1 Division of Exercise Science, University of Mississippi, University, Mississippi 38677; 2 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and 3 Department of Clinical Physiology and 4 Sports Medicine Research Unit, Bispebjerg Hospital, DK-2400 Copenhagen, Denmark
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
To determine the
importance of basal glucagon to the stimulation of net splanchnic
glucose output (NSGO) during exercise, seven healthy males performed
cycle exercise during a pancreatic islet cell clamp. In one group (BG),
glucagon was replaced at basal levels and insulin was adjusted to
achieve euglycemia. In another group (GD), only insulin was replaced at
the identical rate used in BG, and basal glucagon was not replaced.
Exogenous glucose infusion was necessary to maintain euglycemia during
exercise in BG and during rest and exercise in GD. Arterial glucagon
was at least twofold greater in BG than in GD throughout the pancreatic islet cell clamp. Although basal NSGO remained stable in BG (2.5 ± 0.5 mg · kg1 · min
1),
basal NSGO dropped by 70% in GD (0.7 ± 0.3 mg · kg
1 · min
1). NSGO was
also greater in BG than in GD at 10 min of moderate exercise, most
likely due to the residual effect of basal glucagon replacement.
However, NSGO increased slightly and remained similar throughout the
remainder of moderate and heavy exercise in BG and GD. Therefore, a
mechanism independent of changes in pancreatic hormones and/or the
level of glycemia contributes toward modest stimulation of NSGO during
moderate and heavy exercise.
islet cell clamp; hormone replacement
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
STIMULATION OF HEPATIC GLUCOSE PRODUCTION (Ra) is essential for the maintenance of glucose homeostasis during exercise. Exercise-induced increases in portal vein glucagon, which are threefold greater than increments in arterial blood, support the efficacy of glucagon as a primary mediator of Ra (37). The importance of exercise-induced changes in pancreatic hormone in the stimulation of Ra are further supported by studies conducted in dogs that utilize pancreatic hormone suppression and their portal venous replacement under euglycemic conditions (38, 42). Although these studies clearly described the importance of exercise-induced changes in glucagon and insulin in the stimulation of Ra, exercise-induced changes in the peripheral concentrations of these glucoregulatory hormones are known to be relatively minor in humans, and the important levels, those in the portal vein, are unknown (16). Even so, studies that have utilized the pancreatic clamp technique in humans have demonstrated a diminished Ra response to exercise (20, 25, 45). However, arterial glucose was allowed to fall during exercise and complicates the interpretation of the data (30). Therefore, the factors responsible for the precise control of glucoregulation during moderate and heavy exercise are not completely understood.
The present study was designed to determine the importance of basal glucagon levels for the stimulation of net splanchnic glucose output (NSGO) during moderate and heavy exercise in humans under euglycemic conditions. Pancreatic hormone suppression and replacement procedures were used, which either replaced basal glucagon or left the subjects glucagon deficient. Furthermore, a glucose clamp was employed to maintain the subjects at a euglycemic level. This design provided us with a method in which the exogenous glucose infusion as well as the NSGO response to exercise could be used to delineate the relative importance of basal glucagon for the maintenance of glucose homeostasis.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects.
Seven healthy young males (24 ± 1 yr old, 174 ± 5 cm in
height, and 73 ± 3 kg in weight) gave their informed consent to
participate in the study. The protocols for the study were approved by
the Ethical Committee of Copenhagen. All of the subjects were healthy, and none was presently taking any medication or had a family history of
metabolic disorders or any known allergy. Maximal O2 uptake (O2 max) was determined on a
semi-supine bicycle ergometer
1 wk before the experiments.
Semi-supine bicycling has been shown to yield peak O2
uptake (
O2 peak) measurements
equivalent to 91-93% of
O2 max
obtained on an upright bicycle ergometer (29). All seven
subjects participated in two experiments each. In one subject, the data
were incomplete due to displacement of the hepatic vein catheter during
exercise, and thus data reported are from six individuals.
Procedures. All subjects arrived at the laboratory at 0800 and were 10 h fasted. Subjects were advised to abstain from physical training and intake of alcohol and tobacco use 24 h before experiments. Upon a subject's arrival, a cannula (1.0 mm ID) was inserted into the left brachial artery for blood sampling. A separate venous line was inserted into a forearm vein for infusion of indocyanine green (ICG). A catheter was introduced into a femoral vein and was advanced, under fluoroscopy, into a right-side hepatic vein to ~3-4 cm from the wedge position. Its location was verified, both during and after exercise, by use of ultrasonography and fluoroscopy, respectively. Patency of the catheter was maintained by flushing with heparinized saline solution (10 U/ml).
Experimental procedures.
Experiments consisted of an ICG equilibration period (130 to
30
min), a basal period (
30 to 0 min), a moderate-intensity exercise
period (0-40 min; 50%
O2 max),
and a heavy exercise period (40-70 min; 70%
O2 max). The primed/constant rate of
ICG infusion was started at
130 min and continued throughout the
remainder of the study. ICG was used to measure splanchnic blood flow.
