Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615
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ABSTRACT |
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We previously reported that simulation of the
chronic hyperglucagonemia seen during infection was unable to recreate
the infection-induced increase in hepatic glucose production. However,
chronic hyperglucagonemia was accompanied by a fall in the arterial
levels of gluconeogenic precursors as opposed to a rise as is seen
during infection. Thus our aim was to determine whether an infusion of
gluconeogenic precursors could increase hepatic glucose production in a
setting of hyperglucagonemia. Studies were done in 11 conscious
chronically catheterized dogs in which sampling (artery and portal and
hepatic veins) and infusion catheters (splenic vein) were implanted 17 days before study. Forty-eight hours before infusion of gluconeogenic (GNG) precursors, a sterile fibrinogen clot was placed into the peritoneal cavity. Glucagon was infused over the subsequent 48-h period
to simulate the increased glucagon levels (~500 pg/ml) seen during
infection. On the day of the experiment, somatostatin was infused
peripherally, and basal insulin and simulated glucagon were infused
intraportally. After a basal period, a two-step increase in lactate and
alanine was initiated (120 min/step; n = 5). Lactate (479 ± 25 and
1,780 ± 85 µM; expressed as
change from basal in periods I and
II, respectively) and alanine (
94 ± 13 and
287 ± 44 µM) levels were increased. Despite
increases in net hepatic GNG precursor uptake (
0.7 ± 0.3 and
1.1 ± 0.4 mg
glucose · kg
1 · min
1),
net hepatic glucose output did not increase. Because nonesterified fatty acid (NEFA) levels fell, in a second series of studies, the fall
in NEFA was eliminated. Intralipid and heparin were infused during the
two-step substrate infusion to maintain the NEFA levels constant in
period I and increase NEFA
availability in period II (
29 ± 29 and
689 ± 186 µM;
n = 6). In the presence of similar increases in net hepatic GNG precursor uptake and despite increases in
arterial glucose levels (
17 ± 5 and
38 ± 12 mg/dl), net
hepatic glucose output increased (
0.6 ± 0.1 and
0.7 ± 0.2 mg · kg
1 · min
1).
In summary, a chronic increase in glucagon, when combined with an acute
increase in gluconeogenic precursor and maintenance of NEFA supply,
increases hepatic glucose output as is seen during infection.
alanine; lactate; lipolysis; inflammation; gluconeogenesis
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INTRODUCTION |
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A CHARACTERISTIC RESPONSE to infection is an increase in whole body glucose production that is predominantly derived from an increase in gluconeogenesis (19, 25). Multiple counterregulatory hormones are increased during infection, including glucagon, catecholamines, and cortisol. Early studies suggested that hyperglucagonemia plays an important role, since acute removal of the elevated glucagon levels reduced hepatic glucose production to rates seen in corresponding nonstressed controls (12, 14, 19, 30).
However, recent work in our laboratory suggests that hyperglucagonemia alone cannot explain the increase in glucose production during infection. A noninfected animal exposed to chronic simulation of the increase in glucagon seen during infection does not increase hepatic glucose production (20). Hepatic glucose production cannot increase because glucagon, although having potent effects in enhancing the ability of the liver to extract gluconeogenic precursors, does not increase gluconeogenic precursor supply. Consequently, the circulating levels of gluconeogenic substrates decrease markedly during chronic hyperglucagonemia, offsetting the glucagon-mediated rise in the fractional extraction of gluconeogenic precursors by the liver (20).
Simply increasing the supply of gluconeogenic precursors also does not increase hepatic glucose production in vivo. Although in vitro increases in gluconeogenic precursor supply increase hepatic glucose production (7), this has yet to be established in vivo. In vivo, increases in lactate, alanine, or glycerol levels in a setting of fixed insulin and glucagon levels do not increase hepatic glucose production in overnight-fasted dogs and humans (4, 6, 13). Because hepatic glycogenolysis contributes a large portion of hepatic glucose production after an overnight fast, a rise in gluconeogenesis could be offset by a fall in hepatic glycogenolysis. Yet, even in prolonged fasted states in which gluconeogenesis accounts for the majority of the glucose released by the liver, infusion of gluconeogenic substrates does not increase hepatic glucose production (6, 13). Suppression of gluconeogenic precursor availability using dichloroacetate in prolonged fasted humans also does not decrease hepatic glucose production; however, the accompanying suppression of lipolysis complicates the interpretation of the results (13).
