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1.  Adipokines, Body Fatness, and Insulin Resistance Among Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;58(1):31-36.
Following our previous reports of an increased prevalence of insulin resistance and adiposity among acute lymphoblastic leukemia (ALL) survivors, particularly women treated with cranial radiotherapy (CRT), we aimed to (1) assess the relationships between adipokines (leptin and adiponectin), CRT, and measures of body fatness, and (2) determine correlates of insulin resistance, by gender.
We conducted cross-sectional evaluation of 116 ALL survivors (median age, 23.0 years; range, 18–37; average time from treatment: 17.5 years), including fasting laboratory testing (adiponectin, leptin, insulin, glucose), anthropometric measurements (weight, height, waist circumference), DXA (total body fat, truncal-to-lower-body-fat ratio), and abdominal CT (visceral fat). We estimated insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR). Analytic approaches included regression models and Wilcoxon rank sum testing.
Mean leptin per kilogram fat mass was higher for females (0.7 ng/mL/kg) than males (0.4 ng/mL/kg, P<0.01), and among subjects who had received CRT compared to those who had not received CRT (females CRT =0.9 ng/mL/kg, no CRT=0.7 ng/mL/kg; P=0.1; males CRT=0.5 ng/mL/kg, no CRT=0.3 ng/mL/kg; P<0.01). Elevated HOMA-IR was nearly uniformly present, even among subjects with BMI<25 kg/m2, and was associated with higher leptin:adiponectin ratio (P<0.01).
Among survivors of childhood leukemia, higher leptin levels were associated with measures of body fat and insulin resistance. Anthropomorphic and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance.
PMCID: PMC3520427  PMID: 21254377
ALL; adiponectin; insulin resistance; leptin; leukemia
2.  TV Viewing and Physical Activity Are Independently Associated with Metabolic Risk in Children: The European Youth Heart Study 
PLoS Medicine  2006;3(12):e488.
TV viewing has been linked to metabolic-risk factors in youth. However, it is unclear whether this association is independent of physical activity (PA) and obesity.
Methods and Findings
We did a population-based, cross-sectional study in 9- to 10-y-old and 15- to 16-y-old boys and girls from three regions in Europe (n = 1,921). We examined the independent associations between TV viewing, PA measured by accelerometry, and metabolic-risk factors (body fatness, blood pressure, fasting triglycerides, inverted high-density lipoprotein (HDL) cholesterol, glucose, and insulin levels). Clustered metabolic risk was expressed as a continuously distributed score calculated as the average of the standardized values of the six subcomponents. There was a positive association between TV viewing and adiposity (p = 0.021). However, after adjustment for PA, gender, age group, study location, sexual maturity, smoking status, birth weight, and parental socio-economic status, the association of TV viewing with clustered metabolic risk was no longer significant (p = 0.053). PA was independently and inversely associated with systolic and diastolic blood pressure, fasting glucose, insulin (all p < 0.01), and triglycerides (p = 0.02). PA was also significantly and inversely associated with the clustered risk score (p < 0.0001), independently of obesity and other confounding factors.
TV viewing and PA may be separate entities and differently associated with adiposity and metabolic risk. The association between TV viewing and clustered metabolic risk is mediated by adiposity, whereas PA is associated with individual and clustered metabolic-risk indicators independently of obesity. Thus, preventive action against metabolic risk in children may need to target TV viewing and PA separately.
A study of over 1,900 European children showed that TV viewing and physical activity in children are separately associated with obesity and metabolic risk.
