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Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Namdaran, Kiarash, Deanna P. Bracy, D. Brooks Lacy, Janice
L. Johnson, Jennifer L. Bupp, and David H. Wasserman. Gut and
liver fat metabolism in depancreatized dogs: effects of exercise and
acute insulin infusion. J. Appl.
Physiol. 83(4): 1339-1347, 1997.
Excessive
circulating fat levels are a defining feature of poor metabolic control
in diabetes. Splanchnic adipose tissue is a source of free fatty acids
(FFA), and the liver is a key site of FFA utilization and the sole
source of ketones. Despite the role of splanchnic tissues in fat
metabolism, little is known about how these tissues respond to diabetes
under divergent metabolic conditions. Therefore, splanchnic fat
metabolism was studied in poorly controlled diabetes under two
conditions. First, it was studied during exercise, a stimulus that
enhances FFA flux. Second, it was studied while insulin was being
acutely infused to achieve levels normally present during exercise, a
treatment that may be expected to inhibit lipolysis. For this purpose,
liver and gut arteriovenous differences were used during rest and 2.5 h of treadmill exercise in insulin-deficient
(n = 6) and acutely insulin-infused
(n = 4) depancreatized (PX) dogs. The
data show that 1) exercise, in
insulin-deficient PX dogs, leads to an increase in net FFA release from
mesenteric fat that is equal in magnitude to the response in
nondiabetic dogs; 2) net hepatic
fractional FFA extraction is increased twofold during exercise in both
insulin-deficient PX dogs and nondiabetic control dogs;
3) during exercise, ~40 and 75%
of the FFA consumed by the liver is effectively transferred from fat
stores mobilized from splanchnic adipose tissue in insulin-deficient PX
and nondiabetic dogs, respectively;
4) hepatic ketogenic efficiency is
elevated during rest three- to fourfold in insulin-deficient PX dogs
compared with nondiabetic control dogs and remains elevated during
exercise; and 5) surprisingly, acute
insulin replacement is ineffective in normalizing net gut, hepatic, or
splanchnic FFA or ketone body balances in PX dogs.
splanchnic; nonesterified fatty acids; ketone bodies; exertion
INTRODUCTION ONE OF THE HALLMARKS of poor metabolic control in
people with insulin-dependent diabetes mellitus is an excessive level
of circulating free fatty acids (FFA). The increased FFA concentrations contribute to the deranged metabolism caused by insulin deficiency, in
part, by promoting an increase in hepatic fat oxidation. Elevated rates
of hepatic fat oxidation increase the formation of ketone bodies and
fuel the excessive rates of gluconeogenesis that characterize poorly
controlled diabetes.
Studies that have attempted to examine the effects of exercise on
hepatic FFA metabolism in humans with diabetes have been limited by
difficulties associated with distinguishing between hepatic and
extrahepatic splanchnic tissues. Prior studies in humans have assessed
balances across the splanchnic bed by use of sampling from an artery
and the hepatic vein. This measurement alone does not account for the
contribution of adipose tissue within the splanchnic bed to the hepatic
FFA load. This is a critical deficit, especially for an understanding
of hepatic fat metabolism during exercise because studies in normal
dogs have shown that exercise stimulates FFA release from splanchnic
adipose tissue, masking increases in net hepatic FFA uptake (27). As a
consequence, measurements of net splanchnic FFA uptake will not reflect
the effects of exercise on hepatic FFA metabolism. An extension of this
is that the hepatic ketogenic efficiency (the ratio of net hepatic
ketone body output to FFA uptake), an index of the ability of the liver
to convert FFA to ketones, will be overestimated.
