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(Circulation. 2003;108:2653.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Effects of Intense and Prolonged Exercise on Insulin Sensitivity and Glycogen Metabolism in Hypertensive Subjects

Caroline Rhéaume, MSc; Paulo-Henrique Waib, MD, PhD; N’Guessan Kouamé, PhD; André Nadeau, MD; Yves Lacourcière, MD; Denis R. Joanisse, PhD; Jean-Aimé Simoneau, PhD; Jean Cléroux, PhD

From the Hypertension (C.R., P.-H.W., N.K., Y.L., J.C.) and Diabetes (A.N.) Research Units, Laval University Hospital Research Center, and the Kinesiology Division, Laval University (D.R.J., J.-A.S.), Québec, Canada.

Correspondence to Jean Cléroux, PhD, HDQ Research Center, 9, rue McMahon, Québec, Québec, Canada G1R 2J6. E-mail jean.cleroux{at}crhdq.ulaval.ca

Received October 17, 2002; de novo received April 4, 2003; revision received August 14, 2003; accepted August 17, 2003.

	Abstract

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Background— The information that insulin sensitivity and glycogen synthesis are reduced in hypertension arises primarily from studies using insulin infusions. Whether glycogen metabolism is actually altered in a physiological condition, such as during and after prolonged exercise, is currently unknown.

Methods and Results— To examine this issue, 9 hypertensive and 11 normotensive subjects were evaluated on a rest day and after intense and prolonged exercise on a separate day. Insulin sensitivity and hemodynamic variables were measured on both days. On the exercise day, whole-body substrate utilization was assessed and muscle biopsies were taken in the leg at baseline, immediately after exercise, and 2.5 and 4 hours after exercise. Insulin sensitivity at rest was lower in hypertensive than normotensive subjects (P<0.05) and increased after exercise in normotensive (P<0.01) but not in hypertensive (P=NS) subjects. Leg blood flow increased after exercise in both groups but to a lesser extent in hypertensive than normotensive subjects. Baseline glycogen content and maximal glycogen synthase activity were higher in hypertensive than normotensive subjects (P<0.001). Glycogen concentration decreased relatively less (-35 versus -66%) and returned to baseline levels faster in hypertensive subjects after exercise. Hypertensive subjects used 40% less carbohydrates during exercise (P<0.001) at the expense of greater free fatty acid oxidation.

Conclusions— It is concluded that increased intramuscular glycogen storage and resynthesis in hypertension are independent of blood flow and may represent compensatory mechanisms for the reduced insulin sensitivity and carbohydrate metabolism in this condition.

Key Words: exercise • insulin • glycogen • hypertension

	Introduction

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Several epidemiological studies have indicated that hypertension is an insulin-resistant state independent of obesity.^1,2 It has been shown that whole-body insulin-induced glucose uptake is reduced in hypertensive populations.^3,4 The impairment of insulin-mediated glucose utilization in hypertension appears to be restricted principally to nonoxidative glucose disposal, ie, mainly glycogen synthesis in skeletal muscles.^3,5–8 Defects in this pathway can alter the metabolism of glucose and contribute to insulin resistance in muscle tissue.⁹ Studies using intra-arterial infusions of insulin in the forearm have found smaller arteriovenous glucose differences in hypertensive than in normotensive subjects,¹⁰ suggesting that glycogen synthesis in skeletal muscles is lower in hypertensive patients, but the physiological relevance of these findings has not been clearly established.

It was proposed that the pervasive relationship between blood pressure elevation and decreased glucose extraction by skeletal muscle may be secondary to hemodynamic factors.^11,12 Insulin-induced glucose uptake during a hyperinsulinemic euglycemic clamp was positively correlated to capillary density and to percent slow-twitch fiber content of different muscles.¹³ Slow-twitch fibers have a higher oxidative capacity, insulin binding, insulin sensitivity, basal glucose uptake, and a rich capillary supply than fast-twitch fibers.^14,15 Because a reduced proportion of slow-twitch fibers was reported in hypertensive individuals,¹⁶ this alteration could contribute to the increased insulin resistance in hypertension.^17,18 These observations are consistent with the concept that insulin sensitivity could be related to skeletal muscle blood flow and relative muscle fiber type.

