Increased hepatic glucose production response to glucagon in trained subjects

Réjean Drouin, Carole Lavoie, Josée Bourque, Francine Ducros, Danielle Poisson, and Jean-Louis Chiasson

Research Group on Diabetes and Metabolic Regulation, Research Center, Centre Hospitalier de l'Université de Montréal, Hôtel-Dieu Pavilion Department of Medicine, University of Montréal, Montreal, Quebec H2W 1T8; and Department of Physical Activities, Université du Québec à Trois-Rivières, Trois-Rivières, Quebec, Canada G9A 5H7

    ABSTRACT
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Abstract
Introduction
Methodology
Results
Discussion
References

This study was designed to characterize the impact of endurance training on the hepatic response to glucagon. We measured the effect of glucagon on hepatic glucose production (HGP) in resting trained (n = 8) and untrained (n = 8) healthy male subjects (maximal rate of O2 consumption: 65.9 ± 1.6 vs. 46.8 ± 0.6 ml O2 · kg-1 · min-1, respectively, P < 0.001). Endogenous insulin and glucagon were suppressed by somatostatin (somatotropin release-inhibiting hormone) infusion (450 µg/h) over 4 h. Insulin (0.15 mU · kg-1 · min-1) was infused throughout the study, and glucagon (1.5 ng · kg-1 · min-1) was infused over the last 2 h. During the latter period, plasma glucagon and insulin remained constant at 138.2 ± 3.1 vs. 145.3 ± 2.1 ng/l and at 95.5 ± 4.5 vs. 96.2 ± 1.9 pmol/l in trained and untrained subjects, respectively. Plasma glucose increased and peaked at 11.4 ± 1.1 mmol/l in trained subjects and at 8.9 ± 0.8 mmol/l in untrained subjects (P < 0.001). During glucagon stimulation, the mean increase in HGP area under the curve was 15.8 ± 2.8 mol · kg-1 · min-1 in trained subjects compared with 7.4 ± 1.6 mol · kg-1 · min-1 in untrained subjects (P < 0.01) over the first hour and declined to 6.8 ± 2.8 and 4.9 ± 1.4 mol · kg-1 · min-1 during the second hour. In conclusion, these observations indicate that endurance training is associated with an increase in HGP in response to physiological levels of glucagon, thus suggesting an increase in hepatic glucagon sensitivity.

exercise; endurance training; insulin-to-glucagon ratio

    INTRODUCTION
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Abstract
Introduction
Methodology
Results
Discussion
References

THE INCREASE IN GLUCOSE utilization by skeletal muscle during exercise poses a major challenge to glucose homeostasis. The liver remains the sole source of glucose delivery into the circulation during exercise in the postabsorptive state. Although hyperglycemia and hypoglycemia may occur during exercise under certain conditions, plasma glucose concentration usually remains relatively constant during moderate intensity exercise of prolonged duration (11). This equilibrium between glucose utilization and production requires that the increase in hepatic glycogenolysis and gluconeogenesis parallels the accelerated rate of glucose uptake by working muscles.

Human and animal studies support the concept that such glucose homeostasis is regulated by neurohormonal signals. It has been well documented that prolonged exercise of moderate intensity is associated with a decrease in plasma insulin and an increase in plasma glucagon and catecholamines (16, 18). However, these hormonal responses are markedly altered by endurance training. Plasma glucagon and catecholamine responses to prolonged exercise of moderate intensity are much lower in trained subjects (21). Conversely, plasma insulin concentration, although lower at rest, decreases less and therefore tends to be higher during exercise in trained individuals (21). Paradoxically, despite a higher insulin-to-glucagon ratio in trained compared with untrained subjects, glucose homeostasis is improved during prolonged exercise of moderate intensity by an increased hepatic glucose production response (5, 21). Because glucagon is the major factor regulating the rise in hepatic glucose production during prolonged exercise of moderate intensity (31), the improved glucose homeostasis observed in trained subjects (5) may be due to increased sensitivity of the liver to glucagon.

The present study was designed to assess the influence of endurance training on the effect of glucagon on hepatic glucose production in resting trained and untrained healthy male subjects using tracer methodology. Our data indicate that endurance training is indeed associated with an increased liver response to glucagon.

