|Year : 2015 | Volume
| Issue : 1 | Page : 66-71
Correlations among obesity-associated gene polymorphisms, body composition, and physical activity in patients with type 2 diabetes mellitus
Sanae Saitoh1, Taeko Shimoda1, Yukie Hamamoto2, Yutaka Nakaya3, Shigeru Nakajima2
1 Division of Medical Nutrition, Faculty of Healthcare, Tokyo Healthcare University, Tokyo, Japan
2 Nakajima Internal Medicine Clinic, Yokosuka, Japan
3 Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
|Date of Web Publication||12-Dec-2014|
Division of Medical Nutrition, Faculty of Healthcare, Tokyo Healthcare University, 3-11-3 Setagaya, Setagaya-ku, Tokyo 154-8568
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: Various studies have focused on the correlation between β2-adrenergic receptor (β2AR), the β3-adrenergic receptor (β3AR), and the uncoupling protein 1 (UCP1) polymorphisms and obesity in patients with type 2 diabetes mellitus (T2DM). Aims: We examined the correlation between these polymorphisms and body composition variables and between body composition and lifestyle variables in Japanese T2DM patients. Materials and Methods: Of the 48, T2DM outpatients in Kanagawa prefecture recruited for participation, 32 (6 men and 26 women) met the study criteria and were enrolled. Obesity-related gene polymorphisms were identified in 3 genes β3AR, UCP1, and β2AR using the SMart amplification process. Body composition variables were measured using a body composition analyzer. Data regarding food and nutrient consumption, family history, and lifestyle factors were collected via administration of questionnaires. Results: Because significant differences in body composition variables were found between men and women, statistical analysis was performed with data from the 25 female subjects only. On the basis of results of genetic testing, the subjects were divided into genotype groups for two-group and three-group comparison. The β3AR, UCP1, and β2AR polymorphisms and body composition significantly correlated with the percentage of subcutaneous fat in both arms as compared with the wild type or hetero groups with β3AR polymorphisms. However, physical activity correlated with several body composition variables. Conclusions: These results suggest that obesity in T2DM patients is not the result of presence of an obesity-related gene polymorphism but rather the absence of daily physical activity.
Keywords: β2AR, β3AR gene polymorphism, obesity, uncoupling protein 1, type 2 diabetes
|How to cite this article:|
Saitoh S, Shimoda T, Hamamoto Y, Nakaya Y, Nakajima S. Correlations among obesity-associated gene polymorphisms, body composition, and physical activity in patients with type 2 diabetes mellitus. Indian J Endocr Metab 2015;19:66-71
|How to cite this URL:|
Saitoh S, Shimoda T, Hamamoto Y, Nakaya Y, Nakajima S. Correlations among obesity-associated gene polymorphisms, body composition, and physical activity in patients with type 2 diabetes mellitus. Indian J Endocr Metab [serial online] 2015 [cited 2020 Aug 15];19:66-71. Available from: http://www.ijem.in/text.asp?2015/19/1/66/131757
| Introduction|| |
The etiology of type 2 diabetes mellitus (T2DM) is thought to involve various genetic and environmental factors, such as overeating and the level of physical activity. Various genes associated with heat production and lipolysis have also been associated with obesity. Among these genes, Walston et al.,  reported that Trp64Arg polymorphism of the β3-adrenergic receptor (β3AR) gene is correlated with early onset of T2DM, higher body mass index (BMI), and lower resting metabolic rate in Pima. Approximately 1/3 rd of the Japanese population carries the β3AR polymorphism. Yoshida et al.,  reported that homologous (Arg/Arg) or heterologous (Trp/Arg) β3AR polymorphism carriers burn 200 kcal/day less than noncarriers. Kogure et al.,  reported that carriers of the uncoupling protein 1 (UCP1) polymorphism A3826G burn 200 kcal/day less than that noncarriers, whereas Sakane et al.,  reported that the carriers of the β2-adrenergic receptor (β2AR) polymorphism Arg16Gly have a higher resting metabolism and burn 100 kcal/day more than noncarriers.
