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Medicine & Science in Sports & Exercise:
doi: 10.1249/01.mss.0000246998.02095.bf
CLINICAL SCIENCES: Clinically Relevant

Physical Activity, Diet, and Incident Diabetes in Relation to an ADRA2B Polymorphism

LAAKSONEN, DAVID E.1,2; SIITONEN, NIINA3; LINDSTRÚM, JAANA4; ERIKSSON, JOHAN G.4; REUNANEN, PIRITTA3; TUOMILEHTO, JAAKKO4,5; UUSITUPA, MATTI3; for the FINNISH DIABETES PREVENTION STUDY GROUP

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1Department of Medicine, Kuopio University Hospital; Departments of 2Physiology and 3Clinical Nutrition, University of Kuopio, Kuopio, FINLAND; 4Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute; 5Department of Public Health, University of Helsinki, Helsinki, FINLAND

Address for correspondence: Matti Uusitupa, M.D., Ph.D., Department of Clinical Nutrition and Food and Health Research Center, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland; E-mail: Matti.Uusitupa@uku.fi.

Submitted for publication June 2006.

Accepted for publication September 2006.

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Abstract

Purpose: The 12Glu9 polymorphism of the α2B-adrenergic receptor gene may impair insulin secretion and modify the effects of a lifestyle intervention on the risk of type 2 diabetes, but the interaction with specific lifestyle components is unknown. We assessed the associations of leisure-time physical activity (LTPA), dietary changes, and weight loss on the risk of type 2 diabetes according to the 12Glu9 polymorphism in 481 participants of the Finnish Diabetes Prevention Study.

Methods and Results: The lifestyle intervention decreased the risk of diabetes in 9Glu carriers (9Glu9, intervention vs control, relative risk (RR) = 0.23, 95% confidence interval (CI) 0.09-0.62), but not in 12Glu12 homozygotes. In the combined intervention and control groups, increased total LTPA as estimated with a questionnaire decreased the risk of diabetes in 12Glu carriers (12Glu12, upper vs lower third, RR = 0.12, 95% CI 0.03-0.53) but not in 9Glu9 homozygotes (P for the interaction 0.033). In contrast, favorable dietary changes, estimated using a dietary score, reduced the risk of diabetes in those with the 9Glu9 genotype (upper vs lower third, RR = 0.21, 95% CI 0.06-0.75) but not in those with the 12Glu allele. Weight loss significantly decreased the risk of diabetes only in 12Glu carriers.

Conclusion: Increased LTPA decreased the risk of type 2 diabetes more in those with the 12Glu allele of the ADRA2B gene, whereas dietary changes may have mediated the greater risk reduction of the lifestyle intervention in 9Glu homozygotes.

The interactions of genes with lifestyle factors in the pathogenesis of type 2 diabetes are poorly understood. In the Finnish Diabetes Prevention Study (DPS), a moderate lifestyle intervention, which included increased physical activity, dietary changes towards current recommendations, and modest weight loss, decreased the risk of type 2 diabetes by 58% in overweight men and women with impaired glucose tolerance (IGT) (30).

Increased leisure-time physical activity (LTPA) during the follow-up was associated with a substantially reduced risk of type 2 diabetes in the DPS cohort (12). Total time or energy expenditure of physical activity seemed to be more important in these high-risk individuals than its intensity. Moreover, modest weight loss was a major factor in decreasing the risk of diabetes by improving insulin sensitivity, which was shown in a subset of the DPS cohort who underwent an intravenous glucose-tolerance test (32). Also, none who met at least four of the five stated goals of the DPS (three of which were dietary: decreased intake of total and saturated fat and increased intake of fiber) developed diabetes during the study (30).