We recently reported that changes in hemodynamics did not contribute to the increased insulin sensitivity found after 30 minutes of mild exercise in hypertensive subjects.¹⁹ In the present study, we used a more prolonged and intense exercise protocol to reduce intramuscular glycogen content. We also examined exercise substrate metabolism and postexercise hemodynamics, insulin sensitivity, and glycogen resynthesis in hypertensive and normotensive subjects. The primary goals of the present study were therefore to determine whether the insulin-resistant state of hypertension was associated with altered intramuscular glycogen stores and/or substrate utilization during exercise as well as slower rates of glycogen resynthesis after prolonged exercise. Secondary goals were to determine the role of skeletal muscle fiber type distribution, blood flow, and glycogen synthase activity in any alteration in glycogen synthesis in hypertension.

	Methods

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Patients with mild to moderate essential hypertension and age-matched normotensive subjects gave their written informed consent to participate in this study. The procedures followed were in accordance with our institutional guidelines and the protocol approved by Laval University Hospital Research Center’s Ethics Committee on Human Research. All hypertensive subjects underwent a 4-week screening period during which they visited the Hypertension Clinic at our institution weekly, and antihypertensive medication was stopped 1 month before the study in previously treated patients. Peak oxygen uptake was measured 1 week before the laboratory evaluations.

The subjects underwent 2 evaluations on separate days at 1-week intervals in random order (Figure 1). On the control rest day and on the exercise day, insulin sensitivity and hemodynamic variables were measured in subjects fasting from midnight on. Hemodynamic variables measured were blood pressure, heart rate, forearm blood flow, and leg blood flow. On the exercise day, whole-body carbohydrate and lipid metabolisms were assessed during exercise, and muscle biopsies were taken together with hemodynamic measurements at baseline, immediately after exercise, and 2.5 and 4 hours after exercise (Figure 1). All subjects exercised on a cycle ergometer at 70% of peak oxygen uptake during 90 minutes according to the protocol of Boulay et al.²⁰ During exercise, blood samples were taken to measure insulinemia and glycemia. Three hours after the end of exercise, all subjects received a second intravenous glucose bolus (identical to that given during the measurement of insulin sensitivity) to help replenish muscle glycogen stores. These techniques are explained briefly below, because most have been described in detail elsewhere.^19,21

View larger version (39K): [in this window] [in a new window]   Figure 1. Illustration of study protocol. Insulin sensitivity and hemodynamic variables were measured (1) on a control rest day and (2) on an exercise day in random order. On exercise day, all subjects exercised on a cycle ergometer at 70% of Omax during 90 minutes. Muscle biopsies were made before exercise, immediately after exercise, and 2.5 and 4 hours after exercise. An intravenous glucose bolus was given on control rest day, 0.5 hour after end of exercise, and 3 hours after end of exercise.

Measurements
Oxygen uptake and carbon dioxide production were determined by analysis of expired gases. These values were used to calculate the respiratory exchange ratio to assess amounts of carbohydrates and fatty acids consumed during exercise.²² Peak oxygen uptake was measured during an increased work test schedule on a cycle ergometer with 50-W increments every 2 minutes until volitional exhaustion. Blood pressure (mercury sphygmomanometer), heart rate (from ECG), and forearm and leg blood flow (plethysmography) were measured in sequence.

Insulin sensitivity was assessed with the method of Galvin et al²³ from the ratio of glucose disappearance rate (K_g) over insulin area under the curve (I_AUC) during an intravenous glucose tolerance test as previously described.¹⁹ The intravenous glucose tolerance test consisted of the injection of 20 g/m² body surface area of 50% dextrose in an antecubital vein within 3 minutes (Figure 1). Glucosuria was measured over a period of 2 hours after the glucose bolus to assess whether significant amounts were eliminated via this route and whether differences were present between normotensive and hypertensive subjects.

