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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 2118-2124
Copyright © 2001 by The Endocrine Society

Original Studies

Norepinephrine Infusion during Moderate-Intensity Exercise Increases Glucose Production and Uptake1

Stuart H. Kreisman, Nicholas Ah Mew2, Jeffrey B. Halter, Mladen Vranic and Errol B. Marliss

McGill Nutrition and Food Science Centre (S.H.K., N.A.M., E.B.M.), Royal Victoria, Montréal, Québec, Canada, H3A 1A1; The Department of Internal Medicine and Institute of Gerontology (J.B.H.), University of Michigan and Veterans Affairs Medical Centre, Ann Arbor, Michigan, 48109; and The Departments of Physiology and Medicine (M.V.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8

Address all correspondence and requests for reprints to: Errol B Marliss, McGill Nutrition and Food Science Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: errol.marliss{at}muhc.mcgill.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A role for the increase in circulating norepinephrine (NE) during intense exercise [IE; >=80% maximum O2 uptake (O2max)] in the marked increment in glucose rate of production (Ra) during IE is hypothesized. Seven fit male subjects (27 ± 2 yr old; body mass index, 23 ± 1 kg/m2; O2max, 63 ± 5 mL/kg·min) underwent 40 min of postabsorptive moderate-intensity (53% O2max) cycle ergometer exercise (126 ± 14 W), once without [control (CON)] and once with NE infusion (0.1 µg/kg·min) from 30–40 min (NE). With infusion, plasma NE reached 15.9 ± 1.0 nM (8-fold rest, 2-fold CON). Ra doubled to 4.40 ± 0.44 in CON, but rose to 7.55 ± 0.68 mg/kg·min with NE infusion (P = 0.003). Ra correlated strongly (r2 = 0.92, P < 0.02) with plasma NE during and immediately after infusion. With NE infusion, peak glucose uptake [rate of disappearance (Rd), 6.57 ± 0.59 vs. 4.53 ± 0.55 mg/kg·min, P < 0.02] and glucose metabolic clearance rate (P < 0.05) were higher than in CON. Glycemia rose minimally during the NE infusion but did not differ between groups at any time during exercise. Glucagon-to-insulin ratio increased minimally, and epinephrine increased approximately 2.5- to 3-fold at peak but did not differ between groups. Thus, NE infusion during moderate exercise led to increments in Ra and Rd in fit individuals, supporting a possible contributory role for the increase of plasma NE in IE. NE effects on Rd and metabolic clearance rate during exercise may differ from its effects at rest.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ALTHOUGH CIRCULATING LEVELS of norepinephrine (NE) increase dramatically (~15-fold) during intense exercise [IE; >=80% of maximum O2 uptake (O2max)] in humans, NE is primarily considered to be a neurotransmitter. It is released from terminals of sympathetic postganglionic neurons, and the human liver is known to have a rich sympathetic innervation (1). Thus, the increment in hepatic glucose production (Ra) in IE may be contributed to by local sympathetic release of NE. However, liver denervation studies in rats (2) and guinea pigs (who, like humans but unlike rats, have rich innervation) (3), as well as studies of humans with a liver transplant (4) or undergoing celiac ganglion blockade (5), have not demonstrated a lesser increment in Ra during exercise. In contrast, NE infusion, both in dogs (6) and humans (7), though having lesser effects than similar infusions of epinephrine (Epi) (7, 8), stimulated Ra, thereby supporting its hormonal role under certain conditions (9).