Nonesterified free fatty acids (NEFAs) may play an important role in modulating hepatic glucose production (27). NEFAs can inhibit insulin suppression of glucose production. Thus they may interact with gluconeogenic substrate availability to support an increased rate of gluconeogenesis and glucose production. NEFA levels have generally not been measured in studies in which gluconeogenic substrates were infused. Infusion of gluconeogenic precursors, such as lactate, can alter the availability of NEFA (4). NEFAs are the major fuel oxidized by the liver (15). In fact, inhibition of fat oxidation using a fatty acid oxidation inhibitor suppresses hepatic glucose production (22). Thus sustaining an increase in gluconeogenesis may necessitate adequate fat oxidation by the liver.
We hypothesized that to recreate the increase in glucose production and gluconeogenesis seen in our model of infection, both the appropriate hormonal environment and the supply of gluconeogenic precursors and NEFA must be adequate to support an increase in gluconeogenesis. Thus the aim of this study was to determine in a chronically hyperglucagonemic state whether acute increases in gluconeogenic precursor supply can increase hepatic glucose production and whether this interaction is dependent on NEFA availability. Studies were done in chronically catheterized conscious dogs in which gluconeogenic precursor and NEFA supply were modulated in livers primed to support an increase in gluconeogenesis by chronic glucagon infusion.
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MATERIALS AND METHODS |
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Animal preparation. Experiments were carried out on 11 conscious mongrel dogs (21 ± 1 kg) of either gender. Before being studied, they received a diet consisting of KalKan meat (Vernon, CA) and Purina dog chow (St. Louis, MO) once daily. The composition of the diet was 52% carbohydrate, 31% protein, 11% fat, and 6% fiber based on dry weight. The dogs were housed in a facility that met American Association for Accreditation of Laboratory Animal Care guidelines, and the experimental protocols were approved by the Vanderbilt University Medical Center Animal Care Subcommittee.
Experimental protocol. Fourteen to seventeen days before study, a laparotomy was performed under general anesthesia (isoflurane). As previously described (20), infusion catheters were placed into the splenic vein and a jejunal vein for intraportal infusion of insulin and glucagon. Sampling catheters (0.04 inch ID) were also inserted into the portal vein and the left common hepatic vein for blood sampling. In addition, a catheter (0.04 inch ID) for blood sampling was inserted into the femoral artery after an incision in the left inguinal area. The catheters were then filled with saline containing heparin (200 U/ml). Doppler flow probes were placed about the portal vein and hepatic artery after the gastroduodenal vein was ligated. The venous catheters and the Doppler flow probe leads were exteriorized and placed in a subcutaneous pocket in the abdominal area. The free end of the splenic venous infusion catheter was exteriorized, tunneled subcutaneously, and placed under the skin between the clavicles. The femoral arterial catheter was placed under the skin in the inguinal region (19).
Two weeks after catheter implantation, all animals had 1) a good appetite (consuming the entire daily ration), 2) normal stools, 3) a hematocrit above 35%, and 4) a leukocyte count below 18,000 mm
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Fibrinogen clot preparation. A 1% bovine fibrinogen solution (10 ml/kg) was prepared in sterile saline and filtered through a sterile 0.45 µM filter (Corning, Corning, NY). Thrombin was then added (1,000 units), and 30 min were allowed for clot formation (18).
Processing of blood samples. Blood samples were drawn into heparinized syringes and transferred to chilled tubes containing potassium EDTA (15 mg). The collection and immediate processing of blood samples have been previously described (2). Radioactivity in plasma glucose was measured using established methods (2). Blood lactate, glycerol, and alanine were analyzed using the method of Lloyd et al. (16) on a Monarch 2000 centrifugal analyzer (Lexington, MA). Plasma glucose was assayed immediately with the use of a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). Plasma NEFAs were determined spectrophotometrically (Wako Chemicals, Richmond, VA). Immunoreactive insulin (29) was assayed using a double-antibody technique [Pharmacia Diagnostics, Piscataway, NJ; intra-assay coefficient of variation (CV) of 11%]. Plasma treated with 500 KIU of Trasylol (Miles, Kankakee, IL) was assayed for immunoreactive glucagon (1) using a procedure similar to the one for insulin (intra-assay CV of 8%). Plasma cortisol (8) was assayed with Clinical Assays Gamma Coat radioimmunoassay kit (intra-assay CV of 6%). Hepatic arterial and portal venous blood flows were assessed using Transonic flow probes (Transonic Systems, Ithaca, NY). Blood flow was converted to plasma flow by multiplying by 1 hematocrit ratio. Indocyanine green dye was used to verify the placement of hepatic venous catheter and to provide an additional estimate of hepatic plasma flow. The labeled concentrations of plasma alanine and lactate and the unlabeled concentration of alanine were determined using a short column ion exchange chromatographic system (3).
Tracer methods and calculations.