Needle muscle biopsies were performed 4 times in the vastus lateralis under local anesthesia (1% lidocaine hydrochloride) on the exercise day (Figure 1) according to the method of Bergstrom.²⁴ Percentage and area of type I, IIA, and IIB fibers were established by the myofibrillar ATPase staining technique. Glycogen concentration in specific fiber types was determined by staining transverse sections with periodic acid–Schiff reagent. Glycogen-stained sections were matched with serial sections stained for myosin ATPase for determination of exercise-induced depletion patterns in specific fiber types. Glycogen concentrations are expressed in relative units (RU) of staining intensity. Glycogen content was also measured by calculating an index that takes into account the amount of glycogen (RU) in each fiber type, the surface area (µm²) of each fiber type, and the proportion (percentage) of each fiber type with the following equation: [(glycogen type Ixsurface type Ix% fiber type I)+ (glycogen type IIAxsurface type IIAx% fiber type IIA)+(glycogen type IIBxsurface type IIBx% fiber type IIB)]x10^-6.

Glycogen synthase activity was measured as described by Schalin-Jantti et al,²⁵ a modification of the method of Hornbrook et al.²⁶ Glycogen synthase activity is expressed in micromoles of NAD formed per minute per gram wet weight of muscle tissue. Glycogen synthase activity was measured at 0.1 mmol/L of G6P substrate and at 10 mmol/L of G6P substrate. The ratio of activity determined at 0.1 mmol/L of G6P to maximal activity determined at 10 mmol/L of G6P (the fractional activity) reflects dephosphorylation and activation of glycogen synthase.

Statistical Analysis
Data are expressed as mean±SEM. Results were analyzed by ANOVA for repeated measurements²⁷ considering the interaction between time (of measurement of a given variable) and group (hypertensive and normotensive). When a significant (P<0.05) F ratio was found, Fisher’s test was used to locate significant differences.

	Results

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Nine male hypertensive subjects with mild to moderate hypertension and 11 normotensive subjects participated in this study. Hypertensive subjects were similar to normotensives in terms of age (44±3 and 40±2 years, respectively), body weight (85±2 and 82±5 kg), height (176±2 and 178±2 cm), body surface area (2.0±0.1 and 2.0±0.1 m²), and peak oxygen uptake (45±3 and 43±2 mL/kg per minute). Clinic supine blood pressure of hypertensive subjects was higher than that of normotensive subjects (142±4/93±3 and 117±3/75±2 mm Hg, respectively, P<0.001). Four hypertensive subjects (44%) and 6 normotensive subjects (55%) had a normal glucose tolerance on the basis of a glucose disappearance rate (K_g) >1.5 min^-1, 3 hypertensive subjects (33%) and 5 normotensive subjects (45%) had an intermediate glucose tolerance (1.0<K_g<1.5 min^-1), and 2 hypertensive subjects (22%) had glucose intolerance (K_g<1.0 min^-1).

During the 90-minute exercise period, hypertensive and normotensive subjects exercised at similar workloads (135±5 and 152±9 W, respectively, P=NS), oxygen uptake (25±12 and 25±12 mL/kg per minute), and percent peak oxygen uptake (68±2 and 73±2%, P=NS). Hypertensive subjects had a significantly lower respiratory exchange ratio than normotensives (0.80±0.01 versus 0.87±0.01, respectively, P<0.001), indicating that they used 40% less carbohydrates over the 90-minute exercise period (102±10 versus 174±11 g, P<0.001) at the expense of greater free fatty acid oxidation (76±5 versus 49±4 g, P<0.001). Thus, 40% and 67% of the energy cost of exercise (1250 kcal) was derived from carbohydrate metabolism in hypertensive and normotensive subjects, respectively, and 60% and 33% from free fatty acid oxidation.

