Key words
genetics - lifestyle - obesity - type 2 diabetes
Introduction
The prevalence of obesity and type 2 diabetes mellitus (T2DM) is dramatically increasing
worldwide. For less than 2 decades the prevalence of obesity has more than doubled
to exceed 470 million, representing the most common metabolic disease nowadays ([International Obesity Taskforce, ]2010). The rise in obesity prevalence is paralleled by a similar rapid increase in
the prevalence of T2DM demonstrating the close interrelationship between these metabolic
diseases ([Wild et al., 2004]).
Obesity and T2DM are multifactorial health threats caused by a complex interplay between
genetic predisposition and the environment ([Neel, 1999]). The advancements in human genetics and the utilization of genome-wide association
(GWA) approach have recently revealed valuable insights into the interactions between
genetic predisposition and lifestyle factors, namely physical activity (PA) and food
consumption. This current progress may have essential contribution to our understanding
of the pathophysiology of both diseases, as well as, to the development and implementation
of future treatment and prevention strategies. It is, therefore, the aim of the present
review to summarize the available literature on the effect of the interactions between
lifestyle and genetics on obesity and T2DM.
Genetics of Obesity and Type 2 Diabetes Mellitus
Genetics of Obesity and Type 2 Diabetes Mellitus
The role of heritability in the development of obesity and T2DM is well recognized.
A good example in this respect is the existence of severe monogenic forms of both
disorders such as the congenital leptin deficiency ([Montague et al., 1997]), the melanocortin-4 receptor deficiency ([Farooqi et al., 2003]), and the maturity onset diabetes of the young (MODY) ([Vaxillaire and Froguel, 2006]). The strong impact of inherited factors on obesity and T2DM has also been confirmed
in a large number of family, twin and adoption studies. Studies in twins have demonstrated
that 50–70% in the body mass index (BMI) variance may be explained by genetics ([Allison et al., 1996]), and T2DM concordance was reported ranging from 17–37% in dizygotic to 50–70% in
monozygotic twins ([Kaprio et al., 1992]; [Medici et al., 1999]; [Poulsen et al., 1999]). In addition, family and adoption studies have reported heritability ranging from
20–60% for obesity ([Rice et al., 1999]; [Stunkard et al., 1986]) and 30–70% for T2DM ([Meigs et al., 2000]).
During the past 15 years numerous attempts have been made to identify certain genetic
variants determining susceptibility to obesity and T2DM. Until recently candidate
gene and genome-wide linkage studies have been the main genetic epidemiological approaches.
Progress has, however, been slow and success limited with few reproducible results
([Vimaleswaran and Loos, 2010]). Utilization of the GWA approach and the progress made through the International
HapMap project and the Human Genome Project has substantially improved the knowledge
about obesity and T2DM genetics ([Rankinen et al., 2006]). At present, as a result of this technological advancement over 20 loci for respectively
obesity and T2DM have been convincingly confirmed in various populations ([Herder and Roden, 2010]; [Vimaleswaran and Loos, 2010]).
Extensive description of the genetic variants influencing individual susceptibility
to obesity and T2DM is beyond the scope of the current paper (for a detailed review
on the topic, please refer to ([Herder and Roden, 2010]; [Vimaleswaran and Loos, 2010]). We are rather aiming at demonstrating the effect of gene-lifestyle interactions
on the development of diabesity. Most of the genes identified to date have modest
effect on disease risk and both diseases are unlikely to develop without the individual
being exposed to obesity- and/or type 2 diabetes-promoting environment. Therefore,
in the next section the importance of lifestyle in obesity and T2DM will be discussed.
Lifestyle in Obesity and Type 2 Diabetes Mellitus
Lifestyle in Obesity and Type 2 Diabetes Mellitus
Unhealthy lifestyle, characterized by physical inactivity and food overconsumption
is an unequivocally established risk factor for obesity and type 2 diabetes. Increased
PA and energy restriction, on the other hand, are associated with lower incidence
of obesity and T2DM in numerous epidemiological studies.
Lessons from epidemiological studies
Findings from cross-sectional and prospective studies suggest that food overconsumption
and a predominantly sedentary lifestyle may cause obesity and T2DM, while adoption
of a healthier lifestyle may prevent them. It has been demonstrated that lack of non-sedentary
activities, the time spent watching television, and western dietary pattern can substantially
increase the odds of becoming obese and of developing T2DM ([Ching et al., 1996]; [Martinez-Gonzalez et al., 1999]; [Schulze et al., 2006]; [van Dam et al., 2002]). At the same time a healthier lifestyle comprising higher levels of PA and prudent
food consumption have been found to significantly reduce the risk ([Coakley et al., 1998]; [Kriska et al., 2003]; [Meisinger et al., 2005]; [Schulze et al., 2006]; [van Dam et al., 2002]). In a recent paper we reported that low levels of leisure time and sport PA, as
well as, binge eating behavior are associated with increased BMI and higher T2DM prevalence
also among the urban population of Sofia, Bulgaria ([Stefanov et al., 2011]).
