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Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721-0093
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hypertension is often accompanied by insulin resistance of skeletal muscle glucose transport. The male heterozygous TG(mREN2)27 rat, which harbors a mouse transgene for renin, displays local elevations in the renin-angiotensin system and exhibits markedly elevated systolic blood pressure (SBP). The present study was undertaken to characterize insulin-stimulated skeletal muscle glucose transport in male heterozygous TG(mREN2)27 rats and to evaluate the effect of voluntary exercise training on SBP and skeletal muscle glucose transport. Compared with normotensive Sprague-Dawley rats, TG(mREN2)27 rats displayed a 53% elevation (P < 0.05) in SBP, a twofold increase in plasma free fatty acid levels, and an exaggerated insulin response during an oral glucose tolerance test. Moreover, insulin-mediated glucose transport (2-deoxyglucose uptake) in isolated epitrochlearis and soleus muscles of TG(mREN2)27 animals was 33 and 43% less, respectively, than in Sprague-Dawley controls. TG(mREN2)27 rats ran voluntarily for 6 wk and achieved daily running distances of 6-7 km over the final 3 wk. Training caused a 36% increase in peak aerobic capacity and a 16% reduction in resting SBP. Fasting plasma insulin (21%) and free fatty acid (34%) levels were reduced in the trained TG(mREN2)27 rats. Whole body glucose tolerance was improved in the trained TG(mREN2)27 rats and was associated with increases of 39 and 50% in insulin-mediated glucose transport in epitrochlearis and soleus muscles, respectively. Whole muscle GLUT-4 protein was increased in the soleus (23%), but not in the epitrochlearis, of trained TG(mREN2)27 rats. These data indicate that the male heterozygous TG(mREN2)27 rat is a model of both hypertension and insulin resistance. Importantly, both of these defects can be beneficially modified by voluntary exercise training.
skeletal muscle glucose transport; renin-angiotensin system; glucose tolerance; glucose transporter-4
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INSULIN RESISTANCE OF SKELETAL muscle glucose disposal is frequently present in conditions of cardiovascular dysfunction, such as hypertension (4, 28) and cardiac failure (15, 21, 25, 36). Whereas the exact relationship between insulin resistance and cardiovascular disease risk factors remains to be firmly established, the link may be through the compensatory hyperinsulinemia that characterizes most insulin-resistant states (7, 28).
An effective course of action in treating individuals with essential hypertension is the implementation of regular physical activity. Endurance exercise training can lower resting blood pressure in individuals with hypertension and left ventricular hypertrophy (9, 17, 26) and also leads to improvements in glucose tolerance and insulin action on skeletal muscle glucose metabolism in insulin-resistant subjects with impaired glucose tolerance or Type 2 diabetes (16, 32). One potential mechanism for this adaptive response to training by Type 2 diabetics is an upregulation of GLUT-4 protein expression in skeletal muscle (16).
The TG(mREN2)27 rat is a transgenic animal that harbors the mouse
Ren-2 renin gene (22). This animal model
develops severe fulminant hypertension, and the male heterozygous
TG(mREN2)27 rat exhibits resting systolic blood pressures (SBP) of
200 mmHg by 10 wk of age (18, 20). The pathogenesis of
the hypertension is likely a consequence of increases in the local
renin-angiotensin system, which culminates in elevated tissue
angiotensin II levels (20). Importantly, elevations in
angiotensin II have also been associated with the development of
insulin resistance of skeletal muscle glucose transport activity
(30).
There is conflicting information in the literature as to whether the TG(mREN2)27 rat exhibits defects in insulin action. Whereas Vettor et al. (40) found no evidence of insulin resistance in mature, female heterozygous TG(mREN2)27 rats, Holness and Sugden (14) found, in female TG(mREN2)27 rats, that the fasting plasma insulin concentration was 63% greater and the plasma glucose concentration was 22% lower relative to normotensive rats. In addition, the metabolic clearance rate for glucose and in vivo glucose utilization rates in oxidative skeletal muscles were significantly lower in the TG(mREN2)27 rats relative to control animals (14). This latter study provides clear evidence of insulin resistance in the female TG(mREN2)27 rat. However, to our knowledge, there have been no published investigations of insulin action in the male heterozygous TG(mREN2)27 rat, which displays greater elevations in the renin-angiotensin system compared with female heterozygous TG(mREN2)27 rats (20).