Hemodynamic Results
Hemodynamic variables measured on the exercise day appear in Table 1 (baseline hemodynamic variables measured on the control rest day were similar, P=NS, data not shown). Blood pressure was higher in hypertensive than normotensive subjects (P<0.001). Systolic and diastolic blood pressures were significantly lower immediately after exercise than at baseline in both groups. Diastolic blood pressure was reduced 2.5 and 4 hours after exercise in normotensive but only at 2.5 hours in hypertensive subjects. Heart rate was similar in both groups, and the small tachycardia after exercise was similar in both groups (P=NS). Forearm and leg blood flows were respectively similar in both groups (P=NS). Forearm blood flow decreased significantly immediately after exercise and 2.5 and 4 hours after exercise in hypertensives, whereas it remained unchanged in normotensives compared with baseline (P<0.05). Leg blood flow increased only 2.5 hours after exercise (P<0.05) in hypertensives but had already done so immediately after exercise in normotensives. Reciprocal changes in vascular resistance relative to those in blood flow were found in both groups.

View this table: [in this window] [in a new window]   TABLE 1. Hemodynamic Variables Before Exercise (Baseline), Immediately After Exercise, and 2.5 and 4 Hours After Exercise in Normotensive and Hypertensive Subjects During the Exercise Day

Metabolic Results
Insulin Sensitivity
Baseline plasma glucose was not different in hypertensive and normotensive subjects on the control rest day (5.4±0.2 and 5.2±0.2 mmol/L, respectively, P=NS) and on the exercise day (5.2±0.2 and 5.0±0.1 mmol/L, respectively, P=NS), whereas baseline plasma insulin was higher in hypertensives than normotensives on the control rest day (60±5 and 50±4 pmol/L, respectively, P<0.05) and the exercise day (70±10 and 31±5 pmol/L, respectively, P<0.01). At the end of 90 minutes of intense exercise, glycemia was unchanged in hypertensive subjects (5.4±0.3 mmol/L, P=NS) but was significantly reduced in normotensives (4.6±0.2 mmol/L, P<0.5). Insulinemia was reduced at the end of exercise in both groups, but to a lesser extent in hypertensive than normotensive subjects (42±8 and 16±2 pmol/L, respectively, both P<0.01). At the beginning of insulin sensitivity assessment (before the glucose bolus), glucose and insulin levels were not different (P=NS) from baseline values in each group (data not shown).

Insulin sensitivity (K_g/I_AUC) was significantly lower in hypertensive than normotensive subjects on the control rest day (Figure 2). Insulin sensitivity increased after exercise in normotensive subjects but not in hypertensive subjects (Figure 2). Glucose disappearance rate (K_g) was similar in hypertensive and normotensive subjects on the control rest day (1.6±0.3 and 1.7±0.1 min^-1, respectively, P=NS) but was significantly lower in hypertensive than normotensive subjects after exercise (1.3±0.3 and 1.9±0.3 min^-1, respectively, P<0.05). Plasma insulin levels and I_AUCs were similar in both groups during the intravenous glucose tolerance test on the control rest (I_AUC values: HT, 14 578±2604 versus NT, 10 561±1348 pmol/Lxmin, P=NS) but were significantly higher in hypertensives than in normotensives after exercise (I_AUC values: HT, 13 007±2091 and NT, 8405±965 pmol/Lxmin, P<0.05).

View larger version (15K): [in this window] [in a new window]   Figure 2. Line graphs illustrate individual insulin sensitivities measured on control rest day and after exercise in normotensive (NT) and hypertensive (HT) subjects. Circles lying outside individual data points represent mean±SEM. ** indicates significant differences at P<0.01 from respective control value; and indicate significant differences at P<0.05 and P<0.01 from respective value in normotensive subjects.

Glucosuria measured over a period of 2 hours after the glucose bolus was not different in hypertensive and normotensive subjects (control rest day values: 2.3±0.5 and 2.1±0.2 g, respectively, P=NS) and was not affected by the previous exercise (P=NS).