Editors' Summary
Childhood obesity is a rapidly growing problem. Twenty-five years ago, overweight children were rare. Now, 155 million of the world's children are overweight, and 30–45 million are obese. Both conditions are diagnosed by comparing a child's body mass index (BMI; weight divided by height squared) with the average BMI for their age and sex. Being overweight during childhood is worrying because it is one of the so-called metabolic-risk factors that increase the chances of developing diabetes, heart problems, or strokes later in life. Other metabolic-risk factors are fatness around the belly, blood-fat disorders, high blood pressure, and problems with how the body uses insulin and blood sugar. Until recently, like obesity, these other metabolic-risk factors were seen only in adults, but now they are becoming increasingly common in children. In the US, 1 in 20 adolescents has metabolic syndrome—three or more of these risk factors. Environmental and behavioural changes have probably contributed to the increase in metabolic syndrome in children. As a group, they tend to be less physically active nowadays and they eat bigger portions of energy-dense foods more often. Increased TV viewing during childhood (and the use of other media such as computer games) has also been linked to increased obesity and to poorer health as an adult.
Why Was This Study Done?
One popular theory is that TV viewing may affect obesity and other metabolic-risk factors by displacing PA. Instead of playing in the yard after school, the theory suggests, children laze about in front of the TV. However, there is limited evidence to support this idea, and health professionals need to know whether TV viewing and PA are related, and how they affect metabolic-risk factors, in order to improve children's health. In this study, the researchers examined the associations between TV viewing, PA, and metabolic-risk factors in European children.
What Did the Researchers Do and Find?
The researchers enrolled nearly 2,000 children in two age groups from three areas in Europe. They measured the children's height and weight, estimated how fat they were by measuring skin fold thickness, measured their blood pressure, and examined the levels of glucose, insulin, and different fats in their blood. The children completed a computer questionnaire about the lengths of time for which they watched TV and how often they ate while doing so, and their PA was measured using a device called an accelerometer that each child wore for four days. When these data were analyzed statistically, the researchers found that TV viewing was slightly associated with clustered metabolic risk (the average of the individual metabolic-risk factors). This association was due to an association between TV viewing and obesity—the children who watched most TV tended to be the fattest children. However, TV viewing was not related to PA. The most active children were not necessarily those who watched least TV. Most importantly, PA was related to all individual risk factors except for obesity and with clustered metabolic risk. These associations were independent of obesity.
What Do These Findings Mean?
These results suggest that TV viewing does not damage children's health by displacing PA as popularly believed. The finding that the association between TV viewing and clustered metabolic-risk factors is mediated by obesity suggests that targeting behaviours like eating while watching TV might be a good way to improve children's health. Indeed, the researchers provide some evidence that eating while watching TV is associated with being overweight, but the results of this post hoc analysis—one that was not planned in advance—need to be confirmed. Another limitation of the study is the possibility that the children inaccurately reported their TV watching habits. Also, because measurements of metabolic-risk factors were made only once, it is impossible to say whether TV viewing or lack of PA actually causes an increase in metabolic-risk factors.
Nevertheless, these results strongly suggest that promoting PA is beneficial in relation to metabolic-risk factors, but less so in relation to obesity in childhood. TV viewing and PA should be treated as separate targets in programs designed to reverse the obesity and metabolic-syndrome epidemic in children.
Additional Information.
Please access these Web sites via the online version of this summary at
US Centers for Disease Control and Prevention, information on overweight and obesity
International Obesity Taskforce, information on obesity and its prevention, particularly in childhood
Global Prevention Alliance, details of international efforts to halt the obesity epidemic and its associated chronic diseases
American Heart Association, information for patients and professionals on metabolic syndrome and children's health
PMCID: PMC1705825  PMID: 17194189
3.  Abdominal Radiotherapy: A Major Determinant of Metabolic Syndrome in Nephroblastoma and Neuroblastoma Survivors 
PLoS ONE  2012;7(12):e52237.
Reports on metabolic syndrome in nephroblastoma and neuroblastoma survivors are scarce. Aim was to evaluate the occurrence of and the contribution of treatment regimens to the metabolic syndrome.
Patients and Methods
In this prospective study 164 subjects participated (67 adult long-term nephroblastoma survivors (28 females), 36 adult long-term neuroblastoma survivors (21 females) and 61 control subjects (28 females)). Controls were recruited cross-sectionally. Waist and hip circumference as well as blood pressure were measured. Body composition and abdominal fat were assessed by dual energy X-ray absorptiometry (DXA-scan). Laboratory measurements included fasting triglyceride, high density lipoprotein-cholesterol (HDL-C), glucose, insulin, low-density lipoprotein-cholesterol (LDL-C) and free fatty acids (FFA) levels.