    SUBJECTS AND METHODOLOGY
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Abstract
Introduction
Methodology
Results
Discussion
References

Subjects. Eight trained and eight untrained healthy male subjects within 10% of their ideal body weight participated in this study (Table 1). The two groups were paired for age (21.1 ± 0.5 vs. 23.8 ± 0.6 yr) and body mass index (21.5 ± 0.8 vs. 22.7 ± 1.6 kg/m2). All subjects were instructed to follow a well-balanced diet (55% carbohydrates, 30% lipids, and 15% proteins) 3 days before the study. They were also instructed not to participate in any vigorous physical activities at least 48 h before the study. Every subject had a normal 2-h oral glucose tolerance test, a normal history, and physical exam. They also had a normal resting electrocardiogram. Complete blood count, biochemistry profile, and liver function test were also normal. The protocol was approved by the Ethic Committee of the Research Center of Hôtel-Dieu de Montréal Hospital, and signed informed consent was obtained from each volunteer.

                              
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Table 1.   Demographic and baseline clinical data on trained and untrained subjects

Experimental design. The week before the study, each subject had a maximal rate of O2 consumption (VO2 max) measurement using cycle ergometer exercise. Briefly, the subject exercised at 80 revolutions/min, starting at 1 kPa and increasing by 0.5 kPa every 2 min for 14 min and then by 0.3 kp every 2 min until one of the end points for termination of the exercise, as described by the American College of Sports Medicine (2), was reached. Oxygen uptake was measured every 30 s during exercise using an open-circuit spirometry system (MMC; Beckman, Mississauga, ON, Canada).

The subjects were studied at 7:30 AM after an overnight fast (~10-12 h postabsorptive). A catheter was inserted into an antecubital vein for infusion of D-[6,6-2H2]glucose, insulin, glucose, somatostatin [somatotropin release-inhibiting hormone (SRIF)], and glucagon. A second catheter was inserted in retrograde fashion into a hand vein of the contralateral arm, and the hand was placed in a heating box (68°C) to provide "arterialized" venous blood for sampling. During the 4-h study period, endogenous insulin and glucagon were suppressed by SRIF infusion at 450 µg/h, D-[6,6-2H2]glucose was administered as a prime, constant infusion (250 mg-2.5 mg/min), and insulin was replaced at 0.15 mU · kg-1 · min-1. During the first 2 h, plasma glucose was clamped at 5 mmol/l by variable glucose infusion. Over the last 2 h, glucagon was infused at 1.5 ng · kg-1 · min-1, and glucose infusion was then maintained constant at the rate achieved by 120 min. The reason glucose infusion was maintained at the start of glucagon infusion was to avoid having a concomitant decrease in the total rate of glucose appearance (Ra) due to cessation of glucose infusion and an increase in Ra due to glucagon infusion.

Methodology. Blood was collected into heparin syringes for subsequent determinations of plasma glucose concentrations and D-[6,6-2H2]glucose. Plasma glucose concentrations were measured by the hexokinase method using Boehringer Mannheim kit MPR-3 1-442-457 (Boehringer Mannheim Canada, Laval, QC, Canada) while determination of plasma glucose enrichments was performed (model 5890-5970; Hewlett-Packard, Palo Alto, CA) after derivatization according to Küry and Keller (17). Plasma insulin (Immunocorp Sciences, Montréal, QC, Canada) and glucagon (Diagnostic Products, Los Angeles, CA) concentrations were measured by radioimmunoassay. Plasma lactate (no. 826-UV; Sigma Diagnostics, St. Louis, MI) and alanine concentrations were measured by spectrophotometry after deproteinization by perchloric acid. Serum nonesterified fatty acids (NEFA; Wako Pure Chemical, Richmond, VA), glycerol (no. 310-UV; Sigma Diagnostics) and beta -hydroxybutyrate (beta -OH, no. 337-UV; Sigma Diagnostics) were also measured by spectrophotometer. The COBAS BIO analyzer (Roche Analytical Instruments, Nutley, NJ) was used for determination of glucose, lactate, beta -OH, and glycerol concentrations.