Muscle Characteristics and Glycogen Content
The proportion, the surface area of different fiber types, and the number of capillaries around the different muscle fibers were similar in both groups of subjects (Table 2). Fasting muscle glycogen concentration in each fiber type (Figure 3) and the index of whole muscle glycogen content (Table 3) were higher in hypertensive than normotensive subjects (P<0.001). Glycogen content decreased immediately after exercise in both groups (P<0.05). Muscle glycogen tended to decrease less in hypertensives (-34±8 versus -46±7 RU, P=0.13), and this represented a significantly smaller proportion of muscle glycogen reserves in hypertensive than normotensive subjects (-35±8 versus -66±8%, P<0.01). Whereas glycogen remained below baseline up to 4 hours after exercise in normotensive subjects, it increased back to levels not different from baseline in hypertensive subjects 4 hours after exercise (Table 3 and Figure 3).

View this table: [in this window] [in a new window]   TABLE 2. Muscle Characteristics of Hypertensive and Normotensive Subjects

View larger version (17K): [in this window] [in a new window]   Figure 3. Glycogen content (RU) of type I fibers (A), type IIa fibers (B), and IIb fibers (C) at baseline (Base), immediately after exercise (0), and 2.5 and 4 hours after exercise. indicates significant differences (ANOVA) at P<0.001 between hypertensive and normotensive subjects.

View this table: [in this window] [in a new window]   TABLE 3. Skeletal Muscle Glycogen Content Index Integrating Amount of Glycogen, Surface Area, and Proportion of Each Fiber Type at Baseline and After Exercise in Normotensive and Hypertensive Subjects

Glycogen Synthase
Glycogen synthase measured at 0.1 mmol/L of G6P was not different between groups (P=0.89) and increased to a similar extent after exercise in both groups (P<0.001) (Figure 4). Total glycogen synthase measured at 10 mmol/L of G6P substrate was higher in hypertensive than normotensive subjects and was not affected by exercise (P=NS). As a consequence, the fractional activity of glycogen synthase increased after exercise in both groups (P<0.001) but to a lesser extent (P<0.001) in hypertensive subjects (Figure 4).

View larger version (17K): [in this window] [in a new window]   Figure 4. Glycogen synthase activity measured at 0.1 mmol/L of G6P substrate (A), at 10 mmol/L of G6P substrate (B), and fractional activity (percent ratio of 2 activities, C) in muscle biopsy samples taken at baseline (Base), immediately after exercise (0), and 2.5 and 4 hours after exercise. indicates significant differences (ANOVA) at P<0.001 between hypertensive and normotensive subjects.

Relationships Between Hemodynamic and Metabolic Results
Insulin sensitivity did not correlate with percent composition of muscle fiber type I in both groups (r=0.23, P=0.33). Glycogen content index did not correlate with leg blood flow in any situation (data not shown). A significant and inverse correlation coefficient was found between insulin sensitivity and maximal glycogen synthase activity after exercise (r=0.47, P<0.05) but not before exercise (r=0.05, P=NS).

	Discussion

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The results of our study clearly show, first, that whole-body carbohydrate utilization is reduced, that skeletal muscle glycogen depletion is blunted, and that its repletion is more pronounced after prolonged exercise in hypertension. Baseline and postexercise glycogen contents were higher in hypertensive subjects. Second, total glycogen synthase activity is higher in hypertensive than normotensive subjects. Third, similar muscle capillaries and muscle fiber type distributions were found in both groups. These observations will be discussed in the following paragraphs.

The present results confirm that hypertensive subjects are insulin-resistant compared with normotensive subjects.^10,19,28 Studies using insulin infusions have indicated that skeletal muscle was presumably the main site of insulin resistance in hypertension and that nonoxidative glucose disposal (ie, mainly glycogen synthesis) was impaired.^3,5–8 Our hypertensive subjects had elevated baseline and postexercise glycogen concentrations and rates of resynthesis in skeletal muscles after prolonged exercise. The increased capacity for glycogen resynthesis, ie, higher maximal glycogen synthase activity, may be related to direct factors and/or represent compensatory adaptations to insulin resistance. Direct factors include higher plasma glucose and insulin levels in the postexercise period. This is supported by the fact that glycogen resynthesis occurred importantly in type I fibers, ie, those particularly sensitive to insulin. Alternatively, (1) the reduced insulin-induced glucose transport (suggested by the inverse correlation between glycogen synthase and insulin sensitivity after exercise) and/or (2) the reduced carbohydrate metabolism during exercise and/or (3) the reduced ability to mobilize the active fraction of glycogen synthase may promote a compensatory increase in glycogen resynthesis capacity.