The present study accounts for the contribution of the splanchnic
adipose tissue by sampling from the portal vein, which drains the
extrahepatic splanchnic tissue and perfuses the liver, in the
chronically catheterized dog. The contributions of hepatic and
extrahepatic splanchnic tissues to fat metabolism can then be assessed
by combining portal vein with arterial and hepatic vein sampling. This
sampling configuration was used to assess the effects of diabetes on
splanchnic fat metabolism by using the depancreatized (PX) dog. Studies
were conducted with animals in the diabetic state when coupled with
exercise, a stimulus that enhances FFA flux, and acute infusion of
insulin to exercise levels, a treatment that may be expected to inhibit
lipolysis. The purpose was to establish the interaction of diabetes and
exercise with the contributions of the gut and liver to the net
splanchnic balance of FFA and ketone body.
METHODS
160 to
40 min), a basal sampling period (40 to 0 min), a period
of moderate-intensity (100 m/min, 12% grade) exercise (0-150
min), and a period of exercise recovery (160-240
min). The exercise intensity used in these experiments has
been shown to result in a twofold increase in heart rate (26) and an
increase in O2 uptake to
~50% of maximum (17). An infusion of ICG (0.1 mg · m
2 · min1)
was also started at the beginning of the equilibration period and
continued for the duration of the experiment. One group of PX dogs
(n = 6) was studied with a saline
infusion. Another group of PX dogs was studied as described above but
with an intraportal insulin infusion (200 µU · kg1 · min1),
commencing at time (t) = 160
min. Arterial, portal vein, and hepatic vein samples were taken at
t = 40, 20, 0, 10, 30, 60, 90, 120, 150, 160, 180, and 240 min. Data published previously from
a group of nondiabetic control dogs studied in an identical manner to
the insulin-deprived PX dogs (28) are presented in RESULTS for comparison with the PX
dogs. The experiments in nondiabetic control dogs were conducted within
18 mo of those in the experimental groups. Nondiabetic animals were in
the same weight range as the PX dogs, and the same health criteria were
used in all dogs.
Processing of blood samples.
Whole blood 
-hydroxybutyrate concentrations were determined in
samples deproteinized with 4% perchloric acid (0.5 ml whole blood in
1.5 ml perchloric acid) by an enzymatic method developed for the
Technicon Autoanalyzer (15). For determination of acetoacetate, the
perchloric acid-deproteinized blood samples were neutralized with
potassium hydroxide on the day of each study and assayed enzymatically
the following day (18). Plasma FFA concentrations were determined by
the method described by Ho (12). This assay has a coefficient of
variation of 4.0%. The assay was linear over the range of the standard
curve (r2 = 0.992 ± 0.002). Samples exceeding the range of the standards were diluted
as necessary. Plasma immunoreactive insulin was measured by using the
Sephadex-bound antibody procedure (29) or by a double-antibody system
(16). Immunoreactive glucagon concentrations were measured in plasma
samples containing 50 µl of 500 kalikrein inhibitor units/ml Trasylol
(FBA Pharmaceuticals, NY) by radioimmunoassay with the use of a 30,000 antiserum (2). Plasma glucose concentration was measured by using the
glucose oxidase method on a Beckman glucose analyzer (Beckman
Instruments, Fullerton, CA). Plasma ICG was determined
spectrophotometrically (805 nm) in arterial and hepatic vein samples
immediately after the study.
Calculations.
Net gut FFA balances were calculated as PVF × ([PV A]), and net hepatic FFA balances were
calculated by the formula HAF × ([A] [H]) + PVF × ([P] [H]), where [A], [P], and
[H] are the arterial, portal vein, and hepatic vein
substrate concentrations, and HAF and PVF are the hepatic artery and
portal vein blood flows, respectively. The calculations were the same
for the calculation of ketone balances, except that the sign (±)
was reversed. Net splanchnic balance was calculated as the sum of net
gut and hepatic balances. These calculations were performed with flows
measured by using the ICG-extraction technique (14). The ICG-extraction technique measures total hepatic plasma flow but does not differentiate between inputs from the portal vein and hepatic artery. The proportions of the hepatic blood supply provided by the hepatic artery and portal
vein were assumed to be 20 and 80%, respectively, based on flow
measurements made in our laboratory by using the Doppler technique in
dogs exercising at the same exercise intensity and duration as in the
present study (7). Plasma levels and flows were used for the
calculation of net free fatty acids balances, whereas
blood levels and flows were used to calculate net ketone balances.