Glucoregulation at low- and moderate-intensity (e.g. <=50% O2max) exercise is primarily mediated by an increase in the portal venous glucagon-to-insulin ratio [IRG/IRI (10, 11)]. This stimulates Ra and maintains euglycemia largely through a feedback mechanism (12, 13, 14, 15) that matches the increment in Ra to the increased requirements. However, in IE, a rapid and massive increase (<=8-fold) in Ra and a rise in glycemia occur, but plasma IRI either remains constant or decreases slightly, and IRG increases less than 2-fold (16, 17, 18, 19). A feed-forward mechanism has been proposed (15, 20), possibly catecholamine-mediated (16, 17, 18, 19, 20, 21, 22), for the regulation of hepatic glucose output during IE. It might be argued that such a mechanism would be better suited to maintaining homeostasis during such extreme physiologic conditions. Yet, recent studies, by ourselves (23) and others (24), of Epi infusion during moderate-intensity exercise suggest that Epi contributes to, but does not fully account for, the Ra increment of IE. We are unaware of prior studies of NE infusion during exercise. Therefore, to determine whether systemic NE levels similar to those during IE may directly contribute to the Ra increment and other metabolic changes of IE, we studied fit, lean, young males undergoing 40-min postabsorptive exercise at 50% O2max, with and without infusion of 0.1 µg/kg·min NE, from minutes 30–40.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Participants were seven lean, weight-stable, fit men, 19–33 yr old (Table 1Go). All engaged in regular activity such as running, cycling, soccer, and/or rowing; and some of them combined these with resistance training. Screening before the study included medical history, physical examination, hemogram, blood biochemistry, urinalysis, hepatitis B and HIV serology, electrocardiogram, and chest roentgenogram. Subjects were informed of the purpose of the study and of the possible risks, and they gave signed consent as prescribed by the institutional human ethics committee.


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  		Table 1. Subject and exercise data

 
O2max was determined, at a preliminary visit, with breath-by-breath analysis during an incremental workload test (20 W/min) on an electrically braked cycle ergometer (Collins Metabolic Cart, Collins, Braintree, MA). Oxygen uptake (O2, STPD), carbon dioxide output (CO2, STPD), ventilation (L/min, BTPS), and respiratory exchange ratio (RER) and heart rate were measured. The studies with glucose turnover measurements began between 0800–0900 h with subjects in the 12-h overnight fasting state, without having undergone any significant exercise in the preceding 24 h. Twenty-gauge iv cannulas were placed in both arms. A priming bolus of 22 µCi high-performance liquid chromatography-purified 3[-3H] glucose tracer (NEN Life Science Products, Billerica, MA) was followed by a constant infusion of 0.22 µCi/min in 0.9% saline except where otherwise specified. Blood was sampled at six 10-min intervals before time zero (beginning of exercise) to assure a steady-state of plasma 3H-glucose specific activity (SA). The subjects then cycled 40 min at 50% O2max, followed by a 120-min recovery period. The exercise intensity level was achieved using 45% of the maximum workload reached during the incremental workload test and making minor adjustments so that a steady-state at 50% O2max was reached early during the study.

Experiments with and without NE infusion were separated by at least 1 month, and the subjects were unaware of which infusate was received. In five subjects, the NE experiment preceded the control (CON) study; and in two, the order was the reverse. In the NE experiment, NE (as the bitartrate, Sanofi Pharmaceuticals, Inc. Canada, Markham, Ontario) in isotonic saline and 1 mg/ml ascorbic acid (as antioxidant, Sabex, Boucherville, Québec) was infused at 0.1 µg/kg·min from minutes 30–40 of exercise. In the CON experiment, only ascorbic acid in saline was infused. Glucose SA was maintained by increasing the tracer infusion 3-fold during the NE infusion and then returning it to the preexercise rate at minute 40. The goal was to introduce labeled glucose into the circulation at a rate proportional to endogenous Ra, thereby attenuating changes in [3H] glucose SA to less than 25% during the rapid changes in glucose kinetics, as in previous experiments (16, 17, 18, 19, 22, 25). This assures the validity of glucose turnover calculations (26), even if there may be changes in pool fraction during this time. Blood samples were drawn at intervals shown by the data in the figures.

