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Am J Physiol Endocrinol Metab 275: E101-E111, 1998;
0193-1849/98 $5.00
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Vol. 275, Issue 1, E101-E111, July 1998

A negative arterial-portal venous glucose gradient decreases skeletal muscle glucose uptake

Pietro Galassetti, Masakazu Shiota, Brad A. Zinker, David H. Wasserman, and Alan D. Cherrington

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

The effect of a negative arterial-portal venous (a-pv) glucose gradient on skeletal muscle and whole body nonhepatic glucose uptake was studied in 12 42-h-fasted conscious dogs. Each study consisted of a 110-min equilibration period, a 30-min baseline period, and two 120-min hyperglycemic (2-fold basal) periods (either peripheral or intraportal glucose infusion). Somatostatin was infused along with insulin (3 × basal) and glucagon (basal). Catheters were inserted 17 days before studies in the external iliac artery and hepatic, portal and common iliac veins. Blood flow was measured in liver and hindlimb using Doppler flow probes. The arterial blood glucose, arterial plasma insulin, arterial plasma glucagon, and hindlimb glucose loads were similar during peripheral and intraportal glucose infusions. The a-pv glucose gradient (in mg/dl) was 5 ± 1 during peripheral and -18 ± 3 during intraportal glucose infusion. The net hindlimb glucose uptakes (in mg/min) were 5.0 ± 1.2, 20.4 ± 4.5, and 14.8 ± 3.2 during baseline, peripheral, and intraportal glucose infusion periods, respectively (P < 0.01, peripheral vs. intraportal); the hindlimb glucose fractional extractions (in %) were 2.8 ± 0.4, 4.7 ± 0.8, and 3.9 ± 0.5 during baseline, peripheral, and intraportal glucose infusions, respectively (P < 0.05, peripheral vs. intraportal). The net whole body nonhepatic glucose uptakes (in mg · kg-1 · min-1) were 1.6 ± 0.1, 7.9 ± 1.3, and 5.4 ± 1.1 during baseline, peripheral, and intraportal glucose infusion, respectively (P < 0.05, peripheral vs. intraportal). In the liver, net glucose uptake was 70% greater during intraportal than during peripheral glucose infusion (5.8 ± 0.7 vs. 3.4 ± 0.4 mg · kg-1 · min-1). In conclusion, despite comparable glucose loads and insulin levels, hindlimb and whole body net nonhepatic glucose uptake decreased significantly during portal venous glucose infusion, suggesting that a negative a-pv glucose gradient leads to an inhibitory signal in nonhepatic tissues, among which skeletal muscle appears to be the most important.

hyperglycemia; arterial-portal venous glucose gradient

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

AFTER THE INGESTION of a meal rich in carbohydrates, the liver rapidly switches from net glucose production to net glucose uptake. This uptake accounts for the disposal of ~30% of the ingested glucose. After oral glucose consumption, peak rates of net hepatic glucose uptake (NHGU) can reach 5-8 mg · kg-1 · min-1 in both humans and dogs (1, 7, 21, 25). Both hyperglycemia and hyperinsulinemia are known to affect the rate of NHGU; a direct linear relationship has been described between hepatic glucose load and NHGU both when insulin values are uncontrolled (8) and at constant hyperinsulinemic levels (21). A significant correlation was also observed between the plasma insulin concentration and NHGU when the hepatic glucose load was maintained constant (20). For the complete activation of NHGU, however, hyperglycemia and hyperinsulinemia are not sufficient. If levels of hyperglycemia and hyperinsulinemia similar to those observed after the ingestion of a meal are reproduced by glucose infusion into a peripheral vein, the maximal levels of NHGU that can be obtained are about one-third to one-half of the peak rates observed after a meal (9, 29). Interestingly, if the same total amount of glucose is infused directly into the portal vein, rates of NHGU similar to those observed after ingestion of glucose are observed (13). This last situation mimics glucose ingestion, when the glucose level in the portal vein is elevated above that in the arterial system. This negative arterial-portal venous glucose gradient, also referred to as the "portal signal," is now thought to trigger a third factor that must be present, in association with hyperglycemia and hyperinsulinemia, for the full stimulation of NHGU.

In this way, the portal signal allows the liver to discriminate between an increased hepatic glucose load resulting from ingested as opposed to internally produced glucose. It also tightly matches glucose absorption from the intestine to liver glucose uptake, thereby minimizing perturbations of glucose in the systemic circulation.