In the context of the foregoing information, the following hypotheses were tested in the present investigation: 1) the hypertensive male heterozygous TG(mREN2)27 rat will display evidence of whole body glucose intolerance and decreased insulin sensitivity, skeletal muscle insulin resistance, and dyslipidemia; and 2) the implementation of voluntary exercise training will lower SBP and simultaneously elicit beneficial modulation of whole body glucose tolerance and insulin sensitivity, skeletal muscle glucose transport activity, and plasma free fatty acid (FFA) levels.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Male heterozygous TG(mREN2)27 and Sprague-Dawley rats were received from the Hypertension and Vascular Disease Center of Bowman Gray School of Medicine at Wake Forest University (Winston-Salem, NC) at ~6 wk of age. The TG(mREN2)27 rats and nontransgenic Sprague-Dawley control rats were both derived from Hannover Sprague-Dawley rats housed in the breeding colony at this institute. All animals were housed in a temperature-controlled room (20-22°C) with a 12:12-h light-dark cycle (lights on from 7 AM to 7 PM) at the Central Animal Facility of the University of Arizona. The animals had free access to chow (Purina, St. Louis, MO) and water. All procedures were approved by the University of Arizona Animal Use and Care Committee.Experimental Design
Study 1: Assessment of insulin resistance. Animals were acclimated to the tail-cuff plethysmography method for assessing resting SBP (37) for at least 1 wk by daily placement of the animal in a holding tube and placement of the pressure cuff at the base of the animal's tail. At 9 wk of age, SBP measurements were made on all animals. Four days later, after a 12-h fast (chow removed at 8 PM the evening before), a 60-min oral glucose tolerance test (OGTT) was performed. Two days after the OGTT, animals were again fasted, and an assessment of in vitro skeletal muscle glucose transport activity was completed.
Study 2: Effects of voluntary exercise training. Exercising male heterozygous TG(mREN2)27 rats were housed individually in wire-mesh side cages (18 × 26 × 20 cm) and had free access to vertical stainless steel activity wheels (1.13 m in circumference; Lafayette Instruments, West Lafayette, IN) for 6 wk. Running distances were assessed daily, and body weights were measured twice weekly. Sedentary male TG(mREN2)27 rats were housed in identical side cages for 6 wk but were not allowed access to the wheels.
At the end of the 5th wk, SBP measurements were made. Twenty-four hours after the measurement of SBP, exercising animals were activity restricted for 12 h, and peak oxygen consumption (
O2 peak) was determined for all
animals. Two days later, at 7 AM, exercising animals were denied access
to their running wheels, and chow was removed from the cages of all
animals. Six hours later, a 120-min OGTT was completed in all animals.
Exercising animals were then allowed access to their running wheels,
and all animals were provided chow. Three days after the OGTT,
exercising animals were again activity restricted, all animals were
fasted as before at 7 AM, and 6 h later in vitro skeletal muscle
glucose transport activity was assessed.
O2 peak
O2 peak was assessed during a
treadmill test by using the method of Bedford et al. (1).
No exercise was performed on the day before the
O2 peak tests. Animals were run on a
motorized treadmill in an airtight Plexiglas chamber. Grade and speed
of the treadmill were increased every 3 min from an initial level of
0% grade and 16.1 m/min through the following stages: 21.5 m/min at
10%, 26.5 m/min at 10%, 26.5 m/min at 12%, 32.6 m/min at 12%, 32.6 m/min at 15%, 37.2 m/min at 15%, and 41.9 m/min at 15%. The test was
terminated when the rats were unable to keep pace with the treadmill
belt. Oxygen (Ametek S-3A1, Applied Electrochemistry, Pittsburgh, PA)
and carbon dioxide (Ametek CD-3A) were measured in expired gases every
3 min for the determination of oxygen uptake (ml
O2 · kg body
wt
1 · min1). Exercise training
resumed the evening after the O2 peak assessment.