Several tailored weight-loss and dietary-guidance interventions based on research indicating that obesity, T2DM, hyperinsulinemia, and insulin resistance , are correlated with obesity-related gene polymorphisms resulted in improvement in obesity and BMI. , Nevertheless, an increasing number of reports have suggested that obesity-related gene polymorphisms are not correlated with obesity or weight loss. , Whereas many studies of obesity-related gene polymorphisms have focused on their correlation with BMI, total body fat percentage, and physical activity level; very few have evaluated their correlation with percentage of subcutaneous fat and/or skeletal muscle mass at different body sites. To fill this research gap, the present study evaluated the correlation between presence of obesity-related gene polymorphisms and body composition variables in T2DM patients to assess whether the patients' obesity could be primarily attributed to genetic- or lifestyle-related factors.
| Materials and Methods|| |
A total of 48 outpatients who commuted to clinics in Kanagawa prefecture for treatment of previously diagnosed T2DM were provided with an oral and written explanation of the objectives of the present study for possible participation. Patients unable to answer the food frequency questionnaire were excluded from the study. Of the 48 patients, 32 (6 men and 26 women) provided informed consent for participation and were enrolled in the study. Approval for the human study was obtained from the Ethical Review Board of Tokyo Medical Healthcare University. Participant confidentiality was maintained to the greatest possible extent, including by anonymous labeling of the specimens.
Measurement of variables
The variables of interest were investigated via review of the results of blood sample testing, body composition evaluation, participant responses to food intake frequency, and dietary habit questionnaires. After extraction of genomic DNA from 5 μL of peripheral blood, real time quantitative polymerase chain reaction was performed using the MX 3005P system (Stratagene. Cedar Creek, TX, USA). Polymorphisms in the β3AR, UCP1, and β2AR genes, which have been previously associated with obesity, were identified using the SMart amplification process (SMAP) with the Smart Amp ® β3AR, UCP1, and β2AR Typing Kits (Danaform Co. Kanagawa. Japan). A method codeveloped by the Danaform Co. and the Institute of Physical and Chemical Research,  this assay is a unique genotyping technology that can detect a genetic mutation accurately in a single step of 30 min under an isothermal condition using a single drop of whole blood.
Body weight, percentage of total body fat and total skeletal muscle mass, and percentage of total and subcutaneous fat at different body sites of participants, while they were clothed were determined using the Omron Karada Scan HBF 362 Body Composition Analyzer (Omron Corp., Kyoto, Japan). Responses to the food frequency questionnaire based on food groups (FFQg),  for determination of food and nutrient consumption were evaluated using Excel Eiyo-kun FFQg software (version 2.0; Kenpakusha, Tokyo, Japan) that was developed, based on 29 food groups and 10 kinds of cookery, for estimating the energy and nutrient intakes of an individual subject during the previous one to two months. Although the FFQg was developed to be a self-administered questionnaire, it was verbally explained by trained evaluators to compensate for the reduced visual acuity of elderly subjects and to ensure correct understanding of portion size and frequency.
Dietary habits, history of weight change, family history, and lifestyle factors were evaluated via a self-administered questionnaire. Data regarding random blood glucose (RBG) and glycated hemoglobin (HbA1c) levels were collected from medical records; however, the time lag between glucose measurement and last meal consumption was not uniform among the subjects.
Based on the results of genetic testing for β3AR, UCP1, and β2AR polymorphisms, the subjects were divided into the following three groups: the homologous group, which consisted of subjects homozygous for Arg/Arg (β3AR), G/G (UCP1), and Gly/Gly β2AR polymorphisms; the heterologous group, which consisted of subjects with Trp/Arg (β3AR), Arg/Gly (UCP1), and Arg/Gly (β2AR) polymorphisms; and the wild type group, which consisted of subjects without β3AR, UCP1, or β2AR polymorphisms. Two-group comparison was conducted using the t test and three-group comparison was conducted first using the Bartlett test for confirmation of equal distribution, followed by the Tukey-Kramer honestly significant difference (HSD) test for multiple comparisons. Assessment of responses to the questionnaire items was conducted using the Tukey-Kramer HSD test. All statistical analyses were two-tailed and conducted using the JMP 8.0 software (SAS, Chicago, IL, USA) with the level of significance set at P < 0.05.