Both in the 1987 study by Adkins et al. (2) and in the 1996 study by Pagliassotti et al. (26), the observation was made that although NHGU increases in response to intraportal glucose delivery, whole body glucose clearance is unchanged. This implies that during intraportal glucose delivery, a reduction in net glucose uptake by nonhepatic tissues must occur in parallel with the increase in NHGU. In both of the above studies, to maintain constant the glucose load to the liver, changes in the glucose load reaching the skeletal muscle were allowed to occur, thus complicating data interpretation. To date, no attempt has been made to directly identify the specific site at which the reduction in glucose uptake caused by intraportal glucose delivery occurs. The aim of the present study, therefore, was to determine whether net glucose uptake by the hindlimb, which is >70% skeletal muscle, is altered by a negative arterial-portal venous glucose gradient.

    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Animal care and surgical procedures. Studies were performed on 20 42-h-fasted conscious mongrel dogs of either sex, averaging 23.5 ± 1.0 kg in weight. The choice of a fast of this duration was motivated by the metabolic state that it produces, which closely resembles that in the overnight-fasted human (the liver exhibits net glucose output and net lactate uptake), and by the achievement of a stable minimum in liver glycogen content. All animals were maintained daily on a diet of meat and chow (34% protein, 14.5% fat, 46% carbohydrate, and 5.5% fiber based on dry wt). The animals were housed in a facility meeting the American Association for Accreditation of Laboratory Animal Care guidelines, and the protocol was approved by the Vanderbilt University Animal Care Subcommittee.

Seventeen days before each study, dogs underwent a laparotomy under general anesthesia (0.8% isoflurane). Catheters were inserted into the right common hepatic vein, the hepatic portal vein, a common iliac vein, and an external iliac artery as described in detail elsewhere (7, 25). Catheters were also placed in a splenic and a jejunal vein for intraportal infusions. Doppler flow probes (Instrumentation Development Laboratory, Baylor College of Medicine, Houston, TX) were placed around the portal vein, the hepatic artery, and an external iliac artery. The catheters were filled with saline containing heparin (200,000 U/l; Abbott, North Chicago, IL); their free ends were knotted, and, together with the free ends of the Doppler leads, they were placed in a subcutaneous pocket, allowing complete closure of the incision.

Approximately 48 h before a study, blood was drawn to determine the leukocyte count and the hematocrit of each animal. Dogs were studied only if they had a leukocyte count <18,000/mm3, a hematocrit >35%, a good appetite as evidenced by consumption of all the daily food ration, and normal stools.

On the morning of the study, the catheters and Doppler leads were exteriorized from their subcutaneous pocket using local anesthesia (20 g/l of lidocaine; Astra Pharmaceuticals, Worcester, MA). The contents of each catheter were aspirated, and the catheters were flushed with saline. The splenic and jejunal catheters were used for intraportal infusion of insulin and glucagon (Eli Lilly, Indianapolis, IN), glucose, and p-aminohippurate (PAH; Sigma, St. Louis, MO). PAH was used to assess the mixing of glucose in the portal and hepatic veins during intraportal glucose infusion. Portal venous, hepatic venous, common iliac venous, and external iliac arterial catheters were used for blood sampling. On the day of study, venous catheters (16-gauge angiocath; Deseret Medical, Becton-Dickinson, Sandy, UT) were inserted into the left cephalic vein for [3-3H]glucose, [U14C]glucose, and indocyanine green infusions (ICG; Hynson, Westcott and Dunning, Baltimore, MD); into the right cephalic vein for peripheral glucose and PAH infusions; and into the right saphenous vein for somatostatin infusion (Bachem, Torrance, CA). Each dog was allowed to stand quietly in a Pavlov harness for 20-30 min before the experiment was started.

Experimental design. Each experiment consisted of a total of 380 min divided into a 110-min equilibration period (from -140 to -30 min), a 30-min basal period (baseline, from -30 to 0 min), and two 120-min hyperglycemic periods (from 0 to 120 min and from 120 to 240 min) (Fig. 1). In all experiments, a constant infusion of ICG (0.1 mg · m-2 · min-1) and a primed, continuous infusion of HPLC-purified D-[3-3H]glucose (34-µCi bolus + 0.34 µCi/min) and [U-14C]glucose (20-µCi bolus + 0.20 µCi/min) were initiated at -140 min and maintained throughout the study. At 0 min, a constant infusion of somatostatin (0.8 µg · kg-1 · min-1) was begun to suppress endogenous insulin and glucagon secretion, and constant intraportal infusions of insulin (1.0 mU · kg-1 · min-1) and glucagon (0.5 ng · kg-1 · min-1) were established. In this way the insulin level was raised threefold, and glucagon concentration was maintained at basal values.


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  		Fig. 1.   Experimental design. In all animals, hyperglycemia was induced via both peripheral and intraportal glucose infusions, but sequence of hyperglycemic periods was reversed in one-half of dogs. ICG, indocyanine green; @, at.