In the DPS, the 9Glu9 genotype of the 12Glu9 polymorphism of the α2B-adrenergic receptor (ADRA2B) gene was associated with impaired first-phase insulin secretion (23). The 12Gku9 polymorphism also predicted the conversion to type 2 diabetes in individuals with IGT in the control group but not in the lifestyle intervention group (23). The α2-adrenergic receptors modulate sympathetic tone, lipolysis, insulin secretion, and blood pressure (21). Disturbances in autonomic regulation may contribute to the development of insulin resistance, β-cell dysfunction, and type 2 diabetes (9). Exercise training, diet, and weight loss also affect autonomic nervous function in different ways. For example, exercise training enhances β-adrenergic receptor stimulation of lipolytic activity and blunts α2-adrenergic receptor catecholamine-mediated antilipolytic activity (2,22,27). The 9Glu9 deletion polymorphism has a pronounced effect on receptor phosphorylation and results in the loss of agonist-promoted desensitization (25). It has also been associated with a reduced basal metabolic rate (6), increased body weight, and increased sympathetic nervous system activity (28). At least in combination with the Arg64 allele of the β3-adrenergic receptor, Glu12Glu homozygotes seem to lose more fat in response to physical training (20).

The 12Glu9 polymorphism of the ADRA2B gene was not associated with the development of diabetes in individuals randomized to the intervention arm of the DPS, indicating that the ADRA2B 12Glu9 polymorphism may interact with lifestyle factors in the development of type 2 diabetes. The manner in which the ADRA2B 12Glu9 polymorphism may interact with specific components of the intervention-that is, increased physical activity, favorable dietary changes, and weight loss-has not been previously described.

We sought to evaluate the interactions of the physical activity, dietary, and weight loss components of the intervention with the 12Glu9 polymorphism of the ADRA2B gene in the development of type 2 diabetes in the combined intervention and control groups of the DPS. For these post hoc analyses, follow-up of the DPS was extended by 1 yr beyond the end of the actual trial to an average of 4.1 yr to increase the statistical power.

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METHODS

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Participants.

The Finnish DPS is a multicenter randomized controlled trial designed to test the hypothesis that lifestyle changes can prevent type 2 diabetes in high-risk individuals. The design of the DPS has been described in detail (4). Briefly, overweight or obese individuals aged 40-65 yr with IGT were eligible for the study. IGT was defined as a plasma glucose concentration of 7.8-11.0 mM at 2 h after the oral administration of 75 g of glucose in subjects whose fasting glucose concentration was less than 7.8 mM (1).The study protocol was approved by the ethics committee of the National Public Health Institute in Helsinki, Finland. All participants gave written informed consent.

DNA was collected from individuals at the beginning of the study to test the associations of candidate gene polymorphisms with type 2 diabetes, and to test the interactions of lifestyle and genes with the development of diabetes. Of the 522 men and women from five study centers who were randomized (30), 506 had DNA available for determination of the 12Glu9 polymorphism of the ADRA2B gene and are included in the analyses of the effect of the lifestyle intervention according to the 12Glu9 polymorphism (23). Of these 506 persons, 481 completed a questionnaire quantifying the previous 12 months of LTPA at baseline and at least once during follow-up. These 481 persons are included in the analyses of the effect of the specific lifestyle components in the prevention of diabetes according to the 12Glu9 polymorphism. The original trial ended after an average follow-up of 3.2 yr, during which time 86 cases of incident diabetes were diagnosed (30). In this study, we extended follow-up by 1 yr (average 4.1 yr, range 1-6 yr) (12). In all, 115 of the 506 men and women for whom genotyping was carried out and 106 of the 481 participants for whom detailed analysis of the lifestyle interventions was possible developed diabetes during the mean 4.1-yr follow-up.

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Intervention.

The intervention group was given detailed advice on how to achieve the goals of the intervention, which were moderate to vigorous exercise for at least 30 min·d−1; a reduction in body weight of 5% or more, in intake of fat to less than 30% of energy intake, and in intake of saturated fat to less than 10% of energy intake; and an increase in fiber intake to at least 15 g·1000 kcal−1. In addition to endurance exercise and circuit-type resistance training, walking and lifestyle physical activity were also recommended. The control group was given general verbal and written information about exercise and diet at baseline and at subsequent annual visits, but no specific individualized programs were offered.

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Assessment of leisure-time physical activity.

The validated Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) 12-month LTPA questionnaire was filled out at baseline and at yearly follow-up visits as described previously (11,12,15).

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Assessment of dietary intake.