Calculations. Ra was calculated according to the non-steady-state equations of Steele (28) using 200 ml/kg as the glucose distribution volume and 0.65 for the pool fraction. Hepatic glucose production is the difference between Ra and the glucose infusion rate; therefore, in the text, whenever the term hepatic glucose production is used, the glucose infusion rate has already been subtracted.

Statistical analysis. All values are expressed as means ± SE. Two-way analysis of variance with repeated measurements over one factor (time) was employed a priori to test for changes with time and between groups. If this test revealed significant differences, the Student-Newman-Keuls test for paired and unpaired data was used to further assess differences between groups.

    RESULTS
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Abstract
Introduction
Methodology
Results
Discussion
References

VO2 max was significantly higher in trained compared with untrained subjects (65.9 ± 1.6 vs. 46.8 ± 0.6 ml O2 · kg-1 · min-1; P < 0.001). Basal plasma glucose, insulin, and glucagon concentrations were similar in both groups, although plasma glucagon and insulin tended to be lower in trained subjects (Table 1).

During the equilibrium period (0-120 min), mean plasma glucose levels were 5.3 ± 0.1 and 5.2 ± 0.1 mmol/l in trained and untrained subjects, respectively (Fig. 1). The amount of glucose infused to maintain normoglycemia over the last 30 min of the equilibration period (90-120 min) was 15.7 ± 3.9 and 7.6 ± 2.0 µmol · kg-1 · min-1 for the trained and untrained subjects, respectively (P = 0.09). During this period, plasma glucagon levels were similarly suppressed by SRIF to the lower limit of detection in both groups, whereas peripheral insulin levels were maintained slightly over fasting levels (99.8 ± 4.4 and 98.9 ± 3.6, respectively). The increased glucose infusion in the trained subjects to maintain normoglycemia is consistent with the increased sensitivity to insulin observed in trained subjects (24). During glucagon infusion (120-240 min), plasma glucose concentration increased in both groups and reached a plateau during the last hour, which was higher in trained subjects compared with untrained subjects (11.4 ± 1.1 vs. 8.9 ± 0.8 mmol/l; P < 0.001; Fig. 1). This difference occurred despite the fact that the hormonal levels achieved were similar in trained and untrained subjects for both plasma glucagon (138.2 ± 3.1 vs. 145.3 ± 2.1 ng/l; Fig. 2A) and plasma insulin (95.5 ± 4.5 vs. 96.2 ± 1.9 pmol/l; Fig. 2B). Because plasma glucagon levels were similarly suppressed by SRIF during the equilibration period, the increase in the hormone levels during glucagon infusion was the same in both groups.


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Fig. 1.   Plasma glucose concentrations during the equilibrium period and in response to glucagon stimulation in trained and untrained subjects. Values are expressed as means ± SE. * P < 0.001.


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Fig. 2.   Plasma glucagon (A) and plasma insulin (B) concentrations during glucagon stimulation in trained and untrained subjects. Values are expressed as means ± SE (SE too small to be apparent in figure).

The hepatic glucose production during the last 30 min of the equilibration period (90-120 min) was 9.7 ± 1.9 and 10.8 ± 1.9 µmol · kg-1 · min-1 in the trained and untrained subjects, respectively [P = not significant (NS)]. This is very similar to previous observations that we have made in dog studies under a similar hormonal environment (6). In the latter study, hepatic glucose production was slightly more suppressed (~30%) than in our human subjects; this, however, is very likely due to the higher rate of insulin infusion (0.4 vs. 0.15 mU · kg-1 · min-1) and the site of infusion (portal vs. peripheral; see Ref. 6). In the trained subjects, glucagon infusion resulted in a rapid increase in hepatic glucose production to 19.2 ± 7.0 µmol · kg-1 · min-1 above baseline, peaking at 20 min and gradually decreasing to 5.1 ± 3.3 µmol · kg-1 · min-1 by the end of the 2-h study period (Fig. 3A). In untrained subjects, however, glucagon stimulation of hepatic glucose production was much less, reaching a peak of 10.7 ± 4.2 µmol · kg-1 · min-1 and gradually decreasing to 2.3 ± 2.3 µmol · kg-1 · min-1 by the end of the study. This short-lived effect of glucagon on increased hepatic glycogenolysis has been known for a long time (19). Similarly, the glucagon-induced hepatic release of adenosine 3',5'-cyclic monophosphate in humans also follows the same spike decline pattern (19). During the first hour of glucagon infusion, the mean increase in hepatic glucose production area under the curve (AUC) was 15.8 ± 2.8 µmol · kg-1 · min-1 in trained subjects compared with 7.4 ± 1.6 µmol · kg-1 · min-1 in untrained subjects (P < 0.01) (Fig. 3B). In the second hour of glucagon infusion, the increase in hepatic glucose production AUC was 6.8 ± 2.8 µmol · kg-1 · min-1 in trained subjects compared with 4.9 ± 1.4 µmol · kg-1 · min-1 in untrained subjects (P = NS).