At time = 0 min, hyperglycemia was brought about with the goal of doubling the baseline arterial glucose concentration and maintaining it constant until the end of the study. During the 240 min of hyperglycemia, glucose was infused into a peripheral vein only (peripheral glucose infusion period) for 120 min and into the portal vein (intraportal glucose infusion period) at a constant rate (5 mg · kg-1 · min-1) supplemented by infusion in a peripheral vein for 120 min. In all dogs, both peripheral and portal venous infusions were given, but in one-half of them (group A, n = 6), the peripheral infusion was performed first, whereas in the other one-half (group B, n = 6), the sequence was reversed. During peripheral glucose infusion, saline was infused intraportally.

External iliac arterial, portal venous, hepatic venous, and common iliac venous blood samples were taken every 15 min during the baseline period and every 10 min during the last 30 min of both hyperglycemic periods. The hyperglycemic clamp was monitored by means of small (0.4 ml) arterial blood samples drawn every 5 min and analyzed for glucose within 90 s. The peripheral glucose infusion rate was adjusted as required. The total volume of blood withdrawn did not exceed 20% of the animal's total blood volume, and two volumes of normal saline were infused for each volume of blood withdrawn. The methods for collecting and processing blood samples have been described previously (18).

Analytic procedures. Eight determinations of the plasma glucose concentration were made on each arterial and external iliac venous plasma sample; five determinations were made on the portal venous and hepatic venous samples, using the glucose oxidase method on a Beckman glucose analyzer (Beckman Instruments, Fullerton, CA). Blood concentrations of glucose were obtained in triplicate on perchloric acid extracts using a Technicon Autoanalyzer according to the method of Lloyd et al. (15). Blood lactate, alanine, glycerol (perchloric acid extracts), and plasma free fatty acid (FFA) concentrations were determined in triplicate by enzymatic methods, using a Monarch 2000 Centrifugal Analyzer (Instrumentation Laboratory, Lexington, MA) as previously described (15). Plasma glucose radioactivity (3H and 14C) was determined by liquid scintillation counting after deproteinization and evaporation to remove 3H2O (30). Whole blood [14C]glucose and [14C]lactate radioactivities were determined according to the method described by Okajima et al. (24). Whole blood 14CO2 was liberated by acidification with hydrochloric acid and trapped on chromatography paper with the use of hyamine hydroxide. PAH concentrations were determined on perchloric acid extracts of blood according to the method of Brun (6). The immunoreactive glucagon concentration in plasma samples to which 500 KIU/ml of Trasylol (FBA Pharmaceutical) had been added was determined with a modified version of the method of Morgan and Lazarow (19), with an interassay coefficient of variation (CV) of 10%. Immunoreactive insulin was measured as previously described (19), with an interassay CV of 4%.

Calculations and data analysis. Hindlimb blood flow was estimated using a Doppler flow probe (Instrumentation Development Laboratory) implanted on the external iliac artery and connected to an ultrasonic, range-gated, pulsed Doppler flow meter designed by Hartley and co-workers (11, 12). Hepatic blood flow was estimated using both ICG, according to the method of Leevy et al. (14), and Doppler flow probes (Instrumentation Development Laboratory) implanted on the hepatic artery and portal vein. These two independent techniques yielded similar values. Doppler-determined hepatic blood flow was used in data calculation for consistency with the hindlimb measurements and because this technique provides differential hepatic arterial and portal venous blood flow measurements. The ICG technique, in contrast, only allows an estimate of total hepatic blood flow and was used as a backup for the Doppler measurements. The distribution of hepatic blood flow was 81% portal vein and 19% hepatic artery in the baseline period and 75% portal vein and 25% hepatic artery in the hyperglycemic periods, when somatostatin was infused. These data are consistent with others reported in the dog (2, 4, 20, 27), in which, although somatostatin altered the distribution of blood flow between the portal vein and the hepatic artery slightly, total hepatic blood flow was not significantly affected.

When glucose is infused in the slow, laminar flow of the portal venous circulation, mixing of the glucose in the blood can be problematic. PAH, a substance not extracted by the liver or erythrocytes, was mixed with the intraportal glucose infusate at a concentration that resulted in a PAH infusion rate of 0.4 mg · kg-1 · min-1. The recovery of PAH across the liver was measured as described previously (20, 26). The ratio between the recovery of intraportally infused PAH and the actual intraportal PAH infusion rate was calculated and used as an index of mixing of the intraportal infusate with the blood entering and exiting the liver. Because of the magnitude of the CV for the method of assessing PAH balance, samples were considered statistically unmixed (>95% confidence that mixing did not occur) if hepatic vein recovery was >140% or <60% of the actual amount of PAH infused (20). If poor mixing, according to the above definition, was obtained in more than one of the four time points of the intraportal period, the animal was excluded from the study. This occurred in eight animals. Therefore, of the 20 experiments performed, data from only 12 were included in the reported database. In the latter, the ratio of PAH recovery in the portal vein to the intraportal PAH infusion rate was 0.92 ± 0.02, and the ratio of PAH recovery in the hepatic vein to the PAH infusion rate was 0.88 ± 0.02 (a ratio of 1.0 would represent perfect mixing). In the 12 experiments included in the study, the infusate failed to mix with the blood <15% of the time (7 out of 48 measurements). More importantly, when mixing errors did occur, they were random; therefore, all time points from these 12 animals were included in the database.