Samples for glucose turnover measurements were placed into tubes containing heparin and sodium fluoride and were processed as previously (22). Heparinized plasma was collected with aprotinin (Trasylol; 10,000 kallikrein inhibitor U/mL; FBA, New York, NY) for subsequent IRI and IRG assays. For catecholamine measurements, blood was added to EGTA- and reduced-glutathione-containing tubes, and the plasma was frozen at -70 C until assay. One aliquot of whole blood was immediately deproteinized in an equal volume of cold 10% (wt/vol) perchloric acid, kept on ice until centrifuged at 4 C, and then frozen at -20 C for later lactate and pyruvate assays.

Glucose was measured by the glucose oxidase method using a Glucose Analyzer II (Beckman Coulter, Inc., Fullerton, CA). Blood lactate and pyruvate were measured by enzymatic microfluorometric methods, IRI and IRG were measured by RIAs previously detailed (see 44), and free fatty acids (FFA) were measured by an enzymatic method (Wako Pure Chemical Industries Ltd. GmbH, Neuss, Germany). Assays that were performed on aprotinin-containing plasma were corrected for the plasma dilution introduced. Plasma NE and Epi were measured using a radioenzymatic technique (sensitivity < 50 pmol/L) (27). The intra- and interassay coefficients of variation for all assays were less than10%; for the enzymatic assays, they were less than 5%. Ra and peak glucose uptake (Rd) were calculated from the variable isotope infusion protocols, according to the one-compartment model (28), using a glucose distribution space of 25% of body weight, and with a pool fraction of 0.65 representing the part in which the rapid changes of glucose and SA occur. Data were systematically smoothed using the OOPSEG (optimized optimal segments) program, which continually reconstructs and retests the curve until the residual differences between it and the data points are considered random, and thus should represent measurement error (29). Glucose metabolic clearance rate (MCR) was calculated by dividing Rd by the plasma glucose concentration.

Baseline variables, plasma glucose, SA, glucose turnover, MCR, lactate, pyruvate, catecholamine, and hormone results were analyzed by repeated-measures ANOVA. The repeated-measures ANOVA was used for time intervals that are specified, each time a P value is given. Within-study differences that were found to be significant (P < 0.05) by ANOVA were subsequently analyzed by the Student’s-Newman-Keuls t test. Paired Student’s t tests were used for analysis of some differences between groups that were found with ANOVA. Linear correlations were calculated using the Pearson correlation coefficient. Individual correlation coefficients were calculated using all data points for each individual at which catecholamines and Ra were measured in the specified intervals. This correlation coefficient was then treated as a continuous variable on which means and SE were calculated. The SPSS, Inc.-Windows Release 10.0 software package (SPSS, Inc., Chicago, IL), Microsoft Corp. Excel 7.0 Analysis ToolPak (GreyMatter International Inc., Cambridge, MA), and Primer Biostats (McGraw-Hill, New York, NY) were used. Data are presented as means ± SE.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
No untoward effects were experienced, and subjects were not able to identify the infusate. Anthropometric measures, O2max, and workload data are presented in Table 1Go. Percent O2max reached during the two studies was not different. RER was not different at any time between studies, rapidly rising from approximately 0.72 to approximately 0.93 at minute 5 of exercise then slowly falling to approximately 0.88 by the end of exercise in both groups. It was unaffected by NE infusion. Heart rate did not change with NE infusion. Neither systolic nor diastolic blood pressure differed between studies at any time.

Plasma glucose concentrations (Fig. 1Go) were not different between studies at baseline, and they remained constant during the first 30 min of exercise. During NE infusion, glucose tended to rise, but this was not significant or different between groups. A peak of glycemia was reached at minute 5 of recovery, at 5.86 ± 0.26 mM in NE (P = 0.005 vs. minute 40, by paired t test) and 5.16 ± 0.20 mM in CON (P = 0.003 vs. minute 40, by paired t test) and was higher in NE at minutes 5–10 of recovery (by paired t test).



