001
Received 26 December 2001; accepted in final form 24 June 2002.
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