Based on data analyses from the Nurses’ Health Study [Hu et al. (2003a)] concluded that around 30% of the new cases of obesity and 43% of T2DM could be prevented
by adoption of a relatively active lifestyle. Indeed, activities of even moderate
intensity (e. g., brisk walking) have been found to significantly reduce the risk
of obesity and diabetes ([Hu et al., 1999]; [Hu et al., 2003b]; [Mekary et al., 2009]). Remarkably, the effect of PA on diabetes incidence has been observed independently
of BMI demonstrating that regular engagement in activities of moderate to high intensity
may be beneficial not only for high-risk obese individuals, but also for low-risk
lean individuals ([Kriska et al., 2003]; [Meisinger et al., 2005]; [Schulze et al., 2006]). Furthermore, healthier lifestyle has been shown to be associated with decreased
incidence of obesity- and T2DM-related complications such as hypertension and cardiovascular
disease ([Manson et al., 2002]; [Stampfer et al., 2000]).
Evidence from randomized controlled trails
The efficacy of lifestyle changes in obesity and T2DM prevention has been established
in numerous randomized controlled trails (RCTs). Several of them may, however, be
considered of major importance due to their large sample sizes (i. e., 458–3234 individuals)
and long-term duration (i. e., 3–6 years). The Chinese Da Qing diabetes prevention
study was the first to investigate the effect of 6-year lifestyle change on body weight
and diabetes incidence in individuals with impaired glucose tolerance (IGT) ([Pan et al., 1997]). Pan and co-workers (1997) reported 42% reduction in diabetes incidence, although
no significant difference in body weight was present. Similar results were found in
the Finnish Diabetes Prevention Study (DPS) and the US Diabetes Prevention Program
(DPP). DPS and DPP independently reported reduction in diabetes incidence of 58% accompanied
by significant reduction in body weight (5–7%) as a result of the lifestyle modification
([Knowler et al., 2002]; [Tuomilehto et al., 2001]). These findings were also confirmed in Japanese and Indian populations, reporting
67.4% and 28.5% reduction in diabetes incidence, respectively ([Kosaka et al., 2005]; [Ramachandran et al., 2006]). All the above mentioned findings have been also reproduced in several smaller
RCTs ([Eriksson and Lindgarde, 1991]; [Penn et al., 2009]; [Wing et al., 1998]). Remarkably in the Finnish DPS success of achieving study goals was inversely associated
with diabetes incidence and none of the subjects who reached 4 of 5 study goals developed
T2DM ([Tuomilehto et al., 2001]).
Very recently the interventions that proved efficient in clinical research were successfully
translated in a real-world situation ([Sanake et al., 2011]). [Sanake et al. (2011)] reported significant reduction in body weight and diabetes incidence at 1, as well
as, at 3 years during a lifestyle modification program carried out in a primary healthcare
setting among subjects with IGT.
All large-scale interventions have been successful in preventing T2DM during the active
intervention period. Remarkably when the effectiveness of the lifestyle modification
programs was assessed on the long-term after discontinuation of the intervention,
diabetes risk still remained substantially reduced. In the Finnish DPS, for instance,
at extended follow-up 3 years after the 4-year intervention period a substantial reduction
in body weight and T2DM incidence was still present ([Lindstrom et al., 2006]). The follow-up period of the Da Qing study was even longer – 14 year. Interestingly
diabetes risk at that point was reduced to even greater extent in comparison to the
6-year active intervention ([Li et al., 2008]). In addition to these observations, 7 years after the intervention was discontinued
in the U.S. DPP body weight and T2DM incidence still remained significantly lower
in the lifestyle intervention group when compared to the control group ([Knowler et al., 2009]).