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  		Figure 1. Plasma glucose concentration during baseline, 40 min of 50% O2max exercise with and without NE infusion from minutes 30–40, and 120 min of postexercise recovery. Time 0 indicates the beginning of exercise. Data for NE infusion studies (-{diamondsuit}-) (n = 7), and control studies (–{square}–) (n = 7) are indicated. Data are presented as means ± SE. Where SE bars are not present, they are smaller than the symbol or would overlap with the SE from the other group. Significant differences are specified in the text.

 
Ra (Fig. 2AGo) did not differ between studies at baseline (mean, 2.18 mg/kg·min) or during the first 30 min of exercise. Whereas Ra peaked at 4.40 ± 0.44 mg/kg·min at minute 30 in CON and then fell slightly by minute 40, it increased markedly, to more than 6 mg/kg·min by minute 2 of the NE infusion, reaching a maximum of 7.55 ± 0.68 mg/kg·min at minute 40 (P = 0.003, by ANOVA during infusion).



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  		Figure 2. Ra (A), Rd (B), and glucose MCR (C) during baseline, 40 min of 50% O2max exercise with and without NE infusion from minute 30 to 40, and recovery periods. Data are presented as in Fig. 1Go.

 
Neither glucose Rd (Fig. 2BGo) nor MCR (Fig. 2CGo) differed between studies at baseline or during the first 30 min of exercise. Thereafter, values decreased in CON; but in NE, both increased markedly within 2 min of starting the infusion, reaching a maximum Rd of 6.57 ± 0.59 mg/kg·min at minute 40 (vs. 4.53 ± 0.55 mg/kg·min at minute 30 and 3.54 ± 0.37 mg/kg·min at minute 40 in CON) and a maximum MCR of 7.17 ± 0.93 mL/kg·min at minute 40 (vs. 4.17 ± 0.57 mL/kg·min in CON). Throughout the infusion, Rd was higher in NE (P = 0.016). In contrast, MCR was only higher from minutes 38–40 (P = 0.036). Neither differed significantly from CON during the recovery period.

IRI (Fig. 3AGo), IRG (Fig. 3BGo), and the IRG-to-IRI molar ratio (Fig. 3CGo) did not differ between groups at any point during the study. IRI decreased approximately 15% in both groups during exercise, in NE from minutes 0–30 (P = 0.049 by ANOVA) and minutes 0–40 (P = 0.005 by ANOVA) but not from minutes 30–40. IRI rose 28% in CON and 54% in NE (P <= 0.03 by paired t vs. minute 40) by minute 10 of recovery, then returned rapidly to baseline. IRG remained constant for the first 30 min of exercise in both groups but rose 17% from minutes 30–40 (P = 0.004 by ANOVA) in NE. It fell slightly, (P < 0.01 by ANOVA) in both groups during recovery. Mean IRG-to-IRI ratio tended upward slightly during the first 30 min of exercise (NS), then an additional 20% during infusion in NE (P = 0.044 by ANOVA).



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  		Figure 3. Plasma insulin (A), glucagon (B), and glucagon-to insulin-molar ratio (C) during baseline, 40 min of 50% O2max exercise with and without NE infusion from 40, and recovery periods. Data are presented as in Fig. 1Go.

 
Plasma Epi (Fig. 4AGo) did not differ between studies at baseline, during exercise (increasing ~2.5- to 3-fold) or recovery. The plasma NE (Fig. 4BGo) did not differ at baseline or during the first 30 min of exercise, during which it gradually tripled. Whereas in CON, NE increased slightly (from 6.9 ± 0.7 to 8.6 ± 1.1 nM, P = 0.02) from minutes 30–40 of exercise, in NE it rose markedly from 6.6 ± 0.8 to 15.9 ± 1.0 nM (P < 0.001) at minute 35 (P = 0.001 vs. CON, by ANOVA). Levels fell abruptly in recovery, such that baseline values were approached at 5 min and reached at 20 min in both groups (P = NS during recovery). Ra correlated with NE (r2 = 0.92 ± 0.02, P < 0.02) from minute 30 of exercise to minute 20 of recovery. Furthermore, the differences in Ra and in NE (between the two studies for each subject) correlated (mean r2 = 0.80 ± 0.04, P < 0.05 for 6 of 7 subjects) from minute 30 of exercise to minute 20 of recovery.