Subjects were asked to complete a 3-d food record at baseline and yearly follow-up visits (16,18). The nutrient intakes were assessed using a dietary analysis program developed at the National Public Health Institute (16,18).

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Clinical, anthropometric, and dietary assessments.

At baseline and at each annual visit, all study subjects underwent an oral glucose-tolerance test and completed a 3-d food diary, as described elsewhere (4,16,30). Detailed data on changes in dietary factors and body weight have been reported elsewhere (16,30).

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Genotyping.

DNA was available from 506 subjects, 481 of whom had sufficient information for analyses of LTPA and its changes. The 12Glu9 polymorphism leads to the deletion or insertion of three glutamic acid residues from an acidic stretch of 16 amino acids in the third intracellular loop of the ADRA2B gene. The 12Glu9 polymorphism of the ADRA2B gene was analyzed by a polymerase chain reaction and gel electrophoresis as described before (23,24).

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Biochemical assessments.

Plasma glucose was measured using a glucose dehydrogenase method after precipitation of proteins by trichloroacetic acid. The serum insulin concentration was measured by a radioimmunoassay (Pharmacia, Uppsala, Sweden). Serum total and high-density lipoprotein cholesterol and triglycerides were measured by an enzymatic assay at the National Public Health Institute, Analytical Biochemistry Laboratory (4,16,30).

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Determination of diabetes mellitus.

Diabetes was defined according to the 1985 criteria of the World Health Organization (1) as either a fasting plasma glucose concentration of 7.8 mM or higher or a plasma glucose concentration of 11.1 mM or higher 2 h after a 75-g oral glucose challenge. If the diagnosis of diabetes was not confirmed by a second oral glucose-tolerance test, the subject continued in the study (30).

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Statistical analysis.

One-way ANOVA and chi-square tests were used to analyze the differences among the three genotypes with respect to clinical, biochemical, LTPA, and dietary variables at baseline. Total LTPA and its changes were used as the primary LTPA variable because the change in total LTPA was shown previously to be the most strongly associated with incident type 2 diabetes (12). The change in LTPA during the trial was calculated by subtracting the baseline total LTPA and its components (h·wk−1) from corresponding measures of averaged LTPA questionnaires completed during follow-up (12). Changes in dietary and biochemical measures and body weight during the trial were similarly calculated. The change in LTPA for the combined intervention and control groups was categorized into thirds to assess the association of the change in LTPA with the risk of type 2 diabetes according to the ADRA2B genotype, using Cox proportional hazards models. The covariates for the Cox proportional hazards models were forced into the model. Intake of dietary total and saturated fat and fiber (in grams per day) were adjusted by daily energy intake with linear regression analysis before further statistical analyses (13,33).

Changes in total and saturated fat consumption, fiber intake, and total energy intake correlated strongly with each other (absolute value of r = 0.28-0.76). We therefore calculated diet scores. To calculate a corresponding dietary score for the change in diet, the change in total energy from baseline to follow-up and of energy-adjusted intake of total fat, saturated fat, and fiber intake from baseline to follow-up was calculated. The Z statistic of these changes was then saved. Use of the Z statistic allows variance-based standardization of the changes in the dietary components of the intervention as continuous variables, rather than relying on dichotomous variables based on whether a specific dietary goal was achieved. A dietary score for the change based on the Z statistic was then calculated (Z of change in energy-adjusted fiber intake minus Z of energy intake minus Z of change in energy-adjusted total fat intake minus Z of change in energy-adjusted saturated fat intake). The dietary scores were then categorized into thirds for statistical analyses. The baseline dietary score was calculated in a corresponding fashion using the Z statistic of total energy and energy-adjusted intake of fat, saturated fat, and fiber. Statistical significance was defined as P < 0.05. Statistical analyses were performed with SPSS 11.0 for Windows (Chicago, IL).

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RESULTS

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Baseline.

At baseline, body weight, body mass index (BMI), fasting and 2-h plasma glucose and insulin concentrations, total LTPA, and dietary energy and intake of total fat, saturated fat, and fiber did not differ significantly according to the 9Glu12 polymorphism of the ADRA2B gene in the combined intervention and control groups (Table 1). As reported before (23), genotype frequencies were in Hardy-Weinberg equilibrium and did not differ significantly between the intervention and the control group.