A pancreatic islet cell clamp was utilized throughout both experimental
protocols and was initiated
2 h before exercise. Octreotide (a
somatostatin analog) was infused into a peripheral vein at a constant
rate of 30 ng · kg
1 · min
1.
In the first series of experiments (BG), basal levels of glucagon were
maintained by infusion of glucagon (Novo-Nordisk, Bagsvaerd, Denmark)
into a peripheral vein at 1 ng · kg
1 · min
1. Human
insulin (Actrapid, Novo-Nordisk) was also infused into the same
peripheral vein, and the rate of infusion was adjusted to achieve
euglycemia. The insulin infusion rate was adjusted according to plasma
glucose samples taken every 5 min and was determined immediately on an
automatic glucose analyzer (YSI 23AM, Yellow Springs Instrument). After
the last adjustment in the insulin infusion rate, the rate was held
constant throughout the remainder of the experiment. The islet cell
clamp was considered successful when the difference in multiple glucose
samples was less than ~4 mg/dl and remained stable. Exogenous glucose
infusion was initiated at the onset of exercise in BG. In the second
series of experiments [glucose deficiency (GD)], only insulin was
replaced into a peripheral vein at the identical rate previously used
in BG. Basal glucagon was not replaced in GD, and the exogenous glucose
infusion was initiated in the basal period to maintain euglycemia and
adjusted during exercise for the same purpose.
Blood sample collection and processing.
Arterial and hepatic vein blood samples were collected at 150 and
120 min before the basal period, at
30 and 0 min during the basal
period, and every 10 min during the exercise period. Samples were
immediately placed into chilled glass tubes and centrifuged at 4°C.
Heparinized blood was collected for the determination of glucose,
lactate, glycerol, free fatty acids (FFA), growth hormone (GH),
cortisol, and hematocrit (Hct). Lactate, glycerol, and FFA were
determined by enzymatic fluorometric methods (29). Hct was
measured by the microhematocrit method. Insulin, glucagon, GH, and
cortisol were determined by radioimmunoassay, as previously described
(17, 18). Blood for the determination of catecholamines was collected in chilled tubes containing EDTA and glutathione and was
centrifuged at 4°C; plasma was stored at
70°C for subsequent HPLC
analysis. Catecholamine concentrations were calculated on the basis of
a linear regression with dihydroxybenzylamine as an internal standard.
The interassay coefficients of variation with this method were 5 and
7% for norepinephrine and epinephrine, respectively.
Splanchnic blood flow and net splanchnic glucose output.
Splanchnic plasma flow (SPF) was estimated by the ICG dye-extraction
method (32). This technique involves a primed (1.0 mg),
constant (200 µg/min) infusion of ICG (prepared in a 5% solution of
human serum albumin in isotonic saline), with an equilibration period
of 45 min before blood sampling. Arterial and hepatic venous blood
was sampled at
150,
120,
30, and 0 min, and every 10 min during
exercise. Plasma concentrations of ICG were determined spectrophotometrically (805 nm) in duplicate, with correction for
plasma turbidity measured at 900 nm, and Hct was measured with the
microhematocrit method. Plasma glucose concentrations were converted to
whole blood concentrations on the basis of arterial (a)-hepatic vein
(hv) Hct values determined throughout the experiment. The calculation
for this conversion was blood glucose = plasma glucose (1
0.30 × Hct). SPF was estimated according to a modification for
non-steady-state conditions
![]() |
Statistical analysis. SuperAnova (Abacus Concepts, Berkeley, CA) software installed on a Macintosh Power PC was used to perform statistical analyses. Statistical comparisons between groups and over time were made using ANOVA designed to account for repeated measures. Specific time points were examined for significance by use of contrasts solved by univariate repeated measures. Statistics are reported in the corresponding table or figure legend for each variable. Data are presented as means ± SE. Statistical significance was defined as P < 0.05.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Arterial and hepatic vein plasma insulin and glucagon.
Arterial insulin was not different (P > 0.05) between
groups during the preclamp period and rose (P < 0.05)
to similar levels in the basal period in BG (11 ± 3 µU/ml) and
GD (11 ± 1 µU/ml). There was an additional increase
(P < 0.05) in arterial insulin during the heavy
exercise period in both groups (Fig. 1).
Hepatic vein insulin was higher (P < 0.05) in BG
(7 ± 2 µU/ml) compared with GD (5 ± 1 µU/ml) during the
preclamp period. However, hepatic vein insulin was not different
(P > 0.05) between groups during the basal period and
increased (P < 0.05) similarly during moderate and
heavy exercise (Fig. 1). Although arterial glucagon was similar in the
basal and exercise groups during the preclamp period, basal arterial
glucagon was more than twofold higher in BG (75 ± 5 pg/ml) compared with GD (32 ± 6 pg/ml). Arterial glucagon was also
twofold greater (P < 0.05) in BG compared with GD
throughout the moderate (71 ± 5 pg/ml in BG; 33 ± 7 pg/ml
in GD at t = 40 min) and heavy (79 ± 4 pg/ml in BG;
33 ± 6 pg/ml in GD at t = 70 min) exercise (Fig.