Statistics were performed by using SuperAnova and Statview (Abacus
Concepts, Berkeley, CA) on a Macintosh PowerPC. Statistical comparisons between groups and over time were made by using an analysis
of variance designed to account for repeated measures. Between-group
comparisons were tested for significance by using Fisher's protected
least significant difference. Within-group comparisons were examined
for significance by using contrasts solved by univariate repeated
measures. Statistics are reported in the text and corresponding table
or figure legend for each variable. Differences were
considered significant when P values were <0.05. Data are expressed as means ± SE.
RESULTS
Net extrahepatic splanchnic FFA output (Fig. 2) rose from 0.4 ± 0.8 to 4.2 ± 0.9 µmol · kg
1 · min1
by 150 min of exercise in insulin-deficient PX dogs
(P < 0.02). Interestingly, acute
insulin increased basal net extrahepatic splanchnic FFA output to 4.1 ± 0.6 µmol · kg1 · min1.
Rates in this group, however, increased no further in response to
exercise. In the nondiabetic control dogs, net extrahepatic splanchnic
FFA output rose from 0.1 ± 0.7 to 6.8 ± 1.5 µmol · kg1 · min1
(P < 0.05). Rates in control dogs
were not significantly different from those in insulin-deprived PX
dogs. Net extrahepatic splanchnic FFA output decreased in the
postexercise state in all protocols (P < 0.05).
Net hepatic FFA uptake (Fig. 3) was elevated by approximately threefold in insulin-deprived PX dogs compared with nondiabetic control dogs in the basal state (P < 0.01). Although rates did not change in response to exercise in insulin-deprived PX dogs, control dogs were characterized by an approximately threefold increase (P < 0.02). Consequently, net hepatic FFA uptake was not significantly different during exercise or exercise recovery. Acute insulin infusion did not significantly affect basal net hepatic FFA uptake in PX dogs, and rates remained above those in nondiabetic control dogs (P < 0.05). In contrast to insulin-deprived PX dogs, insulin-infused PX dogs had a significant increase in net hepatic FFA uptake in response to exercise (P < 0.05), corresponding to the respective difference between hepatic vein FFA concentrations. Differences in net hepatic FFA uptake between PX and control dogs corresponded to the differences in arterial FFA levels. During exercise, net hepatic fractional FFA extraction significantly rose (P < 0.05) in response to exercise in all protocols (Table 1). Because net hepatic FFA uptake exceeded net extrahepatic FFA output, the splanchnic bed was a net consumer of FFAs. Because net extrahepatic splanchnic and hepatic FFA balances generally changed in opposite directions during exercise, net splanchnic FFA uptake was essentially unchanged during exercise in insulin-deprived PX and control groups (data not shown). Net splanchnic FFA uptake doubled during exercise in the insulin-infused PX groups (data not shown).
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-hydroxybutyrate and acetoacetate levels (Fig.
4 and Fig. 5)
in insulin-deprived and insulin-infused PX dogs were, as expected,
substantially higher than levels in nondiabetic control dogs
(P < 0.02). Because of an increase
in ketone body utilization, -hydroxybutyrate and acetoacetate levels
fell with exercise in PX dogs. Although -hydroxybutyrate and
acetoacetate levels rose during exercise in control dogs, levels were
still considerably lower than in both PX groups
(P < 0.05). These differences were sustained during exercise recovery. In addition to the differences between PX and control dogs, the insulin-deprived PX dogs had higher
arterial -hydroxybutyrate and acetoacetate levels than did PX
animals in which insulin had been infused acutely
(P < 0.05).
-hydroxybutyrate levels in
insulin-deficient depancreatized dogs
(n = 6), acute insulin-replaced (n = 4), and nondiabetic control dogs
(n = 5). Values are means ± SE.