Table 1
Table 1
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9Glu12 polymorphism and the effect of the intervention on the risk of diabetes.

We have previously reported that there was a statistically significant interaction between the 9Glu12 polymorphism of the ADRA2B gene and the intervention with respect to the risk of diabetes during the trial (23). The lifestyle intervention did not significantly reduce the risk of diabetes in participants with the 12Glu12 genotype. In contrast, the intervention markedly decreased the risk of diabetes in heterozygotes and, especially, homozygotes with the 9Glu allele (Table 2). The present study included additional cases of diabetes 1 yr after the end of the active intervention. In the updated analyses, the interaction between intervention and the 9Glu12 polymorphism still tended to be statistically significant (P = 0.093).

Table 2
Table 2
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9Glu12 polymorphism, increased LTPA, and the risk of diabetes.

In analyses in the combined intervention and control groups, participants whose change in the total duration of LTPA was in the upper third were much less likely to develop diabetes than those whose change was in the lower third if they had the 12Glu allele of the ADRA2B gene (Table 3). For participants with the 9Glu9 genotype, increased total LTPA did not decrease the risk of diabetes. The interaction between changes in total LTPA and the 12Glu9 polymorphism was statistically significant (P = 0.033).

Table 3
Table 3
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9Glu12 polymorphism, dietary changes, and the risk of diabetes.

In analyses in the combined intervention and control groups, men and women with the greatest improvement in the dietary score had a lower risk of developing diabetes during the follow-up in analyses adjusting for age, sex, and intervention group (upper vs lower third, RR 0.56, 95% CI 0.33-0.98). After adjustment for changes in BMI and physical activity, the association was no longer significant (Table 3). In those who were homozygous for the 9Glu allele of the ADRA2B gene, those with more favorable dietary changes were much less likely to develop diabetes than those whose dietary changes were least favorable, even after adjustment for changes in BMI and physical activity (Table 3). For participants with the 12Glu allele, an improved dietary score did not decrease the incidence of diabetes. The interaction between dietary changes and the 12Glu9 polymorphism was not statistically significant, however.

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9Glu12 polymorphism, weight loss, and the risk of diabetes.

In analyses in the combined intervention and control groups, men and women whose BMI decreased the most were much less likely to develop diabetes than those whose BMI change was least favorable (Table 3). Weight loss did not have a clear beneficial effect for those with the 9Glu9 genotype. The interaction between changes in BMI and the 12Glu9 polymorphism did not reach significance.

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DISCUSSION

The main finding of this study was that the 9Glu12 variant of the ADRA2B gene modified the effect of increased physical activity on the risk of type 2 diabetes in the Finnish DPS. Increased LTPA decreased the likelihood of diabetes more in those with the 12Glu allele of the ADRA2B gene. Because the effect of the intervention was more effective in 9Glu homozygotes (23), dietary changes likely mediated the greater effect of the lifestyle intervention in decreasing the risk of diabetes in 9Glu homozygotes.

Increased total duration of LTPA strongly decreased the risk of type 2 diabetes in 12Glu carriers, but not in 9Glu homozygotes. This interaction of physical activity and the 12Glu9 polymorphism of the ADRA2B gene with the risk of type 2 diabetes is a novel finding. Increased LTPA was strongly associated with a lower risk of type 2 diabetes in the DPS cohort as a whole and seemed to be an important component of the intervention in reducing the risk of diabetes (12). It is clear that increased LTPA does not explain the greater effectiveness of the overall lifestyle intervention in decreasing type 2 diabetes in 9Glu homozygotes, because increased physical activity had little effect in individuals with the 9Glu9 genotype.

In contrast, the dietary intervention as estimated using a composite diet score seemed to be most effective in 9Glu9 homozygotes, even though the interaction was not significant. Because increased physical activity and weight loss had little impact on alleviating the risk of diabetes in the 9Glu9 homozygotes, it is likely that the dietary component may explain the greater effectiveness of the lifestyle intervention in those with the 9Glu9 genotype.