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Fig. 3.   Increase in hepatic glucose production in response to glucagon infusion in trained and untrained subjects. Data are expressed as means ± SE in time (A) and as the mean incremental area under the curve (AUC) ± SE for the first (120-180 min) and second hours (180-240 min) (B) of glucagon infusion. * P < 0.01.

Baseline serum NEFA concentrations (Table 2) were higher in untrained than in trained subjects (0.8 ± 0.2 vs. 0.3 ± 0.04 mmol/l; P < 0.05); although baseline plasma glycerol levels tended to be higher in untrained subjects (28.4 ± 5.0 vs. 13.9 ± 5.0 mg/dl), they did not reach statistical significance. Baseline serum beta -OH concentrations were similar in both groups. During insulin infusion (0-120 min) in the absence of glucagon, serum NEFA decreased gradually in both groups (P < 0.01), but, at all time points, NEFA values were higher in untrained subjects (P < 0.01). Serum glycerol levels also decreased in response to insulin infusion, reaching significantly lower levels in trained subjects (P < 0.05). Serum beta -OH concentrations decreased to similar levels in both groups. Glucagon infusion (120-240 min) did not affect the downward trend in any of these metabolites.

                              
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Table 2.   Plasma NEFA, glycerol, beta -OH, lactate, and alanine concentrations in trained and untrained subjects

Baseline plasma alanine and lactate concentrations were not different in trained and untrained subjects (Table 2). During insulin infusion when glucagon was suppressed by SRIF, there was a rapid and significant decrease of the two gluconeogenic precursors in both groups (P = 0.05). Although mean levels of the two substrates were always higher in trained subjects, they only became significant for alanine (P < 0.01). During glucagon infusion, there was a trend for the precursors to increase, which was more apparent for lactate and more so in trained subjects.

    DISCUSSION
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Abstract
Introduction
Methodology
Results
Discussion
References

The present data show that, in endurance-trained subjects, glucagon infusion resulting in physiological hormonal level leads to a faster and greater response of hepatic glucose production compared with untrained subjects under identical insulin levels. These results suggest that endurance training is associated with increased hepatic sensitivity to glucagon.

It is well known that small changes in the insulin-to-glucagon ratio result in significant modifications in hepatic glucose production (29). In the present study, however, the experimental protocol was designed to achieve similar physiological levels of plasma insulin and plasma glucagon in both groups. This is confirmed by the hormonal levels illustrated in Fig. 2, A and B, with a calculated mean insulin-to-glucagon ratio of 2.4 ± 0.1 and 2.7 ± 0.08 for trained and untrained subjects, respectively. It indicates that the greater response of hepatic glucose production observed in trained subjects was not due to a change in the insulin-to-glucagon ratio. Furthermore, the increase in plasma glucagon levels was identical in both the trained and untrained subjects. Therefore, physical fitness remains the main difference between the two groups. How endurance training increases liver response to glucagon remains unclear. The following possibilities have to be considered: upregulation of glucagon receptors, increased liver glycogen content, and decreased NEFA levels.