OGTTs
A 0.5-ml sample of blood was collected from a small cut at the tip of the tail immediately before and at 15, 30, and 60 min after administration of a 1 g/kg body wt glucose load by gavage (study 1) or at 30, 60, 90, and 120 min after the glucose load (study 2). Whole blood was thoroughly mixed with EDTA (final concentration of 18 mg/ml) and centrifuged at 13,000 g to isolate the plasma. The plasma was stored at
80°C and subsequently
assayed for glucose (Sigma Chemical, St. Louis, MO), insulin by
radioimmunoassay (Linco, St. Louis, MO), and FFA (Wako, Richmond, VA).
After the final blood collection, each animal was given 2.5 ml of
sterile saline subcutaneously to account for plasma volume loss.
Muscle Glucose Transport Activity
Animals were deeply anesthetized by using an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt). One soleus and both epitrochlearis muscles were dissected and prepared for incubation. Whereas the epitrochlearis muscles were incubated intact, the soleus muscle was prepared into two strips (~25 mg) and incubated. Each muscle was incubated for 1 h at 37°C in 3 ml of oxygenated (95% O2-5% CO2) Krebs-Henseleit buffer (KHB) supplemented with 8 mM glucose, 32 mM mannitol, and 0.1% BSA (radioimmunoassay grade, Sigma Chemical). One muscle was incubated in the absence of insulin, and the second muscle was incubated in the presence of a maximally effective concentration of insulin (2 mU/ml; Humulin, Eli Lilly, Indianapolis, IN). After this initial incubation period, the muscles were rinsed for 10 min at 37°C in 3 ml of KHB containing 40 mmol/l mannitol, 0.1% BSA, and insulin, if previously present. Thereafter, the muscles were transferred to 2 ml of KHB containing 1 mM 2-deoxy-[1,2-3H]glucose (300 µCi/mmol; Sigma Chemical), 39 mM [U-14C]mannitol (0.8 mCi/mmol; ICN Radiochemicals, Irvine, CA), 0.1% BSA, and insulin, if previously present. At the end of this final 20-min incubation period at 37°C, the muscles were removed, trimmed of excess fat and connective tissue, quickly frozen between aluminum blocks cooled in liquid nitrogen, weighed, and divided into two pieces, and each frozen piece was weighed. The specific intracellular accumulation of 2-DG was determined in one piece as described previously (10).Biochemical Assays
The remaining pieces of muscle were homogenized in 20 vol of ice-cold 20 mM HEPES (pH 7.4) containing 1 mM EDTA and 250 mM sucrose. These homogenates were used for the determination of total protein content by using the bicinchoninic acid method (Sigma Chemical) and for GLUT-4 protein level (33).Statistical Analysis
All data are presented as means ± SE. The comparison between two means was evaluated statistically with Student's t-test for independent means, except in the context of a timed measurement (i.e., during the OGTT), when the comparisons were made with an ANOVA, followed by Fisher's protected least significant difference test. P < 0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study 1: Assessment of Insulin Resistance in the TG(mREN2)27 Rat
The initial and final average body weights and the wet weights for the soleus muscle were not different between the age-matched TG(mREN2)27 rats and Sprague-Dawley control rats (Table 1). The average resting SBP for the TG(mREN2)27 rats was 53% higher (P < 0.05) than that in the Sprague-Dawley rats. The wet weight of the heart was 40% greater in the TG(mREN2)27 animals compared with the normotensive control animals, reflective of the cardiac hypertrophy associated with the hypertensive state of the transgenic animals. Fasting plasma glucose and insulin were not different between the groups (Table 1). However, the fasting plasma FFA concentration in the TG(mREN2)27 rats was twofold greater than that observed for the Sprague-Dawley rats.