2). Despite similar hepatic vein glucagon
levels during the preclamp period, the concentration of glucagon in the
hepatic vein was greater (P < 0.05) in BG compared
with GD throughout the basal, moderate, and heavy exercise periods
(Fig. 2).
|
|
Arterial plasma cortisol and GH.
Arterial plasma cortisol was similar (P > 0.05) in BG
(13 ± 1 mg/dl) and GD (14 ± 1 mg/dl) during the preclamp
period and remained stable in both groups during the moderate exercise
period. Arterial cortisol increased (P < 0.05)
similarly, to 18 ± 3 mg/dl in BG and 17 ± 2 mg/dl in GD,
during the heavy exercise period (Fig.
3). Arterial plasma GH was different
(P > 0.05) between BG (3.6 ± 1.4 mIU/l) and GD
(2.3 ± 1.4 mIU/l) during the preclamp period. During moderate
exercise, arterial GH fell (P < 0.05) similarly to
almost zero and then increased (P < 0.05) to 2.6 ± 0.7 mIU/l in BG and 2.5 mIU/l in GD by 30 min of heavy exercise (Fig. 3).
|
Arterial plasma epinephrine and norepinephrine.
Arterial plasma epinephrine was greater (P < 0.05) in
BG compared with GD during the basal period, although epinephrine was not different (P > 0.05) and increased
(P < 0.05) in BG and GD during the moderate and heavy
exercise periods (Fig. 4). Basal arterial
plasma norepinephrine values were similar (P > 0.05) in BG and GD. Even though norepinephrine increased (P < 0.05) in both groups during moderate and heavy exercise,
norepinephrine levels were consistently greater (P < 0.05) in BG compared with GD (Fig. 4).
|
Blood glucose (a-hv), NSGO, and exogenous glucose infusion.
Arterial glucose was similar (P > 0.05) in both groups
during the preclamp, basal, moderate, and heavy exercise periods (Fig. 5). In addition, there were no
significant differences between groups in hepatic vein glucose in the
preclamp, basal, and moderate exercise periods. However, hepatic vein
glucose was less (P < 0.05) in BG (115 ± 7 mg/dl) compared with GD (151 ± 19 mg/dl) by the end of the heavy
exercise period (Fig. 5). During the preclamp period, NSGO was stable
and not different (P > 0.05) between BG and GD. In
contrast, basal NSGO was about threefold higher (P < 0.05) in BG (2.5 ± 0.5 mg · kg1 · min
1) compared
with GD (0.7 ± 0.3 mg · kg
1 · min
1). There was
a modest difference (P < 0.05) in NSGO in BG (3.5 ± 0.9 mg · kg
1 · min
1)
compared with GD (1.7 ± 0.4 mg · kg
1 · min
1) at 10 min
of moderate exercise, which was most likely due to the residual effect
of glucagon replacement during the basal period. Basal glucagon
replacement was less important during the remainder of moderate and
heavy exercise, because of support by similar NSGO
(P > 0.05) in BG (3.7 ± 1.0 mg · kg
1 · min
1
at t = 40 min; 4.7 ± 1.2 mg · kg
1 · min
1 at t
= 70 min) and GD (3.4 ± 0.9 mg · kg
1 · min
1
at t = 40 min; 5.0 ± 0.9 mg · kg
1 · min
1 at t
= 70 min; Fig. 6). Exogenous glucose
infusion was required during the basal period in GD, and the rate of
infusion was slightly lower (P < 0.05)
throughout most of the exercise sessions in BG compared with GD
(Fig. 6). Finally, it is important to note that the NSGO plus the
exogenous glucose infusion rate (total glucose entry into the
circulation) was similar (P > 0.05) in the groups throughout the preclamp, basal, and moderate and heavy exercise periods
(Fig. 6).
|
|
Arterial metabolite concentrations and splanchnic metabolite
balances.
Arterial lactate was similar (P > 0.05) in the groups
before the islet cell clamp and during the basal period. Arterial
lactate increased similarly (P < 0.05) in BG and GD
during moderate and heavy exercise (Fig.
7). Splanchnic lactate balance was
similar (P > 0.05) during the basal period in BG
(2.6 ± 1.5 µmol · kg1 · min
1) and GD
(4.0 ± 0.6 µmol · kg
1 · min
1) and
increased in a similar fashion during the moderate exercise period.
Splanchnic lactate balance shifted toward significantly greater uptake
during heavy exercise in BG compared with GD (Fig. 7). Although
arterial glycerol was less in BG compared with GD before the islet cell
clamp, glycerol levels fell (P < 0.05) similarly during the basal period and increased (P < 0.05)
throughout the moderate and heavy exercise periods (Fig.