As already pointed out in several of the T2DM prevention studies the reduction in
diabetes risk has been paralleled by substantial weight loss and weight reduction
has been considered to have major importance for diabetes prevention ([Knowler et al., 2002]; [Kosaka et al., 2005]; [Lindstrom et al., 2003]; [Tuomilehto et al., 2001]). In some studies although no or just minor weight loss was achieved, diabetes incidence
was also reduced ([Pan et al., 1997]; [Ramachandran et al., 2006]). In addition, on the long term weight was partially or totally regained in all
of the studies ([Knowler et al., 2009]; [Li et al., 2008]; [Lindstrom et al., 2006]; [Lindstrom et al., 2003]). Despite this regain T2DM risk remained low or decreased further, thus the effect
of lifestyle is unlikely to be solely due to body weight reduction. In support of
this notion [Pan et al. (1997)] reported comparable decrease in T2DM incidence in the intervention group of Da Qing
among overweight and lean individuals.
Furthermore, significant improvement in various metabolic parameters has been observed
irrespectively of the degree of weight loss ([Eriksson and Lindgarde, 1991]; [Knowler et al., 2002]; [Kosaka et al., 2005]; [Pan et al., 1997]; [Ramachandran et al., 2006]; [Tuomilehto et al., 2001]; [Wing et al., 1998]). This reduction remained lower even when weight was partially or totally regained
in some of the studies ([Pan et al., 1997]; [Wing et al., 1998]). Hence, lifestyle modification seems to have an effect on T2DM not only through
reduction in body weight, but also through improvement in insulin sensitivity, blood
glucose control and lipid profile.
Whereas there is convincing evidence that lifestyle changes can prevent T2DM in randomized
controlled studies, so far little is known whether a lifestyle intervention could
also modify cardiovascular morbidity and mortality. The 20-year follow-up results
from the Chinese Da Qing diabetes prevention study showed a non-significant 17% reduction
in cardiovascular mortality in the combined (diet and/or PA) intervention group vs.
controls ([Li et al., 2008]). Similarly, lifestyle intervention in the Finnish DPS was not found to reduce significantly
cardiovascular mortality during the first 10 years of follow-up ([Uusitupa et al., 2009]). However, this study was not initially designed to examine the effect of lifestyle
intervention on total mortality or cardiovascular morbidity, and therefore the statistical
power may not have been sufficient to detect small differences in cardiovascular events
between the 2 groups. Besides, a longer follow-up period might be needed to answer
this question. In the Malmö Preventive trial with a 12-year follow-up of men with
IGT total and cardiovascular mortality were lower among participants in the lifestyle
intervention group, however, these results should be considered with caution due to
the non-randomized design of the study ([Eriksson and Lindgarde, 1998]). Recent findings of bariatric surgery treatment of very obese subjects showed that
weight loss indeed may reduce not only T2DM risk but also total mortality ([Sjöström et al., 2007]). Further investigations are needed to clarify whether prevention of T2DM by lifestyle
modification is associated with cardiovascular disease prevention; until then decisions
have to be made on the basis of the best available information.
In conclusion, evidence from epidemiological studies and RCTs demonstrate that lifestyle
modification comprising higher levels of PA and prudent food consumption may be effective
in obesity and T2DM prevention. The positive effect of lifestyle on body weight seems
somewhat transient, whereas the effect on T2DM is sustained for longer periods. Furthermore,
lifestyle modification appears to have an effect on diabetes risk independently of
body weight and even of weight loss.
Lifestyle and Genetics in Obesity and Type 2 Diabetes
Lifestyle and Genetics in Obesity and Type 2 Diabetes
Recent advancement in human genetics has led to the identification of a relatively
big number of obesity- and T2DM-associated loci. Their contribution to disease risk
has, however, been shown to be small and their predictive value low, suggesting that
lifestyle plays crucial role in obesity and T2DM development ([Vimaleswaran and Loos, 2010]). Indeed, studies investigating the gene-lifestyle interactions in obesity and T2DM
have suggested that the biological effect of genetic predisposition may be partially
or totally abolished by healthy lifestyle or lifestyle modification and vice versa.