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The glucose and insulin responses during a short-term (60-min) OGTT are
displayed in Fig. 1. The absolute values
for the glucose response were not different at each time point during
the OGTT between the two groups. However, insulin concentrations were
55 and 30% higher in the TG(mREN2)27 rats compared with the
Sprague-Dawley controls at 15 and 30 min of the OGTT (P < 0.05). The incremental areas under curve (AUC) for these glucose and
insulin responses were significantly greater in the TG(mREN2)27 animals
than in the control animals by 33 and 86% (both P < 0.05), respectively. The glucose-insulin index, defined as the product
of the glucose and insulin AUCs, is an indirect index of in vivo
peripheral insulin action (2, 11), with a greater value of
the glucose-insulin index being associated with a reduced insulin
sensitivity. The glucose-insulin index was threefold (P < 0.05) greater in the TG(mREN2)27 rats compared with the
Sprague-Dawley rats, indicating a substantially lesser whole body
insulin sensitivity in the hypertensive transgenic animals (Fig. 1).
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To determine the cellular locus for the lesser peripheral insulin
action in the transgenic animals, insulin-mediated glucose transport
activity was assessed in isolated epitrochlearis and soleus muscle
(Fig. 2). The rate of 2-DG uptake in the
absence of insulin was not different between the control and transgenic groups for either muscle. In the TG(mREN2)27 rats, the rates of insulin-stimulated 2-DG uptake in the epitrochlearis and soleus muscles
were 25 and 30% lower (P < 0.05), respectively, than
those observed in the controls, and the increases in 2-DG uptake due to
insulin were 33 and 43% lower, respectively (P < 0.05), in the transgenic animals, clearly indicating in vitro skeletal
muscle insulin resistance.
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Study 2: Voluntary Exercise Training by the TG(mREN2)27 Rat
The pattern of running activity in the TG(mREN2)27 rats during the 6-wk training protocol is shown in Fig. 3. Over the last 3 wk of this training period, the running distances of the transgenic animals averaged ~6-7 km/day. This training regimen resulted in a 36% greater (P < 0.05) peak aerobic capacity compared with that in the sedentary transgenic animals (Table 2). The increase inO2 peak was associated with an 80%
increase in the maximum running times of the trained compared with the
sedentary animals (data not shown). Moreover, the voluntary exercise
training significantly reduced SBP in the TG(mREN2)27 rats by 16%
(P < 0.05) (Table 2).
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The initial and final average body weights were not different between the sedentary and trained TG(mREN2)27 rats (Table 2). The wheel running induced a 17% increase (P < 0.05) in the soleus muscle wet weight, with no change in heart mass relative to the sedentary group (Table 2). Whereas the fasting plasma glucose level was not altered by training, the fasting plasma insulin and FFA levels were reduced by 21 and 34%, respectively, in the trained compared with the sedentary TG(mREN2)27 rats (Table 2).
The glucose and insulin responses during a 120-min OGTT are shown in
Fig. 4. There were significantly lower
glucose concentrations at 30, 60, and 90 min (26, 29, and 27%,
respectively) in the trained compared with the sedentary animals.
Additionally, at all time points during the OGTT, the trained rats had
significantly lower insulin concentrations (28-47%). The
incremental AUCs for glucose and insulin were significantly lower (70 and 59%, respectively) in the trained TG(mREN2)27 animals compared
with the sedentary controls. The glucose-insulin index was sevenfold
greater in the sedentary group compared with the trained group,
indicating that exercise training significantly improved whole body
insulin sensitivity in the TG(mREN2)27 rats (Fig. 4).
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The rate of 2-DG uptake in the absence of insulin was not different
between the sedentary control group and the trained group for both the
epitrochlearis and soleus muscles (Fig.
5). In the presence of insulin, the rate
of 2-DG uptake was 25 and 26% greater in the trained epitrochlearis
and soleus muscles than in respective sedentary control muscles.
Moreover, the increase in 2-DG uptake due to insulin was 39 and 50%
greater in the epitrochlearis and soleus muscles, respectively, of the
trained animals compared with the muscles of the sedentary TG(mREN2)27
rats.