8). Furthermore, the rate of net
splanchnic glycerol uptake before the islet cell clamp decreased
(P < 0.05) in both groups. Net splanchnic glycerol
uptake increased (P < 0.05) and remained similar
(P > 0.05) in the groups throughout the moderate and
heavy exercise periods (Fig. 8). Arterial plasma FFA levels were
similar (P > 0.05) in BG and GD before the islet cell
clamp and fell substantially (P < 0.05) in both groups
during the basal period. Arterial FFA increased (P < 0.05) to 241 ± 37 µmol/l in BG at 40 min of moderate exercise
but remained similar (P > 0.05) to basal levels at
179 ± 20 µmol/l in GD. During heavy exercise, arterial FFA was
similar (P > 0.05) in BG and GD (Fig.
9). Net splanchnic FFA uptake was similar
(P > 0.05) in BG and GD before the islet cell clamp
and decreased (P < 0.05) markedly during the basal
period in both groups. Although net splanchnic FFA balance remained
similar throughout most of the exercise bout, it was increased
(P < 0.05) to an uptake of 0.18 ± 0.08 µmol · kg
1 · min
1 in BG
and shifted to an output of 0.04 ± 0.04 µmol · kg
1 · min
1 in GD
at 30 min of moderate exercise (Fig. 9).
|
|
|
Heart rates, hepatosplanchnic blood flows, oxygen consumption, and
ratings of perceived exertion.
Heart rates were similar (P > 0.05) in BG and GD
during the basal, moderate, and heavy exercise periods (Table
1). Hepatosplanchnic blood flow was not
different (P > 0.05) between BG and GD in the basal
state or during the moderate exercise period. However, hepatosplanchnic blood flow was slightly higher (P < 0.05) in BG
compared with GD by the end of the heavy exercise period (Table 1). The
percentage of maximal oxygen consumption was not different
(P > 0.05) between BG and GD and rose similarly during
moderate and heavy exercise in both groups (Table
2). The ratings of perceived exertion
were also similar (P > 0.05) in the groups during
moderate and heavy exercise (Table 2).
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The results of the present study demonstrate that the prevention
of exercise-induced changes in glucagon and insulin as characterized by
BG reduces NSGO compared with results of previous investigations conducted under similar conditions in the absence of a pancreatic clamp
(3). Furthermore, BG required an exogenous glucose
infusion to maintain euglycemia during the moderate and heavy exercise periods. GD reduced basal NSGO and also required an exogenous glucose
infusion to maintain euglycemia, not only during rest but also during
moderate and heavy exercise in humans. Despite the effect of glucagon
deficiency on these parameters in GD, the NSGO response to moderate and
heavy exercise was largely similar to that in BG. This is somewhat
surprising, because prior studies have demonstrated that basal glucagon
and the increment in glucagon are necessary for the stimulation of
normal glucose production rates (37). It is important to
recognize that the normal exercise-induced increment in NSGO (2-fold at
50% and 4-fold at 75% O2 max) during
semi-supine cycle exercise (3) was suppressed in BG and
GD, probably due to absence of an increase in glucagon during exercise.
Studies in humans (20, 45) and dogs (41, 42) have demonstrated the importance of exercise-induced increments in
glucagon in the stimulation of hepatic glucose production during moderate exercise. Although evidence supports the efficacy of glucagon
in the stimulation of glucose production, the present study
demonstrates that other mechanisms may stimulate modest increases in
NSGO under basal glucagon or glucagon-deficient conditions.
Results from previous studies utilizing pancreatic hormone suppression and replacement methodology in humans may be somewhat inconclusive because of changes in the arterial glucose concentrations (20, 25). The exercise-induced increment in glucose utilization (Rd) in the presence of a pancreatic clamp results in a reduction in the plasma glucose concentration (20, 25). Therefore, the fall in glucose may serve as a plausible stimulus for the corresponding increase in Ra (4). Studies show that very small changes in glucose can result in the modulation of Ra (1, 9, 22, 40). Furthermore, carbohydrate ingestion during exercise has also been shown to inhibit Ra (24).
Arterial glucose concentrations were maintained at basal levels in the
present study. However, it is important to mention that a fall in
portal vein glucose (decrease of 4-5 mg/dl) has been shown to
occur despite stable arterial glucose concentrations (exercise-induced
change <1-2 mg/dl) during heavy exercise [85% of heart rate
(HR) maximum] in dogs under normal physiological conditions
(11). This may be significant, because a 2.5-6.5 mg/dl reduction in arterial glucose has been demonstrated to produce a
4.0 mg · kg1 · min
1 increase
in hepatic glucose production (2). Therefore, subtle oscillations in portal vein (responsible for 80% of liver perfusion) glucose may exist that cannot be detected in human experimentation.
Further insight into the mechanisms responsible for the stimulation of
NSGO in the present study might be gained from experiments conducted
during especially intense exercise. Heavy exercise is characterized by
dramatic increases in circulating catecholamines, which parallel the
large changes in glucose flux (5, 16, 26, 27). These occur
in the presence of small increases in arterial glucagon (2, 16,
19) and reductions in arterial insulin, as supported by a fall
in C-peptide levels (31, 44). Prior studies in exercising
humans (~85% O2 max) found that
Ra increased normally despite an islet cell clamp that kept insulin and glucagon at peripheral basal levels and led the authors to
suggest that the catecholamines were the primary mediators of the
increase in Ra during heavy exercise (33).