The hepatic substrate load was calculated directly as
load<SUB>in(D)</SUB> = [(C<SUB>A</SUB> × ABF) + (C<SUB>P</SUB> × PBF)]
where CA and CP represent the substrate concentrations in arterial and portal venous blood, respectively, and ABF and PBF represent the hepatic arterial and the portal venous blood flows, respectively. In glucose balance calculations, plasma glucose values were converted to whole blood values by using a correction factor (CF) obtained by calculating the ratio of the whole blood glucose value to the plasma glucose value at each time point throughout the study. A separate CF was established for each sampling site for each dog. The mean CF was 0.72 ± 0.01 in the artery, iliac vein, and hepatic vein throughout the whole study. The CF in the portal vein was 0.71 ± 0.01 during intraportal glucose infusion and 0.72 ± 0.01 during baseline and peripheral glucose infusion. Calculations performed with plasma glucose values converted to blood glucose values yielded similar results to those performed with blood glucose values per se, but the variance was reduced because of the increased accuracy of plasma glucose arteriovenous differences, which can be obtained without deproteinization. The use of whole blood glucose ensures accurate hepatic balance measurements regardless of the characteristics of glucose entry into the erythrocyte. To circumvent any potential errors arising from incomplete mixing of glucose in the circulation during intraportal glucose infusion, a second, indirect method of calculating the hepatic glucose load was used. It utilized the formula
load<SUB>in(I)</SUB> = [(G<SUB>A</SUB> × HBF) + GIR<SUB>P</SUB>] − GUG
where GA represents the blood glucose concentration in the artery, GIRP represents the glucose infusion rate into the portal vein, and GUG represents the uptake of glucose by the gastrointestinal tract. GUG was measured during peripheral glucose infusion as the product of the arterial-portal venous glucose difference and the portal venous blood flow. It was considered to be the same during intraportal glucose infusion as during the peripheral glucose infusion if the arterial glucose concentration was identical between the two hyperglycemic periods. When small differences in arterial glucose concentrations between the peripheral and intraportal infusion periods were measured, the GUG measured during peripheral glucose infusion was corrected, based on the previously demonstrated correlation between GUG and arterial blood glucose concentration (20), and an estimated value of GUG during intraportal glucose infusion was thus derived. The load of substrates exiting the liver was calculated as
load<SUB>out</SUB>  = C<SUB>H</SUB> × HBF
where CH is the concentration of substrate in the hepatic vein, and HBF is the total hepatic blood flow.

Net hepatic glucose balance (NHGB) was calculated by two separate methods as described previously (20, 27). In the first method, which will be referred to as the direct calculation
NHGB<SUB>D</SUB> = load<SUB>out</SUB> − load<SUB>in(D)</SUB>
and in the second, referred to as the indirect calculation
NHGB<SUB>I</SUB> = load<SUB>out</SUB> − load<SUB>in(I)</SUB>
In these calculations, a positive value indicates net output. In RESULTS, the hepatic glucose load and NHGB shown were determined by use of the indirect calculation to be consistent with our earlier publications. However, it should be noted that the estimate of NHGB was similar, regardless of which method was used in calculations. For other substrates, the direct calculation was used to calculate net hepatic balance.

Net hindlimb substrate balances were calculated as the product of external iliac arterial blood flow and the arteriovenous difference in substrate concentration, as measured using samples from the external iliac artery and common iliac vein.

For both the liver and hindlimb, substrate fractional extraction was calculated as the ratio between net substrate uptake and substrate load.

Whole body net nonhepatic glucose balance was calculated during the two hyperglycemic periods as the difference between the total glucose infusion rate and NHGU.

Rates of whole body glucose production (Ra) and utilization (Rd) were estimated on the basis of [3H]glucose specific activities, using a modification of the Steele equation as described previously (5). During the hyperglycemic periods, endogenous glucose production was estimated by subtracting the rate of exogenous glucose infusion from Ra.

Rates of hindlimb glucose oxidation were calculated by dividing net hindlimb 14CO2 production by the arterial [14C]glucose specific activity (corrected for [14C]lactate specific activity at time points at which net lactate uptake was measured). The percentage of lactate derived from glucose across the hindlimb was measured as the ratio of arterial [14C]glucose to venous [14C]lactate specific activities.