Median age at follow-up was 30 (range 19–51) years in survivors and 32 (range 18–62) years in controls. Median follow-up time in survivors was 26 (6–49) years. Nephroblastoma (OR = 5.2, P<0.0001) and neuroblastoma (OR 6.5, P<0.001) survivors had more components of the metabolic syndrome than controls. Survivors treated with abdominal irradiation had higher blood pressure, triglycerides, LDL-C, FFA and lower waist circumference. The latter can not be regarded as a reliable factor in these survivors as radiation affects the waist circumference. When total fat percentage was used as a surrogate marker of adiposity the metabolic syndrome was three times more frequent in abdominally irradiated survivors (27.5%) than in non-irradiated survivors (9.1%, P = 0.018).
Nephroblastoma and neuroblastoma survivors are at increased risk for developing components of metabolic syndrome, especially after abdominal irradiation. We emphasize that survivors treated with abdominal irradiation need alternative adiposity measurements for assessment of metabolic syndrome.
PMCID: PMC3522621  PMID: 23251703
4.  Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with total body irradiation 
Survivors of childhood acute lymphoblastic leukemia (ALL) may face an increased risk of metabolic and cardiovascular late effects. In order to determine the prevalence of and risk factors for adverse cardiometabolic traits in a contemporary cohort of pediatric ALL survivors, we recruited 48 off-therapy patients in remission treated with conventional chemotherapy and 26 treated with total body irradiation (TBI) based hematopoietic cell transplantation (HCT) in this cross-sectional pilot study. At a median age of 15 (range 8–21 years), HCT survivors were significantly more likely than non-HCT survivors to manifest multiple cardiometabolic traits including central adiposity, hypertension, insulin resistance, and dyslipidemia. Overall, 23.1% of HCT survivors met criteria for metabolic syndrome (≥3 traits) compared with 4.2% of non-HCT survivors (p=0.02). HCT survivors also had increased C-reactive protein and leptin levels and decreased adiponectin, suggestive of underlying inflammation and increased visceral fat. In multivariate analyses, history of HCT remained associated with ≥2 (OR 5.13, 95% CI 1.54, 17.15) as well as ≥3 (OR 16.72, 95% CI 1.66, 168.80) traits. Other risk factors included any cranial radiation exposure and family history of cardiometabolic disease. In summary, pediatric ALL survivors exposed to TBI-based HCT as well as any cranial radiation may manifest cardiometabolic traits at an early age and should be screened accordingly.
PMCID: PMC2975816  PMID: 20685399
acute lymphoblastic leukemia; hematopoietic cell transplantation; metabolic syndrome; radiotherapy; survivor
5.  Insulin Resistance and Risk Factors for Cardiovascular Disease in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2009;27(22):3698-3704.
To determine the prevalence of insulin resistance and other risk factors for cardiovascular disease (CVD) in young adult survivors of childhood acute lymphoblastic leukemia (ALL).
Patients and Methods
In this cross-sectional evaluation of 118 survivors of childhood ALL (median age, 23.0 years; range, 18 to 37 years), insulin resistance was estimated using the homeostasis model for assessment of insulin resistance (HOMA-IR). Sex-specific comparisons were made with a cohort of 30- to 37-year-old individuals from the same region participating in the Dallas Heart Study (DHS, N = 782). ALL survivors were stratified by treatment with and without cranial radiotherapy (CRT).
Female ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.6, 95% CI, 3.6 to 5.7; no CRT, mean 3.3, 95% CI, 2.8 to 3.8) in comparison with DHS women (mean 2.4, 95% CI, 2.2 to 2.7). Eighty percent of women treated with CRT had at least three of six CVD risk factors, and they were significantly more likely to have three or more risk factors compared with DHS women (odds ratio [OR], 5.96; 95% CI, 2.15 to 16.47). Male ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.0, 95% CI, 2.8 to 5.6; no CRT, mean 3.4, 95% CI, 2.9 to 3.9) in comparison with DHS men (mean 2.3, 95% CI, 2.1 to 2.6), but were not more likely to have multiple CVD risk factors.