Epidemiological studies have reported that the negative effect of several obesity-
and T2DM-associated genes may be attenuated in individuals with higher PA levels or
healthy lifestyle, whereas low PA and western dietary pattern have been found to accentuate
it. ([Ahmad et al., 2011]; [Andreasen et al., 2008]; [Brito et al., 2009]; [Nelson et al., 2007]; [Qi et al., 2009]; [Rampersaud et al., 2008]; [Ruchat et al., 2010]; [Ruiz et al., ]; [Vimaleswaran et al., 2009]). In addition, physical activity, dietary and combined lifestyle interventions have
been found to induce significant decreases in body weight and other anthropometric
traits, thus abolishing obesity risk among carriers of risk alleles in 2 of the genes
most strongly associated with obesity – FTO and MC4R ([Franks et al., 2008]; [Haupt et al., 2009a]; [Haupt et al., 2008]; [Lappalainen et al., 2009]; [Mitchell et al., 2010]; [Razquin et al., 2010]). With respect to T2DM results from several large-scale studies have provided strong
evidence for amelioration of metabolic traits and attenuation of diabetes risk among
TCF7L2 risk allele carriers by diet and exercise ([Bo et al., 2009]; [Florez et al., 2006]; [Haupt et al., 2010]; [Wang et al., 2007]). The minor allele of PPARgamma gene has also been associated with substantially
increased risk for T2DM and atherosclerosis ([Deeb et al., 1998]; [Temelkova-Kurktschiev et al., 2004]). Lifestyle modification has, however, been suggested to attenuate its negative
effect on metabolic profile, body weight, and diabetes risk ([Franks et al., 2007]; [Kilpelainen et al., 2008]; [Lindi et al., 2002]; [Ruchat et al., 2010]) ([Table 1]). The notion that lifestyle modification can eliminate the increased risk for development
of T2DM in subjects with genetic susceptibility is also supported by findings of [Barwell et al. (2008)] who reported that women with family history of T2DM experience greater improvement
in insulin sensitivity following an exercise intervention than women with no family
history.
Table 1 Gene-lifestyle interaction studies supporting the protective role of diet, exercise
or combined lifestyle interventions in individuals genetically susceptible to obesity
and type 2 diabetes.
|
Study
|
Population
|
Intervention
|
Polymorphism investigated
|
Findings
|
|
SNP, single nucleotide polymorphism
|
|
[Franks et al., 2008]
|
908 individuals with IGT or impaired fasting glucose
|
Combined lifestyle intervention – 24 weeks of intensive counseling and 3-year follow-up
|
FTO
SNP: rs9939609
|
Subcutaneous adipose tissue decreased irrespectively of genotype
|
|
[Lappalainen et al., 2009]
|
502 European individuals with overweight and IGT, aged 40–65 years
|
Combined lifestyle intervention –1 year of intensive counseling and 3-year follow-up
|
FTO
SNP: rs9939609
|
No association between the variant and the magnitude of weight reduction
|
|
[Haupt et al., 2008]
|
204 European individuals with overweight, IGT family history of T2DM or history of
gestational diabetes
|
9-month combined lifestyle intervention
|
FTO
SNP: rs8050136
|
The FTO variant did not affect reduction in body weight, total fat, subcutaneous fat,
visceral, and nonvisceral fat
|
|
[Mitchell et al., 2010]
|
234 white, overweight postmenopausal women, aged 45–75 years
|
6-month moderate intensity exercise intervention
|
FTO
SNP: rs8050136
|
Comparable weight loss occurred among genotypes
|
|
[Razquin et al., 2010]
|
776 subjects at risk of CVD, aged 55–80 years
|
3-year dietary intervention
|
FTO
SNP: rs9939609
|
Risk allele carriers had lower weight gain compared to noncarriers
|
|
Haupt et al., [2009a]
|
242 European individuals with overweight, IGT, family history of T2DM or history of
gestational diabetes
|
9-month combined lifestyle intervention
|
MC4R
SNP: rs17782313
|
The FTO variant did not affect reduction in body weight, total fat, visceral, and
nonvisceral fat
|
|
[Bo et al., 2009]
|
335 nondiabetic, dysmetabolic patients
|
1-year lifestyle intervention
|
TCF7L2
SNP: rs7903146
|
Lifestyle modification improved the metabolic pattern in all genetic subgroups
|
|
[Florez et al., 2006]
|
3 548 individuals with IGT or impaired fasting glucose
|
Combined lifestyle intervention –24 weeks of intensive counseling and 3-year follow-up
|
TCF7L2
SNPs: rs12255372 and rs7903146
|
The effect of the risk alleles in TCF7L2 on the progression to T2DM was abolished
by lifestyle
|
|
[Wang et al., 2007]
|
507 European individuals with overweight and IGT, aged 40–65 years
|
Combined lifestyle intervention –1 year of intensive counseling and 3-year follow-up
|
TCF7L2
SNPs: rs12255372 and rs7903146
|
Genetic susceptibility to T2DM was abolished by lifestyle
|
|
[Haupt et al., 2010]
|
309 nondiabetic German Caucasian subject at increased risk for T2DM
|
9-month combined lifestyle intervention
|
TCF7L2
SNP: rs7903146
|
“At risk” genotype was not associated with changes in fasting or 120-min glucose,