Statistical analysis. Because the two subgroups of six dogs underwent experimental procedures with opposite sequences of routes of glucose infusion, the effect due to sequence was tested using an unpaired t-test that compared the route differences between the groups (peripheral-portal vs. portal-peripheral sequence). Because no difference due to sequence was detected in the relevant variables, a "random-effect model" was then applied to estimate the effect of the change in route of glucose infusion, adjusting for period, time during each period, random differences in individual animals, and, again, sequence. The results indicate that for the relevant variables, there was no significant effect of sequence, period, or time, although for the latter two, both peripheral and hepatic glucose uptake showed a positive trend (i.e., going toward the second one-half of the study, there was a slight increase in uptake; within each period, going toward a later sampling point, there was a slight increase in uptake). The model also allowed us to estimate a value for the difference (portal vs. peripheral glucose infusion) of a given variable that is independent of the time point at which the measurements are made. Once the effect of the sequence of the routes of infusion was ruled out, data from the peripheral glucose infusion period in all dogs and from the intraportal glucose infusion period in all dogs were combined, and statistical comparisons were made using paired t-tests. Differences were considered significant at P < 0.05.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Hormonal levels. The arterial plasma insulin concentration was increased by threefold during each experimental period (Fig. 2A), whereas the arterial plasma glucagon level was kept at a basal value (Fig. 2B). The stability of pancreatic hormone concentrations was demonstrated by the fact that the CV of group mean values within each sampling period was 6% for insulin and 1% for glucagon.


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  		Fig. 2.   Arterial plasma insulin (A) and glucagon (B) concentrations in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is the mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline.

Whole body glucose kinetics, total glucose infusion rates, glucose levels, blood flows, and arterial-portal venous glucose gradient. Endogenous glucose Ra was ~2.3 mg · kg-1 · min-1 during the baseline period and was completely suppressed after the start of exogenous glucose infusion, with no difference between the two hyperglycemic periods. Tracer-determined glucose Ra and endogenous glucose Ra are shown in Table 1.

                              
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  		Table 1.   Tracer-determined total and endogenous glucose production

The achievement of steady state during each of the sampling periods is evident from the stability of the total glucose infusion rates (Table 2) and the glucose concentrations in the artery and portal, hepatic, and common iliac veins (Table 2) and of the blood flows in the external iliac and hepatic arteries and in the portal vein (Table 2). The arterial-portal venous glucose gradient (in mg/dl; Fig. 3) shifted from moderately positive during the baseline (1.9 ± 0.5) and peripheral glucose infusion (4.6 ± 0.6) periods to markedly negative during the intraportal glucose infusion period (-18.0 ± 3.4).

                              
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  		Table 2.   Total exogenous glucose infusion rates, circulating glucose levels, and blood flows


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  		Fig. 3.   Arterial-portal venous glucose gradient (whole blood) in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline. * P < 0.05, intraportal vs. peripheral glucose infusion.

Hindlimb glucose metabolism and whole body net nonhepatic glucose uptake. The glucose load reaching the hindlimb (in mg/min; Fig. 4A) averaged 6.6 ± 0.9 at baseline, 15.8 ± 2.1 during peripheral glucose infusion, and 14.8 ± 2.4 during portal venous glucose infusion (not significant vs. peripheral). The net hindlimb glucose uptake (in mg/min; Fig. 4B) was 5.0 ± 1.2 at baseline, 20.4 ± 4.5 during peripheral glucose infusion, and 14.8 ± 3.2 during intraportal glucose infusion (P < 0.01 vs. peripheral). Importantly, a similar difference in hindlimb glucose uptake between peripheral and intraportal glucose infusion periods was observed, independent of what route was used first. In the six dogs in which the sequence was peripheral-portal, hindlimb glucose uptakes were 18.4 ± 3.8 and 12.4 ± 2.1 mg/min (P < 0.03); in the six dogs in which the sequence was portal-peripheral, glucose uptakes were 17.1 ± 6.2 vs. 22.4 ± 8.6 mg/min (P < 0.05). The application of a random-effect model of statistical analysis allowed us to estimate the effect due to route of glucose infusion, adjusting for order of intervention, experimental period, time within each period, and random differences present in individual animals. The results indicate that there is no significant effect of the order of intervention (P = 0.94), period (P = 0.85), or time (P = 0.22), although the latter two show a positive trend (i.e., hindlimb glucose uptake tended to progressively increase toward a later phase of the study). After adjustment for these trends, there still is a strongly significant difference due to route of infusion (P = 0.008). The model also allowed us to estimate a value for the difference in hindlimb glucose uptake between routes of glucose infusion that is independent of the time point at which the measurements are made. The estimated value was 5.9 mg/min, very close to the measured value of 5.6 mg/min.


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  		Fig. 4.   Hindlimb glucose load (A), net uptake (B), and net fractional extraction (C) in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline. * P < 0.05, intraportal vs. peripheral glucose infusion.