ALL survivors had an increased prevalence of insulin resistance in comparison with a cohort of older individuals from the same community. Importantly, women treated with CRT seem to have an increased prevalence of multiple CVD risk factors, warranting close monitoring and risk-reducing strategies.
PMCID: PMC2720083  PMID: 19564534
6.  Bone mineral density in young adult survivors of acute lymphoblastic leukemia 
Cancer  2008;113(11):3248-3256.
Condensed abstract
In a clinical follow-up study of 74 young adult survivors of childhood acute lymphoblastic leukemia (mean age 30 years), BMD of 1 SD or more below the mean was substantially more prevalent in males than in females and was strongly associated with short height. GH insufficiency, low IGF-I Z-score, and current smoking were also suggestive risk factors for low BMD.
The purpose of this study was to determine the prevalence of low bone mineral density (BMD), i.e. osteopenia, and identify factors associated with low BMD in young adult survivors of childhood acute lymphoblastic leukemia (ALL).
Dual energy X-ray absorptiometry was used to evaluate BMD in 74 randomly selected long-term childhood ALL survivors initially treated in Minneapolis/St. Paul, USA. Growth hormone (GH) releasing hormone-arginine stimulation testing was conducted to evaluate peak GH level, and insulin-like growth factor I (IGF-I) and other markers of endocrine functioning were also evaluated in relation to BMD.
Mean age at interview was 30 years and mean time since diagnosis was 24 years. Low BMD (Z-score ≤ −1) was present in 24% of subjects, including one with osteoporosis. Low BMD was substantially more prevalent in males than in females and was strongly associated with short height. The mean height Z-score for those with low BMD was −1.44, compared with a height Z-score of −0.39 (p<.01) for those with normal BMD. GH insufficiency, low IGF-I Z-score, and current smoking were also suggestive risk factors for low BMD.
In this long-term follow-up of childhood ALL survivors, low BMD was more prevalent than expected based on population normative data, specifically in males. The health consequences of early onset BMD problems in childhood ALL survivors need to be carefully monitored.
PMCID: PMC2597561  PMID: 18932250
Adverse treatment effects; Metabolic bone diseases; Neoplasms; Survivorship
7.  A Population-Based Study of Childhood Cancer Survivors' Body Mass Index 
Journal of Cancer Epidemiology  2014;2014:531958.
Background. Population-based studies are needed to estimate the prevalence of underweight or overweight/obese childhood cancer survivors. Procedure. Adult survivors (diagnosed ≤20 years) were identified from the linked Utah Cancer Registry and Utah Population Database. We included survivors currently aged ≥20 years and ≥5 years from diagnosis (N = 1060), and a comparison cohort selected on birth year and sex (N = 5410). BMI was calculated from driver license data available from 2000 to 2010. Multivariable generalized linear regression models were used to calculate prevalence relative risks (RR) and 95% confidence intervals (95% CI) of BMI outcomes for survivors and the comparison cohort. Results. Average time since diagnosis was 18.5 years (SD = 7.8), and mean age at BMI for both groups was 30.5 (survivors SD = 7.7, comparison SD = 8.0). Considering all diagnoses, survivors were not at higher risk for being underweight or overweight/obese than the comparison. Male central nervous system tumor survivors were overweight (RR = 1.12, 95% CI 1.01–1.23) more often than the comparison. Female survivors, who were diagnosed at age 10 and under, had a 10% higher risk of being obese than survivors diagnosed at ages 16–20 (P < 0.05). Conclusion. While certain groups of childhood cancer survivors are at risk for being overweight/obese, in general they do not differ from population estimates.