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The adaptive response of whole muscle GLUT-4 protein expression to exercise training in skeletal muscle of the TG(mREN2)27 rats was assessed. In soleus muscle, GLUT-4 protein levels were significantly enhanced in the trained group relative to the sedentary group (125 ± 5 vs. 100 ± 4 relative units, P < 0.05). In contrast, there was no apparent upregulation of GLUT-4 protein expression in the epitrochlearis muscle of the trained TG(mREN2)27 rats compared with their sedentary counterparts (108 ± 7 vs. 100 ± 10 relative units).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we have demonstrated for the first time that the male heterozygous TG(mREN2)27 rat possesses characteristics of both hypertension and insulin resistance at the whole body and skeletal muscle levels. These animals displayed greatly elevated resting SBP and cardiac hypertrophy (Table 1) and at the same time exhibited impaired glucose tolerance and whole body insulin resistance (Fig. 1) that was associated with impaired insulin-mediated glucose transport in skeletal muscle (Fig. 2). Furthermore, dyslipidemia was also present, as these animals had markedly elevated plasma FFA levels (Table 1). The male heterozygous TG(mREN2)27 rat, therefore, possesses many of the characteristics that define "syndrome X" (27) and the "insulin resistance syndrome" (3).
The present metabolic results from the male heterozygous TG(mREN2)27 rat are at variance with those of Vettor et al. (40), who reported that the female heterozygous TG(mREN2)27 rat, despite having an elevated resting SBP, was not insulin resistant at the whole body or skeletal muscle levels. However, Holness and Sugden (14) have demonstrated more recently that glucose utilization rates in highly oxidative skeletal muscles (soleus and adductor longus) were substantially less in the female heterozygous TG(mREN2)27 rat compared with transgene-negative control rats. Moreover, after the infusion of an intravenous glucose bolus, the female TG(mREN2)27 rats exhibited an exaggerated insulin secretory response associated with a lesser glucose response (14). These data indicate that, at least in the postabsorptive condition, the female heterozygous TG(mREN2)27 rat is indeed hyperinsulinemic and insulin resistant. Interestingly, when higher insulin levels (~75 µU/ml) were achieved during a euglycemic, hyperinsulinemic clamp, the insulin resistance seen in the postabsorptive state of the female TG(mREN2)27 rat was no longer apparent (14), essentially in agreement with Vettor et al. (40).
In the context of these observations, it is important to note that male heterozygous TG(mREN2)27 rats exhibit both higher resting SBP and components of the renin-angiotensin system, including plasma angiotensinogen, prorenin, angiotensin I, and angiotensin II, compared with their female counterparts (20). The greater expression of angiotensin II may underlie the clear insulin resistance in male TG(mREN2)27 rats that we have demonstrated in the present study, as this factor can induce insulin resistance of skeletal muscle glucose uptake (30), possibly because of its inhibitory effect on phosphatidylinositol 3-kinase (5), a critical component of the insulin signaling pathway for stimulation of glucose transport (35). Indeed, the chronic administration of angiotensin II receptor antagonists to insulin-resistant fructose-fed rats (12) or spontaneously hypertensive rats (SHR) (34) leads to significant improvements in whole body insulin sensitivity. Moreover, our laboratory (11) has also demonstrated very recently that chronic treatment of insulin-resistant obese Zucker rats with an angiotensin II receptor antagonist (AT1 specific) caused improvements in both whole body glucose tolerance and insulin action on skeletal muscle glucose transport. It is clear that further investigations of the exact role of angiotensin II in the etiology of hypertension and insulin resistance in the male heterozygous TG(mREN2)27 rat are warranted.