Changes in hindlimb glucose fractional extraction reflected changes in net glucose uptake (Fig. 4C) and were also significantly different with peripheral vs. portal glucose infusion within each subgroup of six dogs. The decrease of this parameter during portal venous glucose infusion resulted from a small, nonsignificant decrease in iliac arterial blood flow along with a marked decrease of the arteriovenous difference of glucose across the hindlimb (7.7 ± 1.3 vs. 6.1 ± 0.8 mg/dl, P < 0.05; Fig. 4C). The net whole body nonhepatic glucose uptake (in mg · kg-1 · min-1; Fig. 5) was 1.6 ± 1.2 at baseline and increased to 7.9 ± 1.3 (Delta  6.3 mg · kg-1 · min-1) during peripheral glucose. The increase over baseline was blunted by ~40% in the presence of portal glucose infusion, when it was only 5.4 ± 1.1 (Delta  3.8 mg · kg-1 · min-1, P < 0.05 vs. peripheral glucose infusion). Therefore, the difference in whole body nonhepatic glucose uptake measured between the peripheral and intraportal glucose periods was ~2.5 mg · kg-1 · min-1.


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  		Fig. 5.   Net whole body nonhepatic glucose uptake in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline. * P < 0.05, intraportal vs. peripheral glucose infusion.

Of the net hindlimb glucose uptake, the amount that underwent oxidation (in mg/min; Fig. 6A) was 0.33 ± 0.15 (5 ± 3%) at baseline, 2.18 ± 0.72 during peripheral glucose (10.8 ± 3.5%), and 2.25 ± 0.95 during intraportal glucose (15.4 ± 4.8%, not significant vs. peripheral glucose). Conversely, the amount that underwent nonoxidative metabolism (in mg/min; Fig. 6B) was 4.8 ± 1.0 at baseline, 18.2 ± 3.8 during peripheral glucose, and 12.5 ± 2.2 during intraportal glucose. Thus the decrease in hindlimb glucose uptake reflected a change in nonoxidative glucose metabolism.


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  		Fig. 6.   Rates of hindlimb glucose oxidation (A) and nonoxidative glucose metabolism (B) in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline. * P < 0.05, intraportal vs. peripheral glucose infusion.

Lactate, glycerol, and FFA concentrations and hindlimb balances. During hyperglycemia, arterial and iliac venous lactate concentrations rose markedly (Fig. 7A); the slightly higher increase in the arterial lactate concentration, however, was sufficient to suppress net hindlimb lactate output ~80%, but no effect of the route of glucose infusion was observed (Fig. 7B). The fraction of lactate that was derived from glucose was 41 ± 7% during baseline, 62 ± 7% during peripheral glucose infusion, and 56 ± 6% during intraportal glucose infusion.


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  		Fig. 7.   Hindlimb lactate circulating concentrations (A) and net output (B) in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. corresponding baseline value.

Arterial and iliac venous glycerol concentrations were reduced by ~60% during hyperglycemia (Fig. 8A), and a similar reduction was seen in net hindlimb glycerol output (Fig. 8B). Changes from baseline were not altered by the route of glucose infusion. The arterial and iliac venous FFA concentrations decreased by ~80% during hyperglycemia (Fig. 9A). Net hindlimb FFA output decreased by ~90%. Again, no differences were observed between the two hyperglycemic periods (Fig. 9B).


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  		Fig. 8.   Hindlimb glycerol circulating concentrations (A) and net output (B) in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline.


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  		Fig. 9.   Hindlimb free fatty acid circulating concentrations (A) and net output (B) in 42-h-fasted conscious dogs during baseline (euglycemia), peripheral glucose, and intraportal glucose infusion periods (arterial plasma glucose at ~220 mg/dl). Data are group means ± SE; n = 12. In each dog, value from baseline period is mean of 3 measurements, whereas data from peripheral and intraportal glucose infusion periods are means of 4 measurements each. # P < 0.05 vs. baseline.

Hepatic glucose load; net glucose balance; fractional extraction; and lactate, glycerol, and FFA hepatic balances. The glucose load reaching the liver (Table 3) doubled during peripheral glucose infusion. A further small increase (~10%) occurred during intraportal glucose infusion, reflecting the experimental design.

                              
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  		Table 3.   Net hepatic glucose, lactate, glycerol, and free fatty acid balances

NHGU was observed during both hyperglycemic periods, with values 70% higher during intraportal glucose infusion (P < 0.05) than during peripheral glucose infusion (Table 3). The difference in NHGU measured between the peripheral and intraportal glucose periods was ~2.4 mg · kg-1 · min-1, i.e., an amount almost identical to the difference in net nonhepatic glucose uptake during the two hyperglycemic periods. The fractional extraction of glucose by the liver was also higher (P < 0.05) during intraportal glucose infusion (Table 3), suggesting that the slightly higher hepatic glucose load caused by the experimental design only accounted for a small part of the difference in NHGU measured during the two hyperglycemic periods.