PMCID: PMC3913273  PMID: 24527036
8.  Cardiovascular Risk Factors in Adult Survivors of Pediatric Cancer – a report from the Childhood Cancer Survivor Study 
Childhood cancer survivors are at higher risk of morbidity and mortality from cardiovascular (CV) disease compared with the general population.
8,599 survivors (52% male) and 2,936 siblings (46% male).from the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained – prospectively followed study of persons who survived 5 years after childhood cancer diagnosed from 1970–1986 were evaluated for BMI ≥30 kg/m2 based on self reported heights and weights and self-reported use of medications for hypertension, dyslipidemia, and impaired glucose metabolism. The presence of ≥3 of the above constituted Cardiovascular Risk Factor Cluster (CVRFC) a surrogate for Metabolic Syndrome
Survivors were more likely than siblings to take medications for hypertension (OR 1.9 95% CI 1.6–2.2), dyslipidemia (OR 1.6 95% CI 1.3–2.0) or diabetes (OR 1.7 95% CI 1.2–2.3). Among these young adults (mean age 32 years for survivors and 33 years for siblings) survivors were not more likely than siblings to be obese or have CVRFC. In a multivariable logistic regression analysis, factors associated with having CVRFC included: older age at interview (≥ 40 vs. < 30 years of age [OR 8.2 95% CI 3.5–19.9]), exposure to total body irradiation (OR 5.5 95% CI 1.5–15.8) or radiation to the chest and abdomen (OR 2.3 95% CI 1.2–2.4), and physical inactivity (OR 1.7 95% CI 1.1–2.6).
Among adult survivors of pediatric cancer, older attained age, exposure to TBI or abdominal plus chest radiation, and a sedentary lifestyle are associated with CVRFC.
PMCID: PMC2805162  PMID: 20056636
survivor; cardiovascular risk factors; metabolic syndrome
9.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
PMCID: PMC3692470  PMID: 23824655
10.  Metabolic syndrome, insulin resistance, fibrinogen, homocysteine, leptin, and C-reactive protein in obese patients with obstructive sleep apnea syndrome 
Annals of Thoracic Medicine  2011;6(3):120-125.
The prevalence of obstructive sleep apnea syndrome (OSAS) and metabolic syndrome is increasing worldwide, in part linked to epidemic of obesity. The purposes of this study were to establish the rate of metabolic syndrome and to compare fibrinogen, homocysteine, high-sensitivity C-reactive protein (hsCRP), leptin levels, and homeostasis model assessment insulin resistance (HOMA-IR) in the obese patients with and without OSAS.
The study population included 36 consecutive obese patients with OSAS (23 males; mean age, 50.0 ±19.7 years), and 34 obese patients without OSAS (17 males; mean age, 49.7±11.1 years) were enrolled as control group. Metabolic syndrome was investigated; fibrinogen, homocysteine, CRP, and leptin levels were measured, and IR was assessed.
Metabolic syndrome was found in 17 (47.2%) obese OSAS patients, whereas only 29.4% of obese subjects had metabolic syndrome (P > 0.05). Obese patients with OSAS had significantly higher mean levels of triglyceride (P < 0.001), total-cholesterol (P = 0.003), low-density lipoprotein-cholesterol (P = 0.001), fasting glucose (P = 0.01), HOMA-IR (P <0.001), thyroid-stimulating hormone (P = 0.03), fibrinogen (P < 0.003), hsCRP (P <0.001), and leptin (P = 0.03) than control group . Besides, leptin level was positively correlated with waist (r = 0.512, P = 0.03) and neck circumferences (r = 0.547, P = 0.03), and fasting glucose (r = 0.471, P = 0.04) in OSAS patients, but not in obese subjects.
This study demonstrated that obese OSAS patients may have an increased rate of metabolic syndrome and higher levels of serum lipids, fasting glucose, IR, leptin, fibrinogen, and hsCRP than obese subjects without sleep apnea. Thus, clinicians should be encouraged to systematically evaluate the presence of metabolic abnormalities in OSAS and vice versa.