| Results|| |
Because the measurements obtained for all body composition variables significantly differed by sex, data from only female subjects were further analyzed to prevent sex-related confounding results. Of the original 26 female subjects, 1 subject with a lower-limb disability whose body composition evaluation was hindered was excluded after study initiation, resulting in a sample of 25 female subjects of a mean age of 62.8 ± 8.0 years with mean disease duration of 10.3 ± 6.9 years [Table 1]. The β3AR polymorphism was present in 10 subjects in the heterozygous group (40.0%), 15 subjects in the wild type group (60.0%); the UCP1 polymorphism was present in 9 subjects of the homozygous group (36.0%), 14 subjects of the heterozygous group (56.0%), and 2 subjects of the wild type group (8.0%); and the β2AR polymorphism was present in 9 subjects of the homozygous group (36.0%), 9 subjects of the heterozygous group (36.0%), and 7 subjects of the wild type group (28.0%).
Comparison of BMI, percentage of body fat, skeletal muscle, and subcutaneous fat at total body or different sites in subjects with β3AR polymorphisms, percentage of subcutaneous fat in both legs was significantly higher in the heterozygous group compared to the wild-type group [P = 0.037, [Table 2]. In contrast, neither significant differences in any of the body composition variables were found among the groups of subjects with UCP1 and β2AR polymorphisms [Table 3] and [Table 4], nor in the RBG level of the groups of subjects with β3AR, UCP1, or β2AR polymorphisms.
|Table 2: Comparison of body composition variables of β3-adrenergic receptor genotypes|
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|Table 3: Comparison of body composition variables of uncoupling protein 1 genotypes|
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|Table 4: Comparison of body composition variables of β2-adrenergic receptor genotypes|
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Comparison of nutrient intake in each of the three groups of subjects with each type of polymorphism revealed no significant differences between the heterozygous groups and the wild-type groups regarding intake of any nutrient [Table 5].
|Table 5: Comparison of daily nutrient and food group intake by β3-adrenergic receptor genotypes|
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No significant differences in body composition and nutrient intake based on presence of the β3AR, UCP1, or β2AR polymorphisms were found, indicating that obesity and these polymorphisms do not have any significant associations. Based on this finding, we next evaluated the association between lifestyle factors and body composition variables [Table 6]. In response to a questionnaire item that asked whether participants were physically active on a daily basis, 9 subjects responded that they were "active" (36.0%), 5 that they were "inactive" (20.0%), and 11 subjects that they were "neither active nor inactive" (44%). Comparison of body composition variables of the active and inactive groups revealed that the former group had a significantly lower BMI (P = 0.009) and lower percentage of subcutaneous fat in the whole body (P = 0.024) and in the trunk (P = 0.030), and higher percentage of skeletal muscle in both arms (P = 0.021) compared with the latter group. Comparison of the inactive and neither-active-nor-inactive groups revealed that the former had a significantly lower BMI (P = 0.019), percentage of total body fat (P = 0.040), percentage of subcutaneous fat in the whole body (P = 0.025) and in the trunk (P = 0.024), and a significantly higher percentage of total skeletal muscle mass in the whole body (P = 0.042), trunk (P = 0.039), and arms [P = 0.018; [Table 6] Although the mean RBG level of the active group (112.8 ± 31.3 mg/dL) was found to be significantly lower than that of the inactive group (161.8 ± 51.4 mg/dL; P = 0.046), the mean HbA1c levels of the two groups was not found to differ significantly (P = 0.21). Other questionnaire items (e.g. the speed of meal and regularity of eating three meals a day) did not show significant difference by the comparison with the body composition according to either variable.
|Table 6: Relationship between physical activity level and body composition variables or random blood glucose level|
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Comparison of intake of the nutrients shown in [Table 7] by physical activity level revealed that the total dietary fiber intake of both the active (P = 0.033) and neither-active-nor-inactive (P = 0.006) groups was significantly higher than that of the inactive group, but that there were no significant differences between the two groups with regard to energy, protein, lipid, carbohydrate, vitamin, or mineral intake. Regarding intake of all food groups, only the intake of vegetables was found to be higher in the neither-active-nor-inactive and inactive groups (P = 0.006).