However, studies designed to directly assess the role of the
catecholamines have not supported their importance as a primary
mechanism for the stimulation of Ra (37).
It is known that the gut extracts ~50% of the circulating catecholamines delivered to it, resulting in a proportional reduction in the portal vein epinephrine concentrations that are ~50% of the arterial epinephrine concentrations (10). Thus it seems clear that arterial epinephrine levels overestimate those at the liver. The role of the catecholamines has also been specifically investigated with a variety of experimental methods. For example, the use of celiac ganglion anesthesia (blocks sympathetic nerve activity to the liver and adrenal medulla) in exercising human subjects had no additional effect on Ra during an islet cell clamp (25). Furthermore, surgical denervation of the liver in dogs (43), humans with a liver transplant (presumably free of hepatic innervation) (28), or a selective hepatic adrenergic blockade in exercising dogs (85% of maximum HR) (11) have also had no effect on the exercise-induced increment in Ra. Therefore, the greater norepinephrine levels in BG compared with GD were not likely to directly influence the rate of glucose production. This is further supported by studies that show norepinephrine to be 30-fold less effective than epinephrine in stimulating glucose production by the liver (13). However, 30-fold elevations in hepatic sinusoidal norepinephrine have been shown to stimulate modest increases in net hepatic glucose output (7). With respect to epinephrine specifically, experiments in adrenalectomized humans demonstrated exercise-induced increases in Ra that were largely intact (21). Thus, despite a close correlation between exercise-induced changes in Ra and the catecholamines, several studies using a variety of novel experimental techniques have failed to establish causality.
It is important to address the limitations of the islet cell clamp in humans. In humans, pancreatic hormones must be replaced in a peripheral vein. Therefore, the peripheral replacement of glucagon and insulin does not establish the portal vein-to-peripheral gradient in islet hormone concentrations that exists in the normal physiological state. This may create some degree of portal hypoinsulinemia and hypoglucagonemia. Previous studies have demonstrated a greater than threefold increase in Ra during selective portal hypoinsulinemia in dogs (34). However, these prior studies utilized excessive decrements in portal vein insulin compared with the likely levels of portal vein insulin in the present study. A reasonable estimation of portal vein levels in the present study can be drawn from the following considerations. First, insulin is secreted directly into the portal circulation in the absence of a pancreatic clamp. Second, hepatic fractional extraction of insulin removes ~50% of the insulin delivered to the liver (35). Therefore, portal vein insulin may have been threefold higher than peripheral levels (31). The present study was characterized by some degree of peripheral hyperinsulinemia, whereas portal vein insulin levels should have remained relatively similar before and during the islet cell clamp. Due to peripheral hyperinsulinemia, the total glucose requirement (NSGO + exogenous glucose infusion) to maintain euglycemia was greater than the typical amount of glucose production required in humans during exercise in the absence of a pancreatic clamp (3).
In the present study, octreotide administration resulted in an almost total blockade of GH release and a 50% reduction in immunoreactive glucagon (IRG) levels. Although octreotide caused a dramatic decrease in arterial IRG, it was still present at 50% of preclamped values. The antibody used in this assay does not differentiate biologically active glucagon (3,500 molecular weight) from a larger glucagon-like peptide that does not stimulate NSGO (12). The cross-reactivity of proteins other than glucagon is generally accepted, because physiological changes in IRG are thought to primarily represent changes in the level of 3,500 molecular weight glucagon. Therefore, larger peptides may represent up to 40% of the total IRG level (23). As a result, the discrepancy in IRG between groups should represent the absence of 3,500 molecular weight glucagon in GD. Moreover, the minor changes in growth hormone and cortisol during heavy exercise are most likely attributable to exercise and/or octreotide-induced alterations in hepatic blood flow, which would facilitate changes in hepatic extraction of these hormones (14, 36).
Despite the contention that portal vein insulin levels may remain relatively similar in the preclamp and octreotide infusion periods of the present experiment, elevations in the peripheral insulin levels seemed to have significant effects on lipid kinetics. For example, arterial FFA and glycerol decreased immediately in both groups after the start of the islet cell clamp, indicating that lipolysis was decreased. Although there was a reduction in the exercise-induced glycerol response compared with normal physiological conditions (15), the exercise-induced increment in glycerol was similar in both groups in the presence of the islet cell clamp. This indicates that lipolysis was increased even in the presence of peripheral hyperinsulinemia. However, there was an attenuation in the FFA response during exercise. Therefore, the discrepancy between FFA and glycerol levels suggests that FFA reesterification and/or clearance was affected during exercise (39). It is interesting to note that the modest difference in arterial FFA and net splanchnic FFA balance between BG and GD may suggest that glucagon plays a relatively minor role in the regulation of FFA metabolism as proposed by previous investigations (6).