The rates of total glucose production and utilization were calculated
according to the method of Wall et al. (28), as simplified by DeBodo et
al. (5). Net hepatic glucose output was calculated using the formula
[H (Fa × A + Fp × P)] × HBF,
where H, A, and P are the blood glucose concentrations in the hepatic
vein, femoral artery, and portal vein, respectively, and
Fa and
Fp represent the fractional
contribution of the hepatic artery and portal vein, respectively, to
total hepatic blood flow (HBF). Plasma glucose concentrations were
converted to whole blood concentrations using a correction factor of
0.73 (21). The above equation was used to calculate net hepatic
lactate, alanine, and glycerol output. However, because the liver
generally was a net consumer of these substrates (i.e., negative
output), the data are presented as positive values and denoted as net
uptake. Gluconeogenic substrate uptake was obtained by summing net
hepatic lactate, alanine, and glycerol uptake.
Statistics.
Statistical comparisons were made using ANOVA (Systat for Windows;
Systat, Evanston, IL). A univariate post hoc
F test was used when a significant
F ratio was found. Statistical
significance was accepted at P < 0.05. Because previous studies in a similarly fasted dog (26) indicated
that hepatic glucose metabolism is constant over the time course of the
study, the data are expressed as changes from basal and are averaged
over the last 30 min of each period and are indicated by .
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RESULTS |
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Hormone levels, NEFA, and glucose
kinetics.
Chronic glucagon infusion increased arterial plasma glucagon levels in
both groups (574 ± 99 and 499 ± 86 pg/ml; NEFA and +NEFA, respectively) during the basal period (normal range 40-80 pg/ml), and levels remained elevated during the experimental period (Fig. 2). Arterial plasma insulin
levels were 9 ± 2 and 9 ± 2 µU/ml (
NEFA and +NEFA,
respectively) in the basal period and did not change during the
experimental period. Arterial plasma cortisol levels were 1.5 ± 0.6 and 2.3 ± 0.8 µg/dl (
NEFA and +NEFA, respectively) in the
basal period and did not change during the experimental period.
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Gluconeogenic precursor kinetics.
In NEFA, the infusion of lactate increased arterial lactate
levels in a stepwise manner (
479 ± 25 and
1,780 ± 85 µM; Fig 5). Despite this
increase, net hepatic lactate uptake only increased by 5.1 ± 3.6 and 10.0 ± 6.4 µmol · kg
1 · min
1,
because net fractional hepatic lactate extraction decreased (
0.13 ± 0.010 and
0.26 ± 0.11).
In +NEFA, the infusion of lactate increased arterial lactate levels in
a stepwise manner (
358 ± 48 and
1,633 ± 106 µM).
Prevention of the fall in NEFAs altered neither the increase in net
hepatic lactate uptake (
6.3 ± 1.0 and
8.4 ± 1.0 µmol · kg
1 · min
1)
nor the decrease in net fractional hepatic lactate extraction (
0.14 ± 0.05 and
0.48 ± 0.05).
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DISCUSSION |
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These data demonstrate that chronic hyperglucagonemia, when accompanied by increases in gluconeogenic precursor availability and adequate circulating concentrations of NEFA, can contribute to the infection-induced increase in glucose production and gluconeogenesis. These data confirm that even in an animal reliant predominantly on gluconeogenesis, combined increases in lactate and alanine uptake by the liver are unable to increase hepatic glucose output. If the substrate-induced suppression of NEFAs is prevented and/or NEFAs are increased, increases in gluconeogenic precursor supply can support an increase in hepatic glucose production.
Chronic hyperglucagonemia markedly enhanced the importance of the liver
in disposal of the exogenous alanine. As expected, the uptake of
alanine by the liver increased in parallel with the rise in alanine
levels. This is reflected in the constancy of net fractional hepatic
alanine extraction in the face of increases in blood alanine
concentration (6). Remarkably, all of the exogenous alanine infused was
disposed of by the liver. In periods I
and II, net hepatic alanine uptake
increased by ~2 and 4 µmol · kg1 · min
1,
which was equal to the rate of alanine infusion in each period. In the
42-h fasted dog, 50% of the exogenous alanine infused was consumed by
the liver and 50% was removed by peripheral tissues (6). In the
present study, the glucagon-mediated twofold increase in net fractional
hepatic extraction of alanine (20) is the likely explanation for the
enhancement in net hepatic alanine uptake. The lack of a contribution
of the peripheral tissues may be due to the lower alanine levels in
this study or to a decrease in peripheral alanine clearance. Peak
alanine levels in period II were
~350 µM, whereas, in the prior study (6), they were ~500 µM.