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  		Figure 4. Plasma Epi (A) and NE (B) during baseline, 40 min of 50% O2max exercise with and without NE infusion from minute 30–40, and recovery periods. Data are presented as in Fig. 1Go.

 
Neither blood lactate (Fig. 5AGo) nor pyruvate (Fig. 5BGo) were different at baseline or during the first 30 min. During NE infusion, lactate increased (P = 0.003 by ANOVA), but the slight rise in pyruvate fell short of significance (P = 0.08). Neither differed significantly from CON. Only pyruvate remained higher in NE (P = 0.047 by ANOVA) during recovery. Mean plasma FFA (Fig. 5cGo) did not change significantly during exercise, and NE had no effect. An early rise occurred in recovery, followed by a decline to baseline, and a later rise, none of which were different between groups.



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  		Figure 5. Blood lactate (A), pyruvate (B), and FFA (C) during baseline, 40 min of 50% O2max exercise with and without NE infusion from minutes 30–40, and recovery periods. Data are presented as in Fig. 1Go.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Whether the rise in circulating NE levels during IE contributes to the marked increment in hepatic glucose production in IE is not established. The regulation of Ra during IE has been proposed to occur via a feed-forward mechanism (20, 15), with previous results from our group suggesting the plasma catecholamines as the primary mediators of this mechanism, repeatedly demonstrating highly significant correlations of both Epi and NE with Ra during IE (16, 17, 18, 19, 22, 25). However, this hypothesis remains controversial (4, 5, 24, 30, 31, 32). The present results confirm that circulating NE, when present in relevant plasma concentrations, is able to produce a rapid and sizable Ra increment above that of moderate exercise. This implies that at least part of NE’s metabolic effects during exercise occur through a hormonal mechanism and that the endogenous plasma NE response in IE could be a major contributor to the Ra response.

Quantitative analysis and interpretation of the responses require reference to those of exercise at more than 80% O2max (16). The plasma NE levels achieved during this study (~15 nM), although similar to levels seen at minute 10 of a 14-min bout of IE, were less than the peak IE levels achieved at exhaustion (~30–35 nM). The absolute Ra levels in this study (~6.3–7.5 mg/kg·min) approach, but do not reach, those at minute 10 of IE (~8–9 mg/kg·min) and are well short of peak Ra values of 12–14 mg/kg·min at exhaustion in IE. Even if no further Ra increment were to have resulted from obtaining comparable NE levels, NE could still have induced approximately 33% of the Ra increment of IE, reinforcing its potential role. Clearly, however, systemic NE is not the sole factor involved in stimulating Ra during IE. We have recently demonstrated that Epi can induce a portion (~50%) of the Ra of IE (23). Thus, if the effects of circulating NE and Epi were additive, they could account for the entire Ra increment, or all but a small contribution by the changes in the IRG to IRI molar ratio.

The current experiment cannot quantify the contribution of NE released directly within the liver. Because most of the NE released from sympathetic nerve terminals is disposed of through either axonal reuptake or local metabolism, with a smaller portion spilling over into plasma (33), a significant hepatic synaptic cleft-to-plasma NE gradient should exist during the endogenous sympathetic activation of IE. Thus, given the even-higher plasma NE in IE, hepatic sympathetic terminal NE levels in the current study would be predicted to be lower than in IE. This is further consistent with an important hormonal role for NE.