PMCID: PMC3131753  PMID: 21760842
C-reactive protein; fibrinogen; homocysteine; insulin resistance; leptin; metabolic syndrome; obesity; obstructive sleep apnea syndrome
11.  Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy 
Pediatric blood & cancer  2013;60(8):10.1002/pbc.24489.
Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy.
In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, homeostatic metabolic assessment (HOMA), leptin and adiponectin.
Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (p=0.001), median fasting insulin levels increased from 2.9 μU/ml to 3.1 μU/ml (p=0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (p=0.016). Median leptin increased from 2.5 ng/ml to 3.5 ng/ml (p=0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 μg/ml to 14.0 μg/ml (p=0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (p<0.001) and there was a trend to increase in HDL (p=0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively).
Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.
PMCID: PMC3881979  PMID: 23444342
Acute lymphoblastic leukemia; metabolic syndrome; obesity; insulin resistance; pediatrics; long-term side effects
12.  Contribution of diet and physical activity to metabolic parameters among survivors of childhood leukemia 
Cancer causes & control : CCC  2012;24(2):313-321.
Determine the relationship between diet and metabolic abnormalities among adult survivors of childhood acute lymphoblastic leukemia (ALL).
We surveyed 117 adult survivors of childhood ALL using the Harvard Food Frequency Questionnaire. Physical activity energy expenditure (PAEE) was measured with the SenseWear Pro2 Armband. Insulin resistance was estimated using the Homeostasis Model for Insulin Resistance (HOMA-IR). Visceral and subcutaneous adiposity were measured by abdominal CT. Adherence to a Mediterranean diet pattern was calculated using the index developed by Trichopoulou. Subjects were compared using multivariate analysis adjusted for age and gender.
Greater adherence to a Mediterranean diet pattern was associated with lower visceral adiposity (P=0.07), subcutaneous adiposity (P<0.001), waist circumference (P=0.005), and body mass index (P=0.04). For each point higher on the Mediterranean Diet Score, the odds of having the metabolic syndrome fell by 31% (OR 0.69; 95% CI 0.50, 0.94; P = 0.019). Higher dairy intake was associated with higher HOMA-IR (P =0.014), but other individual components of the Mediterranean diet, such as low intake of meat or high intake of fruits and vegetables, were not significant. PAEE was not independently associated with metabolic outcomes, although higher PAEE was associated with lower body mass index.
Adherence to a Mediterranean diet pattern was associated with better metabolic and anthropometric parameters in this cross-sectional study of ALL survivors.
PMCID: PMC3557541  PMID: 23187859
insulin resistance; leukemia; Mediterranean diet; obesity; survivorship
13.  Cardiovascular Status of Childhood Cancer Survivors Exposed and Unexposed to Cardiotoxic Therapy 
Journal of Clinical Oncology  2012;30(10):1050-1057.
To determine whether cardiovascular abnormalities in childhood cancer survivors are restricted to patients exposed to cardiotoxic anthracyclines and cardiac irradiation and how risk factors for atherosclerotic disease and systemic inflammation contribute to global cardiovascular status.
We assessed echocardiographic characteristics and atherosclerotic disease risk in 201 survivors of childhood cancer with and without exposure to cardiotoxic treatments at a median of 11 years after diagnosis (range, 3 to 32 years) and in 76 sibling controls.
The 156 exposed survivors had below normal left ventricular (LV) mass, wall thickness, contractility, and fractional shortening and above normal LV afterload. The 45 unexposed survivors also had below normal LV mass overall, and females had below normal LV wall thickness. Exposed and unexposed survivors, compared with siblings, had higher levels of N-terminal pro-brain natriuretic peptide (81.7 and 69.0 pg/mL, respectively, v 39.4 pg/mL), higher mean fasting serum levels of non–high-density lipoprotein cholesterol (126.5 and 121.1 mg/dL, respectively, v 109.8 mg/dL), higher insulin levels (10.4 and 10.5 μU/mL, respectively, v 8.2 μU/mL), and higher levels of high-sensitivity C-reactive protein (2.7 and 3.1 mg/L, respectively, v 0.9 mg/L; P < .001 for all comparisons). Age-adjusted, predicted-to-ideal 30-year risk of myocardial infarction, stroke, or coronary death was also higher for exposed and unexposed survivors compared with siblings (2.16 and 2.12, respectively, v 1.70; P < .01 for both comparisons).