The attenuation of splanchnic lactate uptake with heavy exercise during GD in the present study supports the results of previous experiments in which the exercise-induced increment in glucagon partially increased Ra through the stimulation of gluconeogenesis (42). It has been demonstrated that the exercise-induced increment in glucagon secretion is largely responsible for the stimulation of net hepatic lactate uptake and gluconeogenesis (42). Therefore, the rise in glucagon facilitates gluconeogenesis by converting the liver to a greater lactate-consuming organ (42). Glucagon deficiency likely attenuates the splanchnic uptake of lactate and consequently reduces the amount of gluconeogenic precursor available for conversion to glucose. It is important to note that, even though glucagon may alter the efficacy of lactate as a gluconeogenic precursor, the relative impact on NSGO is minor, because hepatic glycogenolysis is largely responsible for the increment in glucose production during heavy exercise (37).
From the present study, it can only be speculated as to what factors are responsible for the modest stimulation of NSGO in the absence of glucagon during exercise. It has been shown that sleep (decrease in HR and core temperature) is associated with a decrease in glucose production and utilization despite no detectable change in glucoregulatory hormones (glucagon, insulin, and catecholamines) (8). The mechanisms by which these changes in glucose flux occur are not clearly understood but suggest that unknown endocrine mechanisms are present during exercise and are important for the stimulation of NSGO. However, it should be mentioned that small changes in the portal vein levels of glucagon and/or insulin could have a significant effect on glucose kinetics without any change in the arterial concentrations of these hormones (37).
The present study investigated the role of glucagon deficiency during moderate and heavy exercise under euglycemic conditions. This approach allowed us to investigate the importance of basal glucagon independently of changes in arterial glucose. The results of the study indicate that glucagon deficiency decreased basal NSGO. In addition, the residual effect of glucagon deficiency was associated with a modest difference in the initial exercise-induced increase in NSGO. However, glucagon deficiency or basal glucagon conditions failed to establish the normal exercise-induced increment in NSGO (3). Furthermore, glucagon deficiency may also reduce the splanchnic uptake of lactate and FFA. There are several possible mediators that may be responsible for the slight increase in NSGO, and factors such as the catecholamines and/or substances released from working muscle may have the ability to influence Ra.
In conclusion, glucagon deficiency compromises the ability to establish effective glucoregulation during exercise at moderate and heavy intensities. Even so, basal glucagon replacement is also insufficient to maintain euglycemia during exercise under the same conditions. These data provide additional support to the contention that exercise-induced changes in glucagon and insulin are of primary importance for the accurate regulation of hepatic glucose production. These data also support the view that other undescribed factors can be responsible for the stimulation of NSGO.
![]() |
ACKNOWLEDGEMENTS |
---|
We are grateful to Inge Rasmussen, Dorthe Skovgaard, Annie Hoj, Eric Allen, and the staff of the Clinical Physiology department at Bispebjerg Hospital.
![]() |
FOOTNOTES |
---|
This research was supported by awards from the Danish National Research Council (505), the Danish Sports Research Council, the Novo Nordisk Foundation, and National Institute of Diabetes and Digestive and Kidney Diseases (Grant R01B-DK-50277).
Address for reprint requests and other correspondence: R. H. Coker, 220 Turner Center, Dept. of Exercise Science, Univ. of Mississippi, University, MS 38677 (E-mail: rhcoker{at}olemiss.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 March 2000; accepted in final form 5 February 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Berger, CM,
Sharis PJ,
Bracy DP,
Lacy DB,
and
Wasserman DH.
Sensitivity of exercise-induced increase in hepatic glucose production to glucose supply and demand.
Am J Physiol Endocrinol Metab
267:
E411-E421,
1994
2.
Berger, M,
Berchtold P,
Kuppers HJ,
Drost H,
Kley HK,
Muller MA,
Wiegelman W,
Zimmeran-Telschow H,
Gries FA,
Kruskemper HL,
and
Zimmerman H.
Metabolic and hormonal effects of muscular exercise in juvenile type diabetics.
Diabetologia
13:
355-365,
1977[ISI][Medline].
3.
Bergeron, R,
Kjaer M,
Simonsen L,
Bulow J,
and
Galbo H.
Glucose production during exercise in humans: a-hv balance and isotopic-tracer measurements compared.
J Appl Physiol
87:
111-115,
1999
4.
Bucolo, RJ,
Bergman RN,
and
Marsh DJ.
Dynamics of glucose autoregulation in the isolated, blood perfused canine liver.
Am J Physiol
227:
209-217,
1974[ISI][Medline].
5.
Calles, J,
Cunningham JJ,
Nelson L,
Brown N,
Nadel E,
Sherwin RS,
and
Felig P.
Glucose turnover during recovery from intensive exercise.
Diabetes
32:
734-738,
1983[ISI][Medline].
6.
Carrlson, MG,
Snead WL,
and
Campbell PJ.
Regulation of free fatty acid metabolism by glucagon.