insulin sensitivity or insulin secretion
|
|
[Lindi et al., 2002]
|
490 European individuals with overweight and IGT, aged 40–65 years
|
Combined lifestyle intervention –1 year of intensive counseling and 3-year follow-up
|
PPARgamma
SNP: Pro12Ala
|
Lifestyle modification was associated with reduced T2DM and decreased body weight
irrespectively of genotype
|
|
[Franks et al., 2007]
|
3234 individuals with IGT or impaired fasting glucose
|
Combined lifestyle intervention –24 weeks of intensive counseling and 3-year follow-up
|
PPARgamma
SNP: Pro12Ala
|
In the lifestyle arm reduction in body weight and subcutaneous adipose tissue occurred
irrespectively of genotype
|
|
[Kilpelainen et al., 2008]
|
479 European individuals with overweight and IGT, aged 40–65 years
|
Combined lifestyle intervention –1 year of intensive counseling and 3-year follow-up
|
PPARgamma
SNPs: rs17036314, rs1801282, and rs1152003
|
Increased PA seems to decrease the negative effect of the risk alleles in rs17036314
and rs1801282, whereas combined lifestyle change abolished rs1152003-associated risk
|
|
[Ruchat et al., 2010]
|
481 sedentary, non-diabetic white individuals
|
20-week endurance training program
|
PPARgamma
SNP: rs1801282
|
Improvements in metabolic profile occurred across genotypes
|
Although lifestyle modification has been found efficient in obesity and T2DM prevention
even among genetically susceptible individuals, considerable heterogeneity in intervention
responses has been observed. Genetic influences have been suggested to contribute
to this heterogeneity. Risk allele carriers in several obesity- and T2DM-associated
genes, for instance, have been found to experience suppressed weight reduction and
improvement in various metabolic parameters in response to exercise or combined lifestyle
interventions ([Franks et al., 2007]; [Haupt et al., 2010]; [Lindi et al., 2002]; [Reinehr et al., 2008]; [Ruchat et al., 2010]; [Weyrich et al., 2008]). Thus, genetic variations in PPARD and PPARGC1A were shown to determine mitochondrial
function and change in aerobic physical fitness and insulin sensitivity during lifestyle
intervention ([Stefan et al., 2007]) and individuals carrying the minor alleles of the PPARD SNPs rs1053049, rs6902123,
and rs2267668 were found to benefit from exercise and weight loss to a lesser extent
([Thamer et al., 2008]). Besides, the NDUFB6 gene polymorphism, known to regulate mitochondrial function, was suggested to contribute
to the response of ATP synthesis to exercise training and the A allele carriers of
the NDUFB6 SNP, rs540467, were reported to show a variation in the response to exercise ([Kacerovsky-Bielesz et al., 2009]).
Furthermore, it has been suggested that genetic factors may be involved in determination
of individual PA level and energy intake ([Leibel, 2008]; [Teran-Garcia et al., 2008]). With this respect [Stubbe et al. (2006)] based on analysis from a collaborative study involving 85 198 twins suggested that
heritability of exercise participation may range from 48% to 71%. Family studies have
also reported heritability of PA ranging from 19% to 46% ([Cai et al., 2006]; [Simonen et al., 2002]). In addition obesity-related genetic polymorphisms have been associated with increased
energy intake and preference for foods of high energy density ([Haupt et al., 2009b]; [Speakman et al., 2008]; [Timpson et al., 2008]).
In summary, healthy lifestyle or lifestyle modification may keep genetic predisposition
to obesity and T2DM under control. Genetics has, however, been suggested to influence
the outcome of a lifestyle intervention or even to determine individual PA level,
food intake, and motivation for lifestyle change.
Conclusions
Obesity and T2DM are clearly the results of a complex interplay between inherited
factors and the environment. Recent advancements made through the GWA approach have
substantially contributed to our understanding of obesity and T2DM genetics, however,
most of the loci identified to date have modest effect on disease risk. Hence, lifestyle
factors, namely physical inactivity and food overconsumption seem to have major importance
for the development of both diseases.
Healthy lifestyle and lifestyle modification, on the other hand, appear to be the
most efficient tools for obesity and T2DM prevention. In addition, gene-lifestyle
interaction studies suggest that lifestyle determines whether an individual is likely
to develop the disease and that genetic susceptibility may be partially or totally
kept under control by lifestyle modification. Since genetics seems to influence individual
response to a lifestyle intervention and even the motivation for lifestyle change,
personalized interventions according to genotype may be considered in the future.
By then lifestyle modification targeting dietary change and increased physical activity
may be recommended for successful obesity and T2DM prevention irrespectively of genetic
susceptibility.