|Table 7: Correlation between physical activity level and food and nutrient intake|
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| Discussion|| |
Comparison of the body composition variables of subjects with three obesity-related gene polymorphisms revealed a significant difference between the percentage of subcutaneous fat in the arms in the wild type and heterozygous groups with β3AR polymorphisms. Because other significant differences were not observed, a correlation between tendency toward obesity and the presence of β3AR, UCP1, or β2AR polymorphisms could not be established. This finding is in accordance with that of several earlier studies that reported the absence of correlations between β3AR, UCP1, and β2AR polymorphisms and the variables of body weight, BMI, and amount of body fat. , Based on the indication that presence of β3AR polymorphisms is not a direct cause of weight gain or T2DM  and that polymorphisms other than β3AR, UCP1, and β2AR polymorphisms may be associated with obesity, development of treatments based on the identification of obesity-related genes should be avoided. Comparison of nutrient intake based on the presence or absence of obesity-related gene polymorphisms revealed no significant differences. However, total daily caloric intake, as self-reported by the subjects, ranged from 863 kcal to 2,088 kcal, a very wide interval. Such variation suggests the possibility of underestimation of food intake, which has been identified among overweight individuals, ,, and, as the subjects had received meal guidance for controlling T2DM, may have been very likely in the present study. ,
Having found no correlation between the presence or absence of obesity-related gene polymorphisms and body composition variables, the correlation between lifestyle and body composition variables was next analyzed. Among the lifestyle variables, physical activity level was found to be correlated with several body composition variables. Compared with subjects who reported being inactive, subjects who reported being active were found to have a significantly lower BMI and percentage of total body and trunk fat, and subjects who reported being neither active nor inactive showed a significantly lower BMI and percentage of total body fat. Comparison of food and nutrient intake revealed a significant difference between the active and inactive groups regarding total intake of dietary fiber derived from vegetables, indicating that intake of dietary fiber affects BMI and body fat percentage. , These results indicate that the obesity of the subjects in the present study is likely not the result of presence of an obesity-related gene polymorphism but rather the absence of daily physical activity.
This study faced two limitations that should be considered when reviewing the results. First, to accommodate the subjects' advanced age, the food intake frequency questionnaire was completed via oral interviews and not via self-reporting. However, comparison of oral reporting of intake compared with use of the meal-recording and 24-h recall methods indicates that oral reporting can cause underestimation of food intake. ,, Lack of accurate reporting of caloric intake prevented further exploration of the correlation between body composition variables and levels of daily physical activity, which is necessary before concluding that lifestyle factors affect body composition. Second, the small sample size of the study prevented adequate analysis of different combinations of the three types of gene polymorphisms. To overcome these limitations, future research using larger sample sizes and accurate means of assessing caloric intake should aim to analyze different combinations of the gene polymorphisms examined in this study as well as others that have been associated with obesity, such as UCP2 and UCP3 polymorphisms.
Previous research into the correlation between genes and obesity has proceeded on the premise that identification of obesity-related genes could result in the development of a tailored nutrition program for T2DM patients based on the presence of these genes. However, the results presented here indicate that the presence of β3AR, UCP1, or β2AR polymorphisms, which have previously been associated with obesity, is not the main factor in the obesity of the T2DM subjects in the present study; rather, lack of physical activity appears to be the main factor. While the results do not preclude further research into the genes that may underlie obesity in T2DM patients, particularly as heretofore-uninvestigated gene polymorphisms may be involved; they indicate that lifestyle factors, particularly level of physical activity, are correlated with body composition. It is, thus, important to promote the awareness of the significance of lifestyle factors in general and the possible benefit of increasing the physical activity level of T2DM patients in particular.
| References|| |
Walston J, Silver K, Bogardus C, Knowler WC, Celi FS, Austin S, et al.
Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. N Engl J Med 1995;333:343-7.
Yoshida T, Sakane N, Umekawa T, Sakai M, Takahashi T, Kondo M. Mutation of beta 3-adrenergic-receptor gene and response to treatment of obesity. Lancet 1995;346:1433-4.
Kogure A, Yoshida T, Sakane N, Umekawa T, Takakura Y, Kondo M. Synergic effect of polymorphisms in uncoupling protein 1 and beta3-adrenergic receptor genes on weight loss in obese Japanese. Diabetologia 1998;41:1399.