A contribution of hepatic sympathetic nerve stimulation of Ra during exercise is nonetheless likely, based on increases in glycogenolysis with stimulation (as cited in 34), as well as rising glycemia with hepatic nerve stimulation in humans (1). Some exercise studies have been interpreted as failing to support this, however. Surgical hepatic denervation did not lead to attenuation of glycemic response in exercising rats (2) or of glucose production in rats (35), dogs (36), or guinea pigs (3). Unaltered responses were obtained in humans with a liver transplant (4) or undergoing celiac blockade (5). In all these studies, NE levels were identical between the control and intervention groups. Thus, if NE were functioning primarily through an hormonal mechanism, no effect would be predicted. Alternately, compensation from Epi was also possible (3, 4, 36). Additionally, the two human studies could not definitively exclude a role for NE, because they involved absolute exercise intensities that were less (4, 5) than the thresholds at which we postulate that catecholamines become significant mediators of the Ra response. These and other studies, interpreted as not supporting a catecholamine-mediation hypothesis (30, 31), are discussed elsewhere (23). Furthermore, studies that have supported the role of sympathetic neural NE in mediating the exercise Ra response have been indirect, showing either the absence of hypoglycemia during 60% O2max exercise in bilaterally adrenalectomized, islet cell-clamped subjects (37) or the absence of attenuation of the Ra increment at 80% O2max in islet cell-clamped subjects in whom Epi rose only 4-fold (30). Thus, neither of these studies is a definitive demonstration for a neurotransmitter- vs. hormone-based mechanism of NE action.

Whereas peripheral venous NE infusions (6, 7, 38), including the present study, have shown lesser Ra responses than equivalent Epi infusions, they may lead to underestimates of the effect of circulating NE. The hormonal effect of NE at the liver is determined by its portal vein and hepatic arterial levels. Arterial concentration will be the result of endogenous systemic spillover and the exogenous infusion rate, whereas portal concentrations are determined by whether net splanchnic release or uptake occurs. Nonhepatic splanchnic NE release increases from rest, with progressively higher intensities of exercise (39), whereas uptake may not. Furthermore, a change in portal concentrations may have greater impact than a similar difference in arterial concentrations (40). For the forgoing reasons, the balance between NE actions in stimulating hepatic glucose output in IE remains uncertain. That is, it could play significant roles as both a neurotransmitter and a hormone, implying further redundancy in the system than that suggested by adrenergic blocker studies that implicate both {alpha} and ß receptors (18, 19, 41).

Although NE infusion increased the IRG to IRI molar ratio by 20%, even the corresponding portal venous increment (34, 42, 43) is unlikely to have contributed in a major way to the Ra response. In addition, it occurred with a time-course inappropriate to explain the Ra response, as in other settings (16, 23). Whereas the IRG-to-IRI ratio increased progressively (Fig. 3CGo), the Ra response was a rapid rise to near-maximum (Fig. 2AGo). In contrast, circulating NE closely corresponded to the Ra time course (Fig. 4BGo). The most compelling argument for portal IRG-to-IRI changes being minor contributors to Ra in IE is that, with the islet cell clamp, the Ra response was unaffected (17). In other studies of NE infusion (6, 7), its effects on Ra were not mediated through changes in IRG-to-IRI ratio.