Values in insulin-deprived depancreatized dogs were significantly greater than in insulin-replaced depancreatized dogs
(P < 0.05) and in nondiabetic
control dogs (P < 0.001) in basal,
exercise, and recovery periods.
Net extrahepatic splanchnic
-hydroxybutyrate and acetoacetate
uptakes (Table 2) were generally higher in
both PX groups than in nondiabetic control dogs
(P < 0.05). Only in the case of net
extrahepatic splanchnic -hydroxybutyrate uptake in insulin-deprived PX dogs, which was characterized by great variability, were rates not
uniformly higher than in the control dogs. The higher rates of uptake
that existed occurred as a result of the differences in circulating
levels. In response to exercise, net extrahepatic splanchnic
acetoacetate uptake fell by ~50% in both PX groups (P < 0.05). Recovery from exercise
led to restoration of preexercise rates.
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-hydroxybutyrate (Fig.
6) and acetoacetate (Fig.
7) outputs between groups were relatively
similar to their respective arterial levels. Net hepatic -hydroxybutyrate and acetoacetate outputs were markedly higher in
insulin-deprived and acutely insulin-infused PX dogs than in nondiabetic control dogs in the basal state
(P < 0.01). Exercise did not
significantly affect net hepatic output of the ketone bodies in either
PX group but increased these variables by approximately threefold in
control dogs (P < 0.02). Net hepatic
ketogenic efficiency was approximately fourfold greater in
insulin-deprived PX dogs compared with control dogs
(P < 0.01). Exercise did not
significantly affect this variable in insulin-deprived PX dogs or
control dogs. Acute insulin in PX dogs had no effect on net hepatic
ketogenic efficiency in the basal state but resulted in a decrease in
this variable in response to exercise (Table
3) (P < 0.05).
-hydroxybutyrate output in
insulin-deficient depancreatized dogs
(n = 6), acute insulin-replaced (n = 4), and nondiabetic control dogs
(n = 5). Values are means ± SE.
Rates in insulin-deprived depancreatized dogs were significantly greater than in nondiabetic control dogs in basal, exercise, and recovery periods (P < 0.001).
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DISCUSSION
Experiments conducted in humans have defined the role of splanchnic fat metabolism in adaptations to muscular work in healthy subjects and in individuals with diabetes by sampling from an artery and the hepatic vein (20, 22, 23). The measurement of total splanchnic arteriovenous differences gives a value that is the sum of balances from all tissues drained by the hepatic vein (gastrointestinal tract, adipose tissue, pancreas, spleen, liver). Use of dogs allows for sampling from the portal vein, which drains extrahepatic tissues and perfuses (with the hepatic artery) the liver. As a consequence, hepatic and extrahepatic balances can be distinguished. The present study demonstrates that the presence of extrahepatic splanchnic FFA output and ketone body uptake can result in considerably higher rates of net hepatic FFA uptake and ketone body output than corresponding net splanchnic values. Moreover, the magnitude of the difference between splanchnic and hepatic balances is affected, to some extent, by two factors that lead to marked adjustments in lipid metabolism, i.e., exercise and diabetes.
Wahren and colleagues (22, 23) and Ahlborg et al. (3) have shown that the specific activity of infused [14C]oleic acid is lower in the hepatic vein than in the artery, even in the presence of net splanchnic oleic acid uptake, in both healthy subjects and subjects with diabetes. This indicates that oleic acid is released from some tissues of the splanchnic bed at the same time as it is being consumed by others. It was further shown that splanchnic oleic acid release is increased by exercise in healthy subjects. In subjects with diabetes deprived of insulin for 24 h and having a blood glucose level of ~310 mg/dl, the basal and exercise-induced increment in splanchnic oleic acid release was similar to what was seen in the healthy subjects (22). The responses of net extrahepatic FFA balance presented here for dogs are consistent, from a qualitative standpoint, with the responses for splanchnic oleic acid release reported for humans. In both poorly controlled PX and normal dogs, net extrahepatic FFA output increased similarly with exercise. In people with diabetes deprived of insulin for 24 h, but having a blood glucose level of ~240 mg/dl (compared with ~310 mg/dl in the study described above), splanchnic oleic acid release was elevated at rest but did not increase with exercise (23). Similarly, when the blood glucose level was reduced by ~70 mg/dl in PX dogs with acute basal insulin replacement, basal extrahepatic FFA release was increased but did not rise further during exercise.