Sakane N, Yoshida T, Umekawa T, Kogure A, Kondo M. β2-adrenoceptor gene polymorphism and obesity. Lancet 1999;353:1976.
Kadowaki H, Yasuda K, Iwamoto K, Otabe S, Shimokawa K, Silver K, et al.
A mutation in the beta 3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects. Biochem Biophys Res Commun 1995;215:555-60.
Sakane N, Yoshida T, Umekawa T, Kondo M, Sakai Y, Takahashi T. β3-adrenergic-receptor polymorphism: A genetic marker for visceral fat obesity and the insulin resistance syndrome. Diabetologia 1997;40:200-4.
Imai S, Togawa C, Yamamura T, Oyabu K, Fujimoto S, Matsuda M, et al.
Effect of tailor-made diet on weight loss in obese Japanese patients of type 2 diabetes mellitus with single nucleotide polymorphisms in β3-adrenergic receptor, uncoupling protein 1 or β2-adrenergic receptor genes. J Rehabili Health Sci 2008;6:31-5.
Nagai N, Sakane N, Ueno LM, Hamada T, Moritani T. The -3826 AàG variant of the uncoupling protein-1 gene diminishes postprandial thermogenesis after a high fat meal in healthy boys. J Clin Endocrinol Metab 2003;88:5661-7.
Gagnon J, Mauriège P, Roy S, Sjöström D, Chagnon YC, Dionne FT, et al.
The Trp64Arg mutation of the β3 adrenergic receptor gene has no effect on obesity phenotypes in the Québec Family Study and Swedish Obese Subjects cohorts. J Clin Invest 1996;98:2086-93.
Kurabayashi T, Carey DG, Morrison NA. The beta 3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women. Effects on weight, BMI, abdominal fat, blood pressure, and reproductive history in an elderly Australian population. Diabetes. 1996;45:1358-63.
Mitani Y, Lezhava A, Kawai Y, Kikuchi T, Oguchi-Katayama A, Kogo Y, et al.
Rapid SNP diagnostics using asymmetric isothermal amplification and a new mismatch-suppression technology. Nat Methods 2007;4:257-62.
Omagari K, Murayama T, Tanaka Y, Yoshikawa C, Inoue S, Ichimura M, et al.
Mental, physical, dietary, and nutritional effects on irritable bowel syndrome in young Japanese women. Intern Med 2013;52:1295-301.
Kuriyama S, Shimazu T, Hozawa A, Kure S, Kurokawa N, Kakizaki M, et al.
No effect of the Trp64Arg variant of the beta3-adrenergic receptor gene on weight loss by diet and exercise intervention among Japanese adults. Metabolism 2008;57:1570-5.
Tooze JA, Vitolins MZ, Smith SL, Arcury TA, Davis CC, Bell RA, et al.
High levels of low energy reporting on 24-hour recalls and three questionnaires in an elderly low-socioeconomic status population. J Nutr 2007;137:1286-93.
Scagliusi FB, Ferriolli E, Pfrimer K, Laureano C, Cunha CS, Gualano B, et al.
Characteristics of women who frequently under report their energy intake: A doubly labelled water study. Eur J Clin Nutr 2009;63:1192-9.
Scagliusi FB, Ferriolli E, Pfrimer K, Laureano C, Cunha CS, Gualano B, et al.
Underreporting of energy intake in Brazilian women varies according to dietary assessment: A cross-sectional study using doubly labeled water. J Am Diet Assoc 2008;108:2031-40.
Samuel-Hodge CD, Fernandez LM, Henríquez-Roldán CF, Johnston LF, Keyserling TC.
A comparison of self-reported energy intake with total energy expenditure estimated by accelerometer and basal metabolic rate in African-American women with type 2 diabetes. Diabetes Care 2004;27:663-9.
Sallé A, Ryan M, Ritz P. Underreporting of food intake in obese diabetic and nondiabetic patients. Diabetes Care 2006;29:2726-7.
Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation. Nutr Rev 2001;59:129-39.
Liu S, Willett WC, Manson JE, Hu FB, Rosner B, Colditz G. Relation between changes in intakes of dietary fiber and grain products and changes in weight and development of obesity among middle-aged women. Am J Clin Nutr 2003;78:920-7.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]