Net hepatic lactate balance shifted from net uptake to net output during both hyperglycemic periods. Net hepatic lactate output was 2.4 ± 0.8 µmol · kg-1 · min-1 higher during intraportal glucose infusion compared with peripheral glucose infusion (Table 3). Nevertheless, because its pattern of change paralleled the changes in NHGU, net hepatic lactate output could account for an identical percentage (~9%) of the net glucose taken up during either glucose infusion period.

The net hepatic glycerol and FFA uptakes were decreased by ~75% and ~90%, respectively, in response to hyperglycemia. The negative arterial-portal venous glucose gradient had no effect on their uptake by the liver (Table 2).

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

The skeletal muscle is an important site of glucose removal in the postprandial state. In resting conditions, the amount of glucose taken up by muscle is believed to be regulated by the levels of circulating glucose and insulin. This study sought to determine whether the portal signal created by intraportal glucose infusion could alter hindlimb glucose uptake. The results show that the increase in net hindlimb glucose uptake was 57% greater when hyperglycemia was induced using a peripheral glucose infusion than when it was created via an intraportal glucose infusion. This effect was observed both when peripheral glucose infusion preceded and when it followed intraportal glucose infusion, indicating that our findings were not an artifact due to the particular experimental design (whole body glucose uptake has been shown to progressively increase for at least 4-5 h in hyperglycemic-hyperinsulinemic conditions) (26). Furthermore, this effect was obviously not limited to the hindlimb on which the measurements were performed, as net whole body nonhepatic glucose uptake displayed a pattern of change that reflected the changes in the hindlimb (66% greater increase in glucose uptake during intraportal glucose infusion). Finally, the decrease in net whole body nonhepatic glucose uptake (2.5 mg · kg-1 · min-1) caused by the portal signal was almost identical to the increase (2.4 mg · kg-1 · min-1) that it caused in NHGU. Thus whole body glucose clearance was unchanged by the route of glucose delivery. The elucidation of a molecular mechanism responsible for the observed changes in skeletal muscle glucose uptake is beyond the scope of this study. Among hypothetical mechanisms, the modulation of adenosine release, as well as its interaction with adenosine receptors or metaboreceptors, seems a reasonable candidate, as recent evidence indicates that adenosine inhibits glycogen breakdown in perfused rat muscle simultaneously exposed to insulin and beta -adrenergic stimulation (31). The plasma concentration of FFAs has also been demonstrated to affect muscle glucose uptake via both an intracellular inhibitory effect on key glycolytic enzymes and a direct inhibition of transmembrane glucose transport (28). In our study, however, a similar reduction in FFAs occurred in both hyperglycemic periods; therefore, the enhancement of muscle glucose uptake caused by the decrease in plasma FFAs was probably comparable in the two experimental conditions and did not cause the observed differences in muscle glucose metabolism.

In the work of several investigators (2, 3, 20, 26), experimental conditions were created in which the route of glucose infusion was changed from peripheral to intraportal during hyperglycemia and hyperinsulinemia. In all of these studies, the observation was made that glucose uptake by extrahepatic tissues was reduced when glucose was infused directly in the portal vein as opposed to a peripheral vein. In 1997, Matsuhisha et al. (16) induced hyperglycemia, first via a peripheral vein, then intraportally, and finally intraportally but abolishing the portal signal in the cerebral vessels. A difference in extrahepatic glucose uptake was present but was not significant between the first two periods and became markedly significant between the second and third periods. The lack of significance between the first and second period may have resulted from the time-dependent increase in muscle glucose uptake usually associated with hyperinsulinemia. It should be noted, however, that although the reported observations suggest a double effect of the portal signal (enhancement of net glucose uptake by the liver and simultaneous decreases of extrahepatic glucose disposal), the above studies were focused on changes in liver glucose metabolism. The glucose load to the liver was constant, whereas the arterial glucose concentrations and the glucose load reaching the hindlimb varied substantially between the portal and peripheral glucose infusion periods. More importantly, net glucose uptake by the hindlimb, or by any other muscle district, was never measured directly. In the present study, the glucose load to the limb was controlled and we assessed hindlimb glucose uptake directly. As a result, we were able to provide strong support for the hypothesis that the reduction in nonhepatic glucose uptake observed in response to intraportal glucose delivery occurs primarily in skeletal muscle. The observed effect on skeletal muscle was also specific to glucose. Net hindlimb balances of alanine (data not shown), lactate, glycerol, and FFAs were significantly altered by hyperglycemia but not by the route of glucose infusion.