In the case of lactate, the coupling between the increase in the
arterial lactate level and the increase in the hepatic uptake of
lactate is nonlinear. Net hepatic lactate uptake increased only
modestly from period I to
period II, despite a fourfold increase in the arterial lactate level. Net fractional hepatic lactate extraction decreased progressively from the basal period to
periods I and
II. In addition, although the liver
still removed ~40% of the infused lactate in each period, net
hepatic lactate uptake increased only modestly in
period II, despite the much larger increase in the arterial lactate levels. Interestingly, in the overnight-fasted dog (4), when lactate levels were increased to similar
levels (~3,000 µM), the liver increased its uptake by 9 µmol · kg1 · min
1.
This increase is equal to the increase from basal seen in the second
period (
9
µmol · kg
1 · min
1).
This suggests that chronic hyperglucagonemia does not facilitate concentration-dependent lactate entry.
Consistent with other studies done in vivo, increases in gluconeogenic
precursor supply did not increase net hepatic glucose output even in a
setting of chronic glucagon excess. In the present study, net hepatic
gluconeogenic precursor uptake increased by 0.7 and 1.0 mg
glucose · kg1 · min
1
in periods I and
II, respectively, whereas net hepatic
glucose output was unaltered. This is consistent with previous reports that, even in prolonged fasted states, increases in gluconeogenic substrates alone do not increase glucose production (4, 6, 13).
Presumably, the additional carbon taken up was either oxidized or used
to synthesize lipid or glycogen.
Maintenance of NEFA availability allows increases in gluconeogenic precursor uptake to increase hepatic glucose output. During lactate and alanine infusion, NEFA levels decreased. When the fall in NEFA concentration was prevented (period I) or when levels were allowed to rise (period II), net hepatic glucose output increased. Previous investigators either did not measure NEFA levels when they infused gluconeogenic substrates, or, if NEFAs were assessed, they were not prevented from falling (4). In vitro studies clearly indicate that NEFA can stimulate gluconeogenesis. In vivo it has been difficult to demonstrate that increases in NEFA enhance gluconeogenesis (7, 15). However, NEFA oxidation is essential in maintaining hepatic glucose production in the fasted and infected states (15). NEFAs are important inhibitors of insulin-mediated suppression of hepatic glucose production (9, 27). They restrain glycolysis and subsequent lactate release by the liver of the overnight-fasted dog (27). However, in a prolonged fasted state in which glycolysis is already suppressed, decreases in NEFAs did not alter hepatic glucose production (11). Because NEFAs inhibit pyruvate oxidation, it is possible that they limit the oxidative disposal of the gluconeogenic precursors in the liver and thereby enhance gluconeogenesis (23).
The potency of the NEFA effect is even more evident given that net
hepatic glucose output increased despite increases in arterial glucose
levels that are suppressive to hepatic glucose output. This mild
hyperglycemia should suppress net hepatic glucose output by
~0.5-1
mg · kg1 · min
1
(26). In period I, glucose levels
increased only modestly (17 mg/dl), and net hepatic glucose output
increased by 0.6 mg · kg
1 · min
1.
However, in period II, the arterial
plasma glucose levels increased by 38 mg/dl, yet net hepatic glucose
output remained elevated. Thus, if the suppressive effects of
hyperglycemia are taken into account, net hepatic glucose output
increased by 1-1.5
mg · kg
1 · min
1.
The mechanism whereby NEFAs interact with this suppressive effect of
hyperglycemia is unclear.
Despite maintenance of NEFA levels, the anti-ketogenic effects of
lactate and alanine persisted. Hepatic -OHB production decreased
irrespective of whether NEFA levels were clamped. This is seen in the
perfused rat liver (17), and it is likely due to substrate-induced
increase in malonyl-CoA. Yet, in the overnight-fasted dog, lactate
infusion did not alter ketone body synthesis (4). One possibility is
that the addition of alanine may have combined with lactate to exert an
anti-ketogenic effect. An additional possibility is that the higher
rate of ketogenesis in the longer fasted dog makes it more susceptible
to the anti-ketogenic effects of gluconeogenic substrates.
In summary, in a setting of chronic hyperglucagonemia, combined increases in lactate and alanine levels can increase hepatic glucose production if the anti-lipolytic effect of the substrate infusion is eliminated. Thus these results suggest that the infection-induced increase in glucagon, when combined with increases in gluconeogenic precursor and adequate fatty acid availability, can contribute to the infection-induced increase in glucose production.
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ACKNOWLEDGEMENTS |
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We are grateful for the technical assistance of D. Brooks Lacy, Pat Donahue, Pamela Venson, and Eric Allen.
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FOOTNOTES |
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This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-43748 (O. P. McGuinness, Principal Investigator) and Diabetes Research and Training Center Grant P60-DK-20593.
Address for reprint requests: O. P. McGuinness, 702 Light Hall, Dept. of Molecular Physiology and Biophysics, Vanderbilt Univ., Nashville, TN 37232-0615.
Received 26 November 1997; accepted in final form 6 May 1998.
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