It may seem paradoxical at first that basal net extrahepatic FFA release is higher with insulin infusion (27). Net extrahepatic splanchnic FFA release is a function of both gut FFA uptake and release. Either a reduction in gut FFA uptake or increase in lipolysis could explain the higher basal net extrahepatic FFA release with insulin infusion. A decrease in gut FFA uptake could result if the reduction in glucose levels leads to a decrease in re-esterification of FFAs in the adipose tissue of the gut. A reduction in gut FFA uptake could also result if insulin facilitates the intestinal metabolism of alternative fuels. It is also possible that the reduction in blood glucose level that accompanies insulin infusion facilitates the stimulation of splanchnic lipolysis (24).
The mass action effect of the higher arterial FFA levels in insulin-dependent and insulin-infused PX dogs led to a greater net hepatic FFA uptake compared with that in nondiabetic dogs. Hepatic fractional FFA extraction, a concentration- and flow-independent index of hepatic FFA uptake, was similar in PX and normal dogs throughout the experiments. Hepatic fractional FFA extraction was increased by exercise in all groups. This finding is generally similar to the results obtained by using [14C]oleic acid to measure splanchnic fractional oleic acid extraction during rest and exercise in humans (22, 23). The net release of FFA from the gut counterbalanced the exercise-induced increase in net hepatic fractional FFA extraction and, as a consequence, net splanchnic fractional FFA extraction was unchanged. The presence of net FFA release from extrahepatic tissues may explain the absence of an exercise-induced increase in net splanchnic fractional FFA extraction in some healthy and diabetic people (20). Finally, it can be calculated by comparing net gut to net hepatic FFA balances that ~40 and 70% of the FFAs taken up by the liver, in PX and normal dogs, respectively, are effectively shuttled from mesenteric fat to the liver without contributing to the systemic FFA pool. The hepatic utilizations of glucose (1) and leucine (6) will increase to a greater extent if the hepatic delivery of these substrates is elevated by a selective increase in their portal vein concentrations. If such is also the case for the utilization of FFA by the liver, then the exercise-induced release of FFA into the portal vein may have a greater impact on hepatic FFA utilization than does a similar increase from peripheral fat depots.
Acetoacetate and -hydroxybutyrate were readily taken up by
extrahepatic splanchnic tissue and were presumably oxidized. The higher
arterial ketone body levels led to higher rates of net gut uptakes in
insulin-deprived and insulin-infused PX dogs compared with nondiabetic
dogs. Gut fractional extraction of the ketone bodies was, nevertheless,
actually reduced in the two groups of PX dogs. This finding extends
previous observations that showed that ketone body clearance is reduced
at high ketone concentrations (4, 10, 13, 19) by demonstrating that gut
fractional ketone removal is also reduced at high ketone levels. It is
possible that the impaired gut fractional ketone body extraction is a
function of some aspect of the diabetic state other than the elevated
ketone body levels. This is not likely to be the case because ketone clearance is impaired when ketone levels are increased by prolonged fasting and not by diabetes (10).
