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1 Institute of Health Science, Wuhan Institute of Physical Education, Wuhan 430079, China 2 Department of Kinesiology, University of Maryland, College Park, MD 20742, USA
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Abstract |
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), body composition and glucose tolerance). One hundred and sixty-three of them repeated these tests after 24 weeks of exercise training while on a low-fat diet. At baseline, age, height, body fat, resting systolic blood pressure and all glucose and insulin metabolism markers did not differ among E23K genotype groups. In women at baseline, E23K genotype was associated with body weight, body mass index, 
(ml kg–1 min–1, l min–1) and maximal minute ventilation. In men at baseline, E23K genotype was significantly associated with maximal heart rate, maximal respiratory exchange ratio and diastolic blood pressure at rest. Numerous glucose and insulin metabolism and CV function phenotypes changed significantly with exercise training in the total population. The E23K genotype did not significantly influence any of these training-induced changes. Thus, the common E23K genetic variant at the KCNJ11 gene locus was significantly associated with CV function in the untrained state, although the associations appear to differ between men and women. However, this variant has no significant effect on training-induced CV and glucose and insulin metabolism adaptations.
(Received 9 June 2007;
accepted after revision 17 August 2007; first published online 24 August 2007)
Corresponding author J. M. Hagberg: Department of Kinesiology, University of Maryland, College Park, MD 20742-2611, USA. Email: hagberg{at}umd.edu
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Introduction |
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Endurance exercise training enhances insulin sensitivity (Holloszy et al. 1986; Goodyear & Kahn, 1998; Henriksen, 2002), but the changes in insulin sensitivity with exercise training are highly variable among individuals, even when they undergo a highly standardized exercise training programme. Our laboratory and others have identified a number of polymorphic genetic variants that affect the degree to which individuals improve their glucose and insulin metabolism with exercise training (McKenzie et al. 2004; Adamo et al. 2005; Weiss et al. 2005; Obisesan et al. 2006). However, the potential impact of the KCNJ11 E23K variant on glucose and insulin metabolism changes with exercise training, to our knowledge, has never been assessed.
Exercise training also results in substantial improvements in CV function and fitness as indexed by maximal oxygen consumption (
). The response of 
to exercise training also varies considerably among individuals. Recent studies have shown that 
, like most other physiological capacities of humans, is determined to a significant degree by genetic factors. In the HERITAGE Family Study (Bouchard et al. 1998, 1999), the heritability for baseline 
was as high as 59% and the heritability for the response of 
to exercise training was 47%. However, the associations between KCNJ11 E23K genotype and CV function and CV fitness changes with exercise training have never been assessed.
As a result of previous findings concerning the relationship between the KCNJ11 E23K variant and diabetes and CV phenotypes, and the fact that this gene is expressed in cardiac and skeletal muscle, we hypothesized that KCNJ11 E23K genotype would be associated with baseline glucose and insulin metabolism indices and CV function and their changes with exercise training.
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Methods |
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Subjects for this study were healthy men and women, 50–75 years of age, who were recruited via media and mail advertisements. They underwent a telephone interview to determine their initial eligibility. Study entry requirements included: sedentary (< 20 min of continuous aerobic exercise, < 2 times per week); non-smoking; normotensive or having blood pressure (BP) controlled with medications not affecting glucose metabolism; non-diabetic; no prior history of CV disease; and body mass index (BMI) < 37 kg m–2. Women had to be > 2 years past menopause and had to maintain their hormone replacement therapy (HRT) status (on or not on HRT) constant for the duration of the study. The University of Maryland College Park Institutional Review Board approved the study, all subjects provided their informed written consent prior to participating in the study and all procedures were conducted in accordance with the Declaration of Helsinki. More complete descriptions of all methods used to recruit, screen, test and intervene on these subjects have been presented previously (Wilund et al. 2002).