A recent study by Solini et al⁹ reported normal levels of glycogen and glycogen synthase activity in cultured skin fibroblasts of hypertensive subjects with microalbuminuria and reduced levels in diabetic subjects with and without hypertension. Taken together, these results could indicate an early compensatory adaptation in essential hypertension, ie, increased intramuscular glycogen synthesis and glycogen content (present study) that disappears in conditions with progressively greater insulin resistance, such as hypertension with microalbuminuria and diabetes (study by Solini et al⁹). The results of our study do not support the hemodynamic hypothesis of insulin resistance in hypertension,^11,12 because both groups examined were found to have similar muscle capillaries, muscle fiber type distributions, and resting muscle blood flows, whereas insulin resistance was reduced in hypertensive subjects compared with normotensives. It is possible that alterations of capillaries were undetected with the histochemical method used in the present study. Hernandez et al²⁹ did not find changes in capillaries with similar histochemical methods but found abnormal capillary endothelial cells with electron microscopy. However, vasodilatation was reduced in hypertensive subjects during the hours after prolonged exercise, whereas glycogen resynthesis occurred faster than in normotensive subjects. Furthermore, glycogen content did not correlate with leg blood flow in either group on any occasion.

Our present and previous results underline contrasting adaptations in normotensive and hypertensive subjects after exercise, depending on exercise intensity. Normotensive subjects did not demonstrate an increase in insulin sensitivity after mild-intensity exercise¹⁹ but did so after higher-intensity exercise (present study). These finding agree with other reports in the literature as discussed previously.¹⁹ In hypertensive subjects, we found an increase in insulin sensitivity after mild-intensity exercise in our previous study,¹⁹ whereas no such change was found after intense and prolonged exercise. The absence of an effect on insulin sensitivity in hypertensive patients could be secondary to the lesser glycogen depletion and/or the higher free fatty mobilization and/or the carryover of the higher adrenergic response after intense and prolonged exercise. The mechanisms underlying these contrasting adaptations in hypertension merit further investigation.

In summary, whole-body carbohydrate and skeletal muscle glycogen metabolisms are reduced during intense exercise in hypertension, and postexercise glycogen resynthesis is enhanced. Elevated intramuscular glycogen content and resynthesis in hypertension do not appear to be related to either chronic or postexercise vasodilatory changes. It is concluded that increased intramuscular glycogen storage and resynthesis in hypertension are independent of blood flow and may be related to higher plasma glucose and insulin levels in the postexercise period and/or represent compensatory mechanisms for the reduced insulin sensitivity and carbohydrate metabolism in this condition.

	Acknowledgments

 
This work was supported by grants to Dr Cléroux from the Heart and Stroke Foundation of Canada, la Fondation des maladies du coeur du Québec, and the Natural Sciences and Engineering Research Council of Canada. Dr P.H. Waib was a recipient of a fellowship from the Fundacao de Amparo à Pesquisa do Estado de Sao Paulo, Brazil. C. Rhéaume was supported by studentships from the Heart and Stroke Foundation of Canada, the Medical Research Council of Canada, le Fonds de la recherche en santé du Québec, and the Fonds pour la formation de chercheurs et l’aide à la recherche. We thank Rachelle Duchesne and Marie Tremblay for expert assistance in performing plasma glucose and insulin determinations and Mireille Marceau, Yves Gélinas, and Jean-François Néron for expert technical assistance in various aspects of this study. Dr Germain Thériault’s collaboration in performing initial biopsies is gratefully acknowledged.

	Footnotes

 
Deceased.

	References

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