J Clin Endocrinol Metab
77:
11-15,
1993[Abstract].
7.
Chu, CA,
Sindelar DK,
Neal DW,
Allen EJ,
Donahue EP,
and
Cherrington AD.
Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis.
Am J Physiol Endocrinol Metab
274:
E162-E171,
1998
8.
Clore, JN,
Nester JE,
and
Blackard WG.
Sleep-associated fall in glucose disposal and hepatic glucose output in normal humans.
Diabetes
38:
285-290,
1989[Abstract].
9.
Coker, RH,
Denny J,
Koyama Y,
Lacy DB,
and
Wasserman DH.
Catecholamine and pancreatic hormone independent stimulation of endogenous glucose production prevents overt hypoglycemia during exercise.
Diabetes, Suppl
42OR:
A10,
2000.
10.
Coker, RH,
Krishna MG,
Lacy DB,
Allen EJ,
and
Wasserman DH.
Sympathetic drive to liver and nonhepatic splanchnic tissue during heavy exercise.
J Appl Physiol
82:
1244-1249,
1997
11.
Coker, RH,
Krishna MG,
Lacy DB,
Bracy DP,
and
Wasserman DH.
Role of hepatic alpha- and beta-adrenergic receptor stimulation on hepatic glucose production during heavy exercise.
Am J Physiol Endocrinol Metab
273:
E831-E838,
1997
12.
Coker, RH,
Lacy DB,
Krishna MG,
and
Wasserman DH.
Splanchnic glucagon kinetics in exercising alloxan-diabetic dogs.
J Appl Physiol
86:
1626-1631,
1999
13.
Connolly, CC,
Steiner KE,
Stevenson RW,
Neal DW,
Williams PE,
Alberti KGMM,
and
Cherrington AD.
Regulation of glucose metabolism by norepinephrine in conscious dogs.
Am J Physiol Endocrinol Metab
261:
E764-E772,
1991
14.
Cooper, AM,
Braatvedt GD,
Hlliweel M,
Reed AE,
and
Corrall RJM
Fasting and post-prandial splanchnic blood flow is reduced by somatostatin analogue (octreotide) in man.
Clin Sci (Colch)
81:
169-175,
1991[ISI][Medline].
15.
Friedlander, AL,
Casazza GA,
Horning MA,
Usaj A,
and
Brooks GA.
Endurance training increases fatty acid turnover, but not fat oxidation, in young men.
J Appl Physiol
86:
2097-2105,
1999
16.
Galbo, H.
The hormonal response to exercise.
Diabetes Metab Rev
1:
385-408,
1986[Medline].
17.
Galbo, H,
Christensen NJ,
Mikines KJ,
Sonne B,
Hilsted J,
Hagen C,
and
Fahrenkrug J.
The effect of fasting on the hormonal response to graded exercise.
J Clin Endocrinol Metab
52:
1106-1112,
1981[ISI][Medline].
18.
Galbo, H,
Holst JJ,
and
Christensen NJ.
The effects of different diets and of insulin on the hormonal response to prolonged exercise.
Acta Physiol Scand
107:
19-32,
1979[ISI][Medline].
19.
Hilsted, J,
Galbo H,
Sonne B,
Schwartz T,
Fahrenkrug J,
Muckadell OBSD,
Lauritsen KB,
and
Tronier B.
Gastorenteropancreatic hormonal changes during exercise.
Am J Physiol Gastrointest Liver Physiol
239:
G136-G140,
1980
20.
Hirsch, IB,
Marker JC,
Smith LJ,
Spina R,
Parvin CA,
Holloszy JO,
and
Cryer PE.
Insulin and glucagon in prevention of hypoglycemia during exercise in humans.
Am J Physiol Endocrinol Metab
260:
E695-E704,
1991
21.
Howlett, K,
Galbo H,
Lorentsen J,
Bergeron R,
Zimmerman-Belsing T,
Bülow J,
Feldt-Rasmussen U,
and
Kjaer M.
Effect of adrenaline on glucose kinetics during exercise in adrenalectomised humans.
J Physiol (Lond)
519:
911-921,
1999
22.
Issekutz, B.
Effects of glucose infusion on hepatic and muscle glycogenolysis in exercising dogs.
Am J Physiol Endocrinol Metab
240:
E451-E457,
1981
23.
Jaspan, JB,
Polonsky KS,
Lewis M,
Pensler J,
Pugh W,
Moossa AR,
and
Rubenstein AH.
Hepatic metabolism of glucagon in the dog: contribution of the liver to overall metabolic disposal of glucagon.
Am J Physiol Endocrinol Metab
240:
E233-E244,
1981
24.
Jeukendrup, AE,
Wagenmakers AJ,
Stegen JH,
Gijsen AP,
Brouns F,
and
Saris WH.
Carbohydrate ingestion can completely suppress endogenous glucose production during exercise.
Am J Physiol Endocrinol Metab
276:
E672-E683,
1999
25.
Kjaer, M,
Engfred K,
Fernandez A,
Secher N,
and
Galbo H.