Screening
Medical, health history and physical activity questionnaires were reviewed and BMI was confirmed to be < 37 kg m–2 during the first laboratory visit. A blood sample was drawn to isolate leucocyte DNA for genotyping analyses. A fasting and a 2 h postprandial blood sample were also drawn. Only subjects who had no evidence of diabetes (fasting glucose < 126 mg dl–1; 2 h postprandial glucose < 200 mg dl–1) or liver or renal disease continued in the study. Qualified subjects then underwent a maximal treadmill exercise test with blood pressure (BP), heart rate (HR) and ECG monitoring to screen for any overt evidence of CV disease. Subjects with CV signs or symptoms during this test, or detectable pulmonary or other chronic diseases were excluded from the study.
Dietary control
All qualified subjects then underwent 6 weeks of dietary education (twice per week, 1 h per session) with a registered dietician to adopt a eucaloric American Heart Association Step 1 Diet (Krauss et al. 1996). This diet consisted of < 30% of total caloric intake from fat, 55% from carbohydrates and 15% from protein, and < 300 mg day–1 of cholesterol intake. Subjects maintained this diet for at least 3 weeks prior to beginning baseline testing.
Baseline testing
An oral glucose tolerance test (OGTT) was performed in the morning after a 12–14 h fast, with > 250 g of carbohydrate in the diet for each of the preceding 3 days. Blood samples were drawn from a venous catheter prior to and 30, 60, 90 and 120 min after the ingestion of a flavoured solution containing 75 g of glucose (McKenzie et al. 2004). Glucose levels were measured using the glucose oxidase method (Model 2300 Stat Plus, YSI Inc., Yellow Springs, OH, USA). Plasma insulin levels were determined by radioimmunoassay (kit HI-14K; Linco Research Inc., St Charles, MO, USA). Glucose and insulin total area under the curve (AUC) during the OGTT were calculated using the trapezoidal model (Allison et al. 1995). The 
was measured during a modified maximal treadmill exercise test (Wilund et al. 2002). A computer-based metabolic system analysed expired gases continuously. True 
was considered to be achieved based on standard physiological criteria (Wilund et al. 2002). Blood pressure measurements during seated rest were made before this test. Body composition was measured using DEXA (DPX-L, Lunar Corp., Madison, WI, USA). Two hundred and fourteen men and women completed baseline testing for this study.
Exercise training intervention
Subjects underwent 24 weeks of supervised endurance exercise training three times per week. Exercise training consisted of treadmill running/walking, elliptical machines, and cycle, rowing and cross-country ski ergometers. Exercise duration increased from 20 (week 1) to 40 min (week 5) and exercise intensity progressed from 50 (week 6) to 70%
(week 10). For the remaining 14 weeks, exercise intensity and duration remained at 70%
and 40 min, respectively, and a lower intensity 45–60 min walk at home was added on the weekends. Subjects completed 7 day food records at week 1, 8, 16 and 24 of the exercise intervention and met with the dietitian once every 2 weeks throughout the exercise training intervention. Subjects were required to maintain their caloric intake constant throughout the study; therefore, they could lose no more than 5% of their body weight based on their exercise energy expenditures. Only data from subjects who completed > 80% of the training sessions and who met this weight loss criterion were included in the final analyses.
Final testing
At the end of the 24 weeks of exercise training, subjects completed the same tests as at baseline (
, body composition and glucose tolerance). The OGTT after training was done 24–36 h after the subject's previous exercise training session. One hundred and sixty-three subjects completed all baseline and final testing after the exercise training intervention. Final OGTT data were available on 
100 of these subjects.
Genotyping
Genomic DNA was isolated using standard techniques and genotyped for the E23K polymorphism in the KCNJ11 gene using a Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based method previously described (Hansen et al. 2005). The forward and reverse PCR primers were 5'-GACTCTGCAGTGAGGCCCTA-3' and 5'-ACGTTGCAGTTGCCTTTCTT-3', respectively. The PCR products were digested with BanII overnight at 37°C and the resulting DNA digestion fragments were resolved on 3% agarose gels.
Statistics
Data are presented as means ± S.D. Comparisons between baseline and final glucose and insulin level and AUC were made using Student's paired t tests. Baseline characteristics of the three KCNJ11 genotype groups were compared using ANOVA. Comparisons of the final values of the three KCNJ11 genotype groups were made using repeated measures ANOVA. A P value of < 0.05 was considered to be statistically significant. The statistical software package SAS 6.12 (SAS Inc., Cary, NC, USA) was used for all statistical analyses.