Both NE (6, 44, 45) and Epi (46, 47, 48) are generally viewed as having an inhibitory effect on glucose disposal at rest, though not always (7). We are unaware of prior studies of the effect of NE on Rd during exercise. NE infusion led to considerable increments of both Rd and MCR, with the former essentially matching Ra, resulting in minimal glycemic change. Epi infusion during exercise gave analogous responses (23). It could be viewed as advantageous for the catecholamines to have different effects on Rd between IE- and severe nonexercise-related metabolic stresses. In a dog model of central carbachol-induced stress, Rd rose, suggesting that the integrated stress response may have effects that differ from catecholamine infusions, even at rest (41, 49). FFA could play a role in suppression of glucose use (45, 50), although this is controversial (44). However, plasma FFA were not affected by the NE infusion in this study; they fall during IE (16), whereas they rise in nonexercise forms of stress, so they could mediate part of these differential effects. Part of the NE inhibitory effect on Rd at rest is possibly attributable to {alpha}-adrenergic vasoconstriction (51), which does not occur during exercise. NE stimulates glucose transport in brown adipocytes (52). In contrast, glucose uptake during contraction in porcine vascular smooth muscle is reduced by NE (53). Finally, the possibility of an as-yet-unidentified signaling mechanism between liver and muscle, that causes increased Rd when Ra increases, cannot be excluded, nor can an effect of the catecholamines on muscular contractions (though O2 did not change during the infusions).

The increased Rd with catecholamine infusions is surprising, in light of augmented Rd with ß-blockade (19), and unaltered Rd with {alpha}-blockade (18) in IE. This could be explained by redundant {alpha} and ß effects on Rd during IE, given the higher catecholamine levels caused by adrenergic blockade. If the increased Rd were entering muscle, it would have to affect the balance between muscle glycogenolysis and circulating glucose, as energy sources, and the metabolic fate of the pyruvate generated. More appears in the circulation as lactate, which could account for the unchanged RER and O2, and is consistent with the unchanged plasma FFA. Alternately, the increased Rd could be taken up elsewhere, though it seems improbable that it would be directed to storage under the conditions of the experiment.

Several responses to NE vs. Epi (23) infusion during moderate exercise differed. Peak NE levels (~15 nM) were higher than those of Epi (~9 nM) with the same 0.1 µg/kg·min infusion rate. Plasma levels attained were lower than peak NE in IE (~30–35 nM), whereas those of Epi were higher than peak levels in IE (~ 4–7 nM). Because the Ra response generated by Epi (~8.5 mg/kg·min) exceeded that by NE (~7.5 mg/kg·min) despite the lower Epi levels, it is a more potent stimulator of Ra as a circulating hormone. Epi infusion generated a greater hyperglycemic response than did NE, resulting from a much greater increment in Ra than in Rd for the former but not the latter. This may relate to a greater degree of ß-adrenergic restraint of the Rd increment with Epi (19). Thus, the sum of the NE plus Epi responses in IE explains the greater Ra, which exceeds the rise in Rd by more than that in the infusion studies, accounting for the even-greater hyperglycemia in IE.

In summary, peripheral venous NE infusion during moderate exercise leads to a significant increment in glucose Ra. It demonstrates that systemic NE is capable of contributing directly to Ra during exercise, and it suggests, but does not prove, that a substantial part of the Ra effect of NE may be occurring through a hormonal (as opposed to a neurotransmitter) mechanism. It also adds support to the view that the pronounced rise of plasma catecholamines during IE could be the primary drive behind the marked stimulation of Ra. Additionally, as with Epi, the effect of NE on glucose uptake and clearance during exercise seems to differ from its effect at rest, becoming stimulatory rather than inhibitory.


   Acknowledgments
 
We gratefully acknowledge the contributions of the following, whose roles were essential to this research: Mary Shingler, RN (of the Royal Victoria Hospital Clinical Investigation Unit); Madeleine Giroux, RT, and Marie Lamarche, BSc, and Ginette Sabourin, BSc, for technical assistance in Montreal; Marla Smith, BS, for technical assistance in Ann Arbor; and Josie Plescia and Janice Choma for secretarial assistance.


   Footnotes
 
1 This work was supported by Grants MT9581 (to E.B.M.) and MT2197 (to M.V.) from the Medical Research Council of Canada. The laboratory of Jeffrey B. Halter is supported by the Medical Research Service of the U.S. Department of Veterans Affairs. Back

2 A Summer Research Student in the Faculty of Medicine, McGill University. Back

Received October 26, 2000.

Revised January 23, 2001.

Accepted January 30, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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