Regulation of hepatic glucose production during exercise in humans: role of sympathoadrenergic activity.
Am J Physiol Endocrinol Metab
265:
E275-E283,
1993
26.
Kjaer, M,
Farrell PA,
Christensen NJ,
and
Galbo H.
Increased epinephrine response and inaccurate glucoregulation in exercising athletes.
J Appl Physiol
61:
1693-1700,
1986
27.
Kjaer, M,
Kiens B,
Hargreaves M,
and
Richter E.
Influence of active muscle mass on glucose homeostasis during exercise in humans.
J Appl Physiol
71:
552-557,
1991
28.
Kjaer, M,
Keiding S,
Engfred K,
Rasmussen K,
Sonne B,
Kirkegard P,
and
Galbo H.
Glucose homeostasis during exercise in humans with a liver or kidney transplant.
Am J Physiol Endocrinol Metab
268:
E636-E644,
1995
29.
Kjaer, M,
Secher H,
Bach FW,
and
Galbo H.
Role of motor center activity for hormonal changes and substrate mobilization in humans.
Am J Physiol Regulatory Integrative Comp Physiol
253:
R687-R695,
1987
30.
Moore, MC,
Connolly CC,
and
Cherrington AD.
Autoregulation of hepatic glucose production.
Eur J Endo
138:
240-248,
1998[ISI][Medline].
31.
Rojdmark, S,
Bloom G,
Chou MCY,
and
Field JB.
Hepatic extraction of exogenous insulin and glucagon in the dog.
Endocrinology
102:
806-813,
1978[ISI][Medline].
32.
Rowell, LB,
Blackmon JR,
and
Bruce RA.
Indocyanine green clearance and estimated hepatic blood flow during mild to maximal exercise in upright man.
J Clin Invest
43:
1677-1690,
1964[ISI].
33.
Sigal, RJ,
Fisher SF,
Halter JB,
Vranic M,
and
Marliss EB.
The roles of catecholamines in glucoregulation in intense exercise as defined by the islet cell clamp technique.
Diabetes
45:
148-156,
1996[Abstract].
34.
Sindelar, DK,
Chu CA,
Venson P,
Donahue EP,
Neal DW,
and
Cherrington AD.
Basal hepatic glucose production is regulated by the portal vein insulin concentration.
Diabetes
47:
523-529,
1998[Abstract].
35.
Steinberg, D.
The endocrine pancreas.
In: Best and Taylor's Physiological Basis of Medical Practice, edited by West JB.. Baltimore, MD: Williams & Wilkins, 1990, p. 754-769.
36.
Wade, EE,
and
Freund BJ.
Hormonal control of blood volume during and following exercise.
In: Perspectives in Exercise Science and Sports Medicine, edited by Gisolfi CV,
and Lamb DR.. Carmel, IN: Benchmark, 1990, p. 207-245.
37.
Wasserman, DH.
Control of glucose fluxes during exercise in the postabsorptive state.
Ann Rev Physiol
57:
191-218,
1995[ISI][Medline].
38.
Wasserman, DH,
Lacy DB,
Colburn CA,
Bracy D,
and
Cherrington AD.
Efficiency of compensation for absence of fall in insulin during exercise.
Am J Physiol Endocrinol Metab
261:
E587-E597,
1991
39.
Wasserman, DH,
Lacy DB,
Goldstein RE,
Williams PE,
and
Cherrington AD.
Exercise-induced fall in insulin and the increase in fat metabolism during prolonged exercise.
Diabetes
38:
484-490,
1989[Abstract].
40.
Wasserman, DH,
Lacy DB,
Green DR,
Williams PE,
and
Cherrington AD.
Dynamics of hepatic lactate and glucose balances during prolonged exercise and recovery in the dog.
J Appl Physiol
63:
2411-2417,
1987
41.
Wasserman, DH,
Lickley HLA,
and
Vranic M.
Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs.
J Clin Invest
74:
1404-1413,
1984[ISI][Medline].
42.
Wasserman, DH,
Spalding JS,
Lacy DB,
Colburn CA,
Goldstein RE,
and
Cherrington AD.
Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work.
Am J Physiol Endocrinol Metab
257:
E108-E117,
1989
43.
Wasserman, DH,
Williams PE,
Lacy DB,
Bracy D,
and
Cherrington AD.
Hepatic nerves are not essential to the increase in hepatic glucose production during muscular work.
Am J Physiol Endocrinol Metab
259:
E195-E203,
1990
44.
Wirth, A,
Diehm C,
Mayer H,
Morl H,
Vogel I,
Bjorntorp P,
and
Schlierf G.
Plasma C-peptide and insulin in trained and untrained subjects.
J Appl Physiol
50:
71-77,
1981
45.
Wolfe, RR,
Nadel ER,
Shaw JHF,
Stephenson LA,
and
Wolfe M.
Role of changes in insulin and glucagon in glucose homeostasis in exercise.
J Clin Invest
77:
900-907,
1986[ISI][Medline].