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Results |
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75% whites, 19% blacks, 4% Asian/Pacific Islanders, 1% Hispanics and 2% other.
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6–7%. No such differences or trends were evident for body weight or BMI across genotype groups in men. Similarly, for 
(ml kg–1 min–1 and l min–1) and maximal minute ventilation (
) there were no genotype associations in the total population or men at baseline, but EE genotype women had higher 
and 
values, by 8–15%, than EK genotype women. In the total population, maximal heart rate (HRmax) did not significantly associate with E23K genotype; however, EE genotype men had HRmax values that were significantly and substantially lower, by 9 beats min–1, than KK genotype men. No such differences in HRmax were seen across genotype groups in women. Respiratory exchange ratio (RER) at maximal exercise in the total population was significantly lower, by 0.06 units or 5%, in the EK compared with the KK genotype group. Similar trends were evident in both men and women, but the RERmax difference among genotype groups was only significant in men. Also in men, diastolic BP at rest for the EE genotype group was significantly higher than in the EK genotype group, although there were no trends or significant differences in diastolic BP at rest among genotype groups in the total population or in women. All significant differences for baseline genotype x gender groups were generally statistically significant when analysed only in the white individuals.
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(ml kg–1 min–1 and l min–1) and 
increased significantly with exercise training in both men and women in all three genotype groups, and these changes were not associated with E23K genotype in the total population or in men or women. The RER at maximal exercise decreased with exercise training in all genotype groups, regardless of gender, and again, the changes with training were not a function of E23K genotype in the total population or in the groups of men or women. The HRmax and systolic and diastolic BP at rest did not change significantly with training in any of the groups, and the changes were not associated with E23K genotype.
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Discussion |
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on a population basis, relatively few have sought to determine the association of the training-induced change in 
with specific biologically plausible SNPs (Rankinen et al. 2006). The 
is a critical health issue because of the substantial role it plays in determining an individual's CV disease risk (Blair et al. 1989, 1995). Understanding the genetics of training-induced changes in 
might identify individuals who respond either optimally or suboptimally to reduce their CV disease risk with endurance exercise training.
The E23K polymorphism is a relatively common polymorphism at the KCNJ11 gene locus, and a number of studies indicate that this variant may independently affect various phenotypes related to diabetes and glucose and insulin metabolism (McCarthy et al. 2005). Although some studies have found no impact of KCNJ11 gene variants on diabetes phenotypes (Sakura et al. 1996; Hansen et al. 1997; Altshuler et al. 2000), several groups have found significant associations between KCNJ11 genetic variants and diabetes risk (Hani et al. 1998; Gloyn et al. 2001; Nielsen et al. 2003; Florez et al. 2004). For example, Nielsen and co-workers found that in a large number of type 2 diabetics and glucose-tolerant individuals E23K genotype had a significant diabetogenic effect by impairing glucose-induced insulin release and by increasing BMI (Nielsen et al. 2003). An association study that included three large Caucasian samples (total n
=
9000) found that KCNJ11 E23K genotype was significantly associated with various measures of insulin secretion and resistance (Florez et al. 2004). A recent functional study found that KCNJ11 gene variants induced spontaneous overactivity of pancreatic β-cells, thereby increasing the threshold of ATP concentration for insulin release (Schwanstecher et al. 2002). Another functional study found that the KK genotype markedly reduced glucose-induced β-cell insulin release (Riedel et al. 2003). In the present study, however, our four measures of baseline glucose and insulin metabolism (fasting plasma glucose and insulin levels, glucose and insulin AUC during an OGTT) were not significantly associated with KCNJ11 E23K genotype.