Childhood cancer survivors not receiving cardiotoxic treatments nevertheless have cardiovascular abnormalities, systemic inflammation, and an increased risk of atherosclerotic disease. Survivorship guidelines should address cardiovascular concerns, including the risk of atherosclerotic disease and systemic inflammation, in exposed and unexposed survivors.
PMCID: PMC3341149  PMID: 22393080
14.  Neurocognitive Status in Long-Term Survivors of Childhood CNS Malignancies: A Report from the Childhood Cancer Survivor Study 
Neuropsychology  2009;23(6):705-717.
Among survivors of childhood cancer, those with Central Nervous System (CNS) malignancies have been found to be at greatest risk for neuropsychological dysfunction in the first few years following diagnosis and treatment. This study follows survivors to adulthood to assess the long term impact of childhood CNS malignancy and its treatment on neurocognitive functioning.
Participants & Methods
As part of the Childhood Cancer Survivor Study (CCSS), 802 survivors of childhood CNS malignancy, 5937 survivors of non-CNS malignancy and 382 siblings without cancer completed a 25 item Neurocognitive Questionnaire (CCSS-NCQ) at least 16 years post cancer diagnosis assessing task efficiency, emotional regulation, organizational skills and memory. Neurocognitive functioning in survivors of CNS malignancy was compared to that of non-CNS malignancy survivors and a sibling cohort. Within the group of CNS malignancy survivors, multiple linear regression was used to assess the contribution of demographic, illness and treatment variables to reported neurocognitive functioning and the relationship of reported neurocognitive functioning to educational, employment and income status.
Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all factors assessed by the CCSS-NCQ than non-CNS cancer survivors or siblings (p<.01), with mean T scores of CNS malignancy survivors substantially more impaired that those of the sibling cohort (p<.001), with a large effect size for Task Efficiency (1.16) and a medium effect size for Memory (.68). Within the CNS malignancy group, medical complications, including hearing deficits, paralysis and cerebrovascular incidents resulted in a greater likelihood of reported deficits on all of the CCSS-NCQ factors, with generally small effect sizes (.22-.50). Total brain irradiation predicted greater impairment on Task Efficiency and Memory (Effect sizes: .65 and .63, respectively), as did partial brain irradiation, with smaller effect sizes (.49 and .43, respectively). Ventriculoperitoneal (VP) shunt placement was associated with small deficits on the same scales (Effect sizes: Task Efficiency .26, Memory .32). Female gender predicted a greater likelihood of impaired scores on 2 scales, with small effect sizes (Task Efficiency .38, Emotional Regulation .45), while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor with a moderate effect size (.64). CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p<.01), less household income (p<.001) and less full time employment (p<.001).
Survivors of childhood CNS malignancy are at significant risk for impairment in neurocognitive functioning in adulthood, particularly if they have received cranial radiation, had a VP shunt placed, suffered a cerebrovascular incident or are left with hearing or motor impairments. Reported neurocognitive impairment adversely affected important adult outcomes, including education, employment, income and marital status.
PMCID: PMC2796110  PMID: 19899829
Neurocognitive functioning; brain tumors; CNS malignancies; Childhood Cancer Survivor Study
15.  Reduced Cardiorespiratory Fitness in Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2013;60(8):10.1002/pbc.24492.
Adult survivors of childhood acute lymphoblastic leukemia (ALL) are at increased cardiovascular risk. Studies of factors including treatment exposures that may modify risk of low cardiorespiratory fitness in this population have been limited.