Our direct measurement of net skeletal muscle glucose uptake was solely performed across one hindlimb. The metabolic behavior of the remaining portion of the dogs' muscle mass can therefore only be hypothesized. In 1992, Wasserman et al. (32) reported that, in the dog, the skeletal muscle mass of a single hindlimb is 3.3% of total body weight (32). With the consideration that our dogs averaged 23.5 kg in weight, this would mean that 780 g of muscle accounted for the measured difference of 5.6 mg/min in net hindlimb glucose uptake. With the assumption of a homogenous behavior for the entire skeletal muscle mass (~45% of the total body wt), this would finally correspond to a difference in net glucose uptake of ~76 mg/min or ~3.2 mg · kg-1 · min-1, not far from the value of 2.5 mg · kg-1 · min-1 measured for the change in net whole body nonhepatic glucose uptake. This overestimation by 0.7 mg · kg-1 · min-1 probably reflects the different response to hyperglycemia and hyperinsulinemia in different muscle groups. In particular, in muscle groups that undergo tonic contraction, such as the respiratory muscles, rates of net glucose uptake are probably mostly driven by the constant high metabolic demand, and thus they may be influenced to a lesser degree by the route of glucose administration.

Our experimental design did not allow the measurement of differences in muscle glycogen content and glycogen synthase activity, as tissue samples could only be taken at autopsy and all subjects underwent both peripheral and intraportal glucose infusions. However, we directly measured glucose oxidation across the hindlimb and found identical rates during the two hyperglycemic periods. It is therefore not unreasonable to hypothesize that most of the decrease in net skeletal muscle glucose uptake observed during intraportal glucose infusion was accounted for by a reduction in muscle glycogen deposition. Nevertheless, direct evidence for this hypothesis will require additional work.

A still unresolved issue is the definition of the nature and characteristics of the portal signal itself. The early hypothesis of the involvement of a humoral agent, such as a gastrointestinal peptide, has not been supported by recent data. Conversely, progressively more evidence is being gathered to support the possibility that the portal signal may involve the autonomic nervous system (4, 16, 17). Both adrenergic and cholinergic nerve terminals have been found within the liver, with evidence for both afferent and efferent limbs (22, 23). Further support for neural involvement has been provided by the study of Adkins-Marshall et al. (4), in which the increase in NHGU after intraportal glucose delivery was abolished in dogs that had undergone complete hepatic denervation. In another recent study (16), it was demonstrated in dogs that, if during intraportal glucose infusion glucose was also selectively infused into the arteries reaching the brain, leaving intact the negative glucose gradient between the rest of the arterial blood stream and the portal vein, the increase in NHGU was significantly blunted but not abolished. Conversely, the effect of intraportal glucose infusion on extrahepatic glucose uptake was completely abolished, indicating that skeletal muscle glucose uptake can be regulated independently of glucose and insulin load through the autonomic nervous system. A similar conclusion was drawn by Minokoshi et al. (17), who observed an increase in glucose uptake by the skeletal muscle in response to stimulation of the ventromedial hypothalamus. Finally, an interesting model was proposed by Xie and Lautt (33) in 1996. These authors observed that a surgical or pharmacological blockade of the hepatic parasympathetic nerves induced insulin resistance in the skeletal muscle of hyperinsulinemic cats and speculated that a factor may be released by the liver that is dependent on intact hepatic parasympathetic nerves and that may regulate the responsiveness of skeletal muscle to insulin. Despite these pieces of indirect evidence, the complete elucidation of the mechanisms by which the portal signal exerts its effect on muscle requires additional work.

In summary, when the effect of hyperglycemia resulting from intraportal glucose delivery was compared with the effect of similar hyperglycemia resulting from peripheral glucose delivery in the presence of identical levels of hyperinsulinemia, not only was NHGU enhanced, but net skeletal muscle glucose uptake was proportionally decreased. The changes in skeletal muscle glucose metabolism do not appear to include alterations in the rate of glucose oxidation, suggesting that a reduction in muscle glycogen deposition is likely to be the underlying mechanism. Our findings support the hypothesis that the portal signal is able to direct the flow of carbons throughout the body, producing a coordinated regulation of tissue glucose metabolism at the level of both the liver and skeletal muscle.

    ACKNOWLEDGEMENTS

We thankfully acknowledge the excellent technical assistance of Wanda Snead and Pam Venson from the Hormone Core Laboratory of the Vanderbilt University Diabetes Research and Training Center.

    FOOTNOTES

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R-01-DK-43706, DK-40936, and DK-50277 and the Diabetes Research and Training Center Grant DK-20593.

Address for reprint requests: P. Galassetti, Rm. 754 MRB-I, Vanderbilt Univ. Medical Center, Nashville, TN 37232-0615.

Received 6 October 1997; accepted in final form 13 April 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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Am J Physiol Endocrinol Metab 275(1):E101-E111
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