The markedly elevated net hepatic -hydroxybutyrate and acetoacetate
output rates in insulin-deprived PX dogs were not further increased by
exercise. This contrasts with findings in dogs with intact pancreata
because net hepatic output of the ketone bodies increased with
prolonged exercise in these animals. The presence of these increases in
normal dogs is the result of a greater increase in hepatic FFA load
during exercise and an increase in plasma glucagon (20, 28). Acute
insulin caused a small fall in net hepatic -hydroxybutyrate output
at the end of exercise and during exercise recovery but did not alter
the response of net hepatic acetoacetate output. Compared with
insulin-deficient PX dogs, in insulin-infused animals net rates of
hepatic ketone output were not significantly different. The presence of
net gut ketone body uptake resulted in an ~10-15% lower net
rate of ketone release from the splanchnic bed compared with the liver
alone. As a result, estimates of ketogenesis in human subjects made by
using arteriovenous differences are probably low because net
splanchnic, but not hepatic, ketone body output can be obtained.
Hepatic ketogenic efficiency, the fraction of the net hepatic FFA uptake that can be accounted for by net hepatic ketone output, was approximately fourfold higher in insulin-deprived PX dogs compared with nondiabetic control dogs during both rest and exercise. Intraportal insulin infusion in PX dogs had no effect on this variable. Hepatic ketogenic efficiency was not increased during exercise in any of the three protocols. This was surprising in light of previous studies in humans that show that splanchnic ketogenic efficiency is generally increased by exercise in nonketotic diabetic (22, 23) and healthy (23) subjects. The reason for the difference may relate to measurement differences related to the inability to measure hepatic balances in humans. Although PX dogs have normal basal glucagon levels, they do not exhibit an increase with exercise (21). The increase in glucagon has been shown to be an important determinant of the increase in hepatic ketogenic efficiency during exercise (28). The absence of this increase in PX dogs could be the reason that efficiency does not rise in PX dogs.
Despite a higher EHPF in resting PX dogs, rates were not different during exercise. The higher basal EHPF in PX dogs is consistent with the greater portal vein blood flow in alloxan-diabetic dogs measured by using Doppler techniques (8). We observed a higher EHPF in PX dogs previously, but the difference was not significant (25). These results, however, contrast with those obtained in humans, which show no effect of diabetes on hepatic blood flow (20, 22, 23). The difference between the present study in dogs compared with earlier studies in humans probably relates to the induction of poor metabolic control in the dogs. PX dogs had a pronounced fall in EHPF with exercise. This is consistent with the exaggerated splanchnic bed norepinephrine spillover observed in exercising alloxan-diabetic dogs compared with control dogs (8). The mechanism behind the further increase in EHPF with acute insulin infusion is unclear. Insulin has vascular effects, leading to increased muscle blood flow (5). The insulin levels necessary for these effects are much higher than those present in our study. In addition, these effects probably do not extend to the splanchnic bed. A fall in glucose resulting in hypoglycemia also increases EHPF (11). It is conceivable that the acute fall in glucose, observed with acute insulin, could increase EHPF even without hypoglycemia.
The data presented herein show that 1) exercise, in insulin-deficient PX dogs, leads to an increase in net gut FFA output that is equal in magnitude to the increase seen in nondiabetic control dogs; 2) during exercise, ~40 and 75% of the FFA consumed by the liver is effectively transferred from mesenteric fat stores to the liver in insulin-deficient PX and nondiabetic dogs, respectively; 3) hepatic fractional FFA extraction is increased twofold during exercise in both insulin-deficient PX dogs and nondiabetic control dogs; 4) hepatic ketogenic efficiency is elevated during rest in insulin-deficient PX dogs compared with control dogs and, even though it rises no further, remains elevated during exercise; and 5) surprisingly, acute insulin infusion is ineffective in normalizing net gut, hepatic, or splanchnic balances of FFA and ketones in PX dogs.
ACKNOWLEDGEMENTS
This work was supported, in part, by National Institutes of Health Grants RO1 DK-50277 and Diabetes Research and Training Center Grant 5 P60 DK-20593.
FOOTNOTES
Address for reprint requests: D. H. Wasserman, Light Hall, Rm. 702, Dept. of Molecular Physiology and Biophysics, Vanderbilt Univ. School of Medicine, Nashville, TN 37232 (E-mail: david.wasserman{at}mcmail.vanderbilt.edu).
Received 29 October 1996; accepted in final form 12 June 1997.
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