It is well known that chronic hyperglucagonemia is associated with diminished hepatic sensitivity to glucagon (3, 26, 27). Clinical conditions with hyperglucagonemia, as in patients with insulin-dependent diabetes mellitus (22), patients with uremia (25), and in ob/ob mice (32), are characterized by decreased hepatic glucagon sensitivity in a similar manner as hyperinsulinemia induces insulin resistance. Chronic hyperglucagonemia has been shown to be associated with desensitization of hepatic glucagon receptors (3, 26, 27) and a diminished capacity of glucagon to stimulate hepatic glycogenolysis. In our study as well as in others (10, 21, 32), resting glucagonemia tended to be lower in trained compared with untrained subjects. These observations are compatible with upregulation of glucagon receptors due to lower glucagon concentrations in trained subjects. Such upregulation could explain, at least in part, the increased response of the liver to glucagon stimulation in our trained subjects.

Previous studies (8, 9, 20) indicate that the initial response to glucagon is due mainly to glycogenolysis. Furthermore, Magnusson et al. (20) presented data suggesting that glycogenolysis accounts for 93 ± 9% of net hepatic glucose production during the initial response to a physiological increment of plasma glucagon. Similar studies in dogs have demonstrated that glycogenolysis accounted for ~85-90% of overall glucagon-stimulated hepatic glucose production during the first 15 min compared with ~43% by 165 min (7), and it was suggested that hepatic glycogen content could play a major role in regulating the initial response to glucagon infusion. Increased glycogen content after endurance training has been observed in humans (1, 12, 14, 15) and exercising rats. Vissing et al. (30) have shown that hepatic glycogenolysis during exercise is directly related to hepatic glycogen content. Therefore, the increased hepatic glucose production observed in response to glucagon in the present study may be due, at least in part, to an elevated hepatic glycogen content in trained compared with untrained subjects.

A number of studies have shown that increased free fatty acid levels will decrease the tonic inhibition of insulin on hepatic glucose production (4, 13, 23). In our trained subjects, baseline serum free fatty acid levels were 50% lower than in our untrained subjects (0.30 ± 0.04 vs. 0.76 ± 0.18 mmol/l); even during insulin and glucagon infusion, the free fatty acid levels remained two- to threefold higher in the untrained subjects (Table 2). Because the insulin levels were clamped at the same level in both groups, it is assumed that the tonic inhibitory effect of insulin on hepatic glucose production was stronger in the trained subjects. Therefore, the increased hepatic glucose production in response to glucagon in the trained subjects strongly suggests an increased sensitivity of the liver to glucagon.

The main gluconeogenic precursors, lactate, alanine, and glycerol, were not different between the two groups at baseline. It is very unlikely that, during the 2-h glucagon stimulation, gluconeogenesis became a major contributor to hepatic glucose production (9). As such, it is unlikely that changes in the rate of gluconeogenesis in response to glucagon can account for the differences in early hepatic glucose production responses to glucagon between trained and untrained subjects.

From the present observations, it can be concluded that endurance training increases the liver response to glucagon, suggesting an increase in hepatic sensitivity to glucagon. The brisk and greater response of hepatic glucose production to glucagon is likely to be an increase in glycogenolysis. It is suggested that this increased liver response in trained subjects could be due to upregulation of glucagon receptors and/or greater liver glycogen content. The molecular basis for such mechanisms remains to be elucidated. Furthermore, we would like to propose that, in insulin-dependent diabetes mellitus patients, an exercise training program could increase liver sensitivity to glucagon and thus decrease the risk of severe hypoglycemia.

    ACKNOWLEDGEMENTS

We are grateful to François Péronnet and Éric Bronssard from the University of Montreal for their collaboration, Susanne Bordeleau-Chénier for preparing this manuscript and figures, and Ovid Da Silva for editing the manuscript.

    FOOTNOTES

Address for reprint requests: J.-L. Chiasson, Research Center, CHUM Hôtel-Dieu Pavilion, 3850 St. Urbain St., Montreal, QC Canada H2W 1T8.

Received 1 April 1997; accepted in final form 19 September 1997.

    REFERENCES
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Abstract
Introduction
Methodology
Results
Discussion
References

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AJP Endocrinol Metab 274(1):E23-E28
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