Weight reduction seemed to decrease the risk of diabetes more in 12Glu9 heterozygotes, but the interaction was not significant. On the other hand, it is clear that weight loss did not mediate the greater effect of the lifestyle intervention in 9Glu homozygotes. In the DPS, changes in body weight did not differ among the three genotype groups, but we have previously shown that 9Glu9 homozygotes have a lower basal metabolic rate (7). They may also gain more weight that the other genotypes in the long term (15).

Several mechanisms may explain why physical activity and dietary components of the intervention seemed to vary in their effectiveness in diabetic risk reduction according to the presence of the Glu12 or Glu9 allele. We have shown that insulin secretion is impaired in carriers of the Glu9 allele and, especially, in homozygotes (23). Because LTPA seems to prevent diabetes by increasing insulin sensitivity (31), it may be that physical activity is less effective in individuals with primarily a defect in β-cell function. Diet also influences insulin secretion (8,14,17), but it is not known how the 12Glu9 variant may modulate dietary effects.

Insulin resistance itself is likely mediated through various signaling mechanisms and influenced by multiple genes and their interactions with other genes and environmental factors such as physical activity and diet (19). It is probable that physical activity, diet, and weight loss improve insulin sensitivity through different mechanisms under the influence of different genes. The possible divergent effects of physical activity and diet may also be mediated by interactions of these genes with the 9Glu12 polymorphism of the ADRA2B gene.

Exercise training enhances β-adrenergic receptor stimulation of lipolytic activity and blunts α2-adrenergic receptor catecholamine-mediated antilipolytic activity (2,22,27). At least in combination with the Arg64 allele of the β3-adrenergic receptor, ADRA2B Glu12Glu homozygotes have been shown to lose more fat in response to physical training (20). Findings on insulin sensitivity or insulin secretion as an endpoint have not been reported. We did not find interactions of the Arg64 allele of the β3-adrenergic receptor with the 12Glu12 genotype of the α2-adrenergic receptor (P = 0.22) or with changes in LTPA (P = 0.24). Nonetheless, it is possible that Glu12Glu homozygotes are less susceptible to developing diabetes in part through larger decreases in fat mass and larger increases in insulin sensitivity in response to increased LTPA than Glu9 carriers, even though the interaction of changes in LTPA with the 12Glu9 polymorphism was independent of changes in body mass.

The 9Glu9 deletion has also been associated with increased sympathetic nervous system activity (28). Disturbances in autonomic regulation are associated with insulin resistance and β-cell dysfunction, and autonomic imbalance may contribute to the pathogenesis of the metabolic syndrome and diabetes (9). Exercise training, diet, and weight loss also affect autonomic nervous function in different ways, generally decreasing sympathetic activity (5) and increasing parasympathetic activity (3,10,26,29).

Strengths of the DPS include its randomized controlled design (30) and repeated assessments of leisure-time physical activity and dietary intake. It should be noted, however, that the present analyses are post hoc. Furthermore, the intervention had several components. Detailed assessment of the individual lifestyle components allows statistical disentanglement of their individual effects, but residual confounding is possible. More complex interactions between the 12Glu9 polymorphism of the ADRA2B gene and lifestyle components and other gene polymorphisms may exist, but the statistical power to test such interactions is limited. Also, the statistical power limits the ability to evaluate interactions of genotype with subcategories of physical activity.

Increased LTPA decreased the risk of type 2 diabetes more in those with the 12Glu allele of the ADRA2B gene, whereas dietary changes may have mediated the greater risk reduction of the lifestyle intervention found previously in 9Glu homozygotes. In the future, individual tailoring of lifestyle interventions according to the genetic background may maximize benefit in the prevention of diabetes.

This study was financially supported by grants from the Academy of Finland (38387 and 46558 to J.T. and 40758 to M.U.), the EVO-fund of the Kuopio University Hospital (5106 to M.U.), the Ministry of Education, the Finnish Diabetes Research Foundation, and the Technology Development Center of Finland.

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α2B-ADRENERGIC RECEPTOR; GENETICS; WEIGHT LOSS; TYPE 2 DIABETES MELLITUS; RANDOMIZED CONTROLLED TRIAL

©2007The American College of Sports Medicine

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