A second critical finding of the present study is that voluntary exercise training by the male heterozygous TG(mREN2)27 rat (Fig. 3) was associated with significant reductions in resting SBP (Table 2) and elicited marked improvements in glucose tolerance and whole body insulin sensitivity (Fig. 4) and in insulin action on skeletal muscle glucose transport activity (Fig. 5). The increase in insulin-mediated glucose transport activity in the soleus muscle of the exercise-trained TG(mREN2)27 rats was associated with a significant enhancement of GLUT-4 protein expression, even in the face of a hypertrophic response in this muscle (Table 2), which likely masked some of the increase in this specific protein (10, 31). It is curious that the substantial exercise training did not increase the protein expression of GLUT-4 in the epitrochlearis, as previous studies utilizing normotensive rats have shown that voluntary exercise training is associated with substantial increases in GLUT-4 protein in this predominantly type IIb muscle (31). In addition, voluntary exercise training by the SHR is associated with substantial increases in skeletal muscle GLUT-4 protein expression (19). The possibility exists that the locally elevated angiotensin II in the TG(mEN2)27 rat (20) could have prevented the normal exercise training-induced enhancement of GLUT-4 expression, as our laboratory (11) has shown in the obese Zucker rat that antagonism of angiotensin II action causes an increase in GLUT-4 protein expression in skeletal muscle and myocardium. Future investigations should address this potential connection between angiotensin II and GLUT-4 protein expression and should also investigate the potential role of increased insulin-stimulated GLUT-4 translocation and intrinsic activity in this muscle from the exercise-trained TG(mREN2)27 rats.
The elevation in plasma FFA in the male heterozygous TG(mREN2)27 rat (Table 1) may be mechanistically related to the reduced whole body insulin sensitivity seen in these animals (Fig. 1), as FFA can negatively impact skeletal muscle glucose disposal, possibly via inhibition of insulin receptor substrate-1 phosphorylation and insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity (8). Consistent with this hypothesis is our observation that exercise training by the TG(mREN2)27 rats caused a significant reduction in plasma FFA levels (Table 2) and an enhancement of whole body glucose disposal (Fig. 4) and skeletal muscle glucose transport (Fig. 5). Although this study was not designed to specifically investigate the underlying mechanisms for this exercise training-induced reduction in the fasting plasma FFA concentration, it may be associated with a decrease in adipocyte lipolysis, possibly secondary to a reduction in resting sympathetic activity.
The TG(mREN2)27 rat can now be included in the list of hypertensive rodent models that undergo beneficial cardiovascular adaptations in response to endurance exercise training. For example, the SHR (13, 19, 23, 24, 39), the fructose-induced hypertensive rat (29), and the Lyon hypertensive rat (6) experience a significant lowering of resting SBP after endurance exercise training, whether done by treadmill running, wheel running, or swimming. However, one must exercise caution in the implementation of physical activity as an intervention in hypertensive states, as exercise training performed by rats with a more severe condition of hypertension, such as the stroke-prone SHR, leads to a worsening of SBP and a shortening of life span (24, 38).
In conclusion, we have shown that the male heterozygous TG(mREN2)27 rat displays elevated resting SBP and clear indexes of insulin resistance of glucose disposal, both at the whole body and the skeletal muscle level. Moreover, voluntary exercise training by the male heterozygous TG(mREN2)27 rat is associated with both a reduction of resting SBP and improvements in whole body glucose tolerance and skeletal muscle glucose transport activity. The male heterozygous TG(mREN2)27 rat is, therefore, an appropriate model with which to study the cardiovascular disease risk factors associated with the insulin resistance syndrome (hypertension, glucose intolerance, insulin resistance, and dyslipidemia) and how these risk factors can be beneficially modified by endurance exercise training.
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ACKNOWLEDGEMENTS |
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The authors thank the Hypertension and Vascular Disease Center of Bowman Gray School of Medicine at Wake Forest University (Dr. Carlos M. Ferrario, Director) for providing us with the male heterozygous TG(mREN2)27 and Sprague-Dawley rats used in this study.
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. J. Henriksen, Dept. of Physiology, Ina E. Gittings Bldg. #93, Univ. of Arizona, Tucson, AZ 85721-0093 (E-mail: ejhenrik{at}u.arizona.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.
May 3, 2002;10.1152/japplphysiol.00236.2002
Received 19 March 2002; accepted in final form 30 April 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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).
Values are means ± SE for 5-6 animals per group.
* P < 0.05 vs. Sprague-Dawley group.
0.05 vs. sedentary group.