Potassium channels play important roles in vital cellular signalling processes in both excitable and non-excitable cells. Changes in K+ channel function have been associated with cardiac hypertrophy and failure, apoptosis and oncogenesis, and various neurodegenerative and neuromuscular disorders (Shieh et al. 2000). In the heart, for instance, the voltage-gated KCNQ1 (KvLQT1, Kv7.1) potassium channel plays a crucial role in shaping the cardiac action potential as well as in controlling water and salt homeostasis in several epithelial tissues (Jespersen et al. 2005). In an animal model of hypertension, knocking out the KCNJ11 gene predisposed the animals to heart failure and death (Kane et al. 2006). Therefore, the intact KCNJ11-encoded KATP channel is required to prevent hypertension-induced heart failure, with channel dysfunction being a molecular basis for stress-associated channelopathy in CV disease.
In the present study, the E23K variant at the KCNJ11 gene locus was significantly associated with various baseline measures of CV function, although many of these associations were gender dependent. In fact, women with the EE genotype had 
and 
values that were 10% higher than those of women with the EK genotype. Clearly, if this magnitude of difference is confirmed in future studies, this genetic marker could provide sedentary women with substantial information about their 
, and hence their CV disease risk (Blair et al. 1989). Women with the EE genotype also had significantly lower body weight and BMI than women with the EK genotype. It is important to keep in mind that the significant differences in 
between these genotype groups in women included both the absolute 
in units of litres per minute as well as that normalized for body weight, expressed in units of millilitres per kilogram per minute. In men, the three KCNJ11 genotype groups had 
values that averaged within 2% of each other. However, in men at baseline E23K genotype was significantly associated with HRmax, RERmax and diastolic BP at rest. Thus, the KCNJ11 E23K variant clearly has a significant impact on various measures of CV function in sedentary individuals, although the associations appear to differ between men and women.
Endurance exercise training has substantial beneficial effects on CV function and on glucose and insulin metabolism (Holloszy et al. 1986; Haskell et al. 1992; Goodyear & Kahn, 1998; Henriksen, 2002). Our results in the entire population are consistent with this conclusion, with 
increasing by 15%, fasting plasma insulin levels decreasing by 15%, and insulin AUC during the OGTT decreasing by 20%. These are clearly very benficial responses to exercise training for middle-aged to older sedentary men and women, and these beneficial outcomes of exercise training significantly reduce their future risk of developing type 2 diabetes and CV disease. However, contrary to our initial hypothesis, KCNJ11 E23K genotype was not significantly associated with the changes in CV function or glucose or insulin metabolism that occurred with the 6 month endurance exercise training programme in these middle-aged to older men and women.
The major strengths of this study included the dietary control imposed prior to the measurement of the baseline phenotypes and which was then maintained throughout the 6 month endurance exercise training programme. We also used a prolonged exercise training programme to ensure that a more than adequate stimulus was applied to result in significant training adaptations. The exercise training protocol was also highly standardized to ensure that any training-induced response differences among individuals were not the result of different training stimuli. The strict screening for initial physical activity level and evidence of CV disease controlled for additional environmental factors that could contribute to interindividual variability in our phenotype measurements.
This study, however, also had a number of limitations. First, we used fasting plasma glucose and insulin levels and their responses to an OGTT as indices of glucose and insulin metabolism, rather than the more repeatable glucose clamp methods. In addition, our sample size for assessing the potential for genotype-dependent training-induced changes in glucose and insulin metabolism consisted of only 100 individuals, with only 15 in the E23K KK genotype group. This may well have limited our power to detect significant genotype-dependent training-induced adaptations in these outcome phenotype measures. Furthermore, because of reduced sample sizes we were not able to make a valid comparison of the baseline values and responses to training between men and women with the same genotype.
In conclusion, a number of baseline CV function measures, especially 
in women and HRmax in men, were significantly related to KCNJ11 E23K genotype, with substantial and physiologically important differences evident between genotype groups. However, contrary to our original hypotheses, KCNJ11 E23K genotype did not associate significantly with baseline measures of glucose or insulin metabolism, or with training-induced changes in CV function or glucose or insulin metabolism. Therefore, the E23K variant at the KCNJ11 gene locus contributes to the variation in CV function in sedentary men and women, although this effect may be gender dependent.
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Acknowledgements |
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Author's present address
E. P. Weiss: St Louis University, Department of Nutrition and Dietetics, St Louis, MO 63104 USA.
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