To assess cardiorespiratory fitness, maximal oxygen uptake (VO2max) was measured in 115 ALL survivors (median age, 23.5 years; range 18–37). We compared VO2max measurements for ALL survivors to those estimated from submaximal testing in a frequency-matched (age, gender, race/ethnicity) 2003–2004 National Health and Nutritional Examination Survey (NHANES) cohort. Multivariable linear regression models were constructed to evaluate the association between therapeutic exposures and outcomes of interest.
Compared to NHANES participants, ALL survivors had a substantially lower VO2max (mean 30.7 vs 39.9 ml/kg/min; adjusted P<0.0001). For any given percent total body fat, ALL survivors had an 8.9 ml/kg/min lower VO2max than NHANES participants. For key treatment exposure groups (cranial radiotherapy [CRT], anthracycline chemotherapy, or neither), ALL survivors had substantially lower VO2max compared with NHANES participants (all comparisons, P<0.001). Almost two-thirds (66.7%) of ALL survivors were classified as low cardiorespiratory fitness compared with 26.3% of NHANES participants (adjusted P<0.0001). In multivariable models including only ALL survivors, treatment exposures were modestly associated with VO2max. Among females, CRT was associated with low VO2max (P=0.02), but anthracycline exposure was not (P=0.58). In contrast, among males, anthracycline exposure ≥100 mg/m2 was associated with low VO2max (P=0.03), but CRT was not (P=0.54).
Adult survivors of childhood ALL have substantially lower levels of cardiorespiratory fitness compared with a similarly aged non-cancer population.
PMCID: PMC3725590  PMID: 23418044
childhood cancer; acute lymphoblastic leukemia; survivor; cardiorespiratory fitness
16.  Obesity Is Underestimated Using Body Mass Index and Waist-Hip Ratio in Long-Term Adult Survivors of Childhood Cancer 
PLoS ONE  2012;7(8):e43269.
Obesity, represented by high body mass index (BMI), is a major complication after treatment for childhood cancer. However, it has been shown that high total fat percentage and low lean body mass are more reliable predictors of cardiovascular morbidity. In this study longitudinal changes of BMI and body composition, as well as the value of BMI and waist-hip ratio representing obesity, were evaluated in adult childhood cancer survivors.
Data from 410 survivors who had visited the late effects clinic twice were analyzed. Median follow-up time was 16 years (interquartile range 11–21) and time between visits was 3.2 years (2.9–3.6). BMI was measured and body composition was assessed by dual X-ray absorptiometry (DXA, Lunar Prodigy; available twice in 182 survivors). Data were compared with healthy Dutch references and calculated as standard deviation scores (SDS). BMI, waist-hip ratio and total fat percentage were evaluated cross-sectionally in 422 survivors, in who at least one DXA scan was assessed.
BMI was significantly higher in women, without significant change over time. In men BMI changed significantly with time (ΔSDS = 0.19, P<0.001). Percentage fat was significantly higher than references in all survivors, with the highest SDS after cranial radiotherapy (CRT) (mean SDS 1.73 in men, 1.48 in women, P<0.001). Only in men, increase in total fat percentage was significantly higher than references (ΔSDS = 0.22, P<0.001). Using total fat percentage as the gold standard, 65% of female and 42% of male survivors were misclassified as non-obese using BMI. Misclassification of obesity using waist-hip ratio was 40% in women and 24% in men.
Sixteen years after treatment for childhood cancer, the increase in BMI and total fat percentage was significantly greater than expected, especially after CRT. This is important as we could show that obesity was grossly underestimated using BMI and waist-hip ratio.
PMCID: PMC3419210  PMID: 22905245
17.  Effect of Exercise on Metabolic Syndrome Variables in Breast Cancer Survivors 
Objective. Breast cancer survivors are highly sedentary, overweight, or obese, which puts them at increased risk for comorbid chronic disease. We examined the prevalence of, and changes in, metabolic syndrome following 6 months of an aerobic exercise versus usual care intervention in a sample of sedentary postmenopausal breast cancer survivors. Design and Methods. 65 participants were randomized to an aerobic exercise intervention (EX) (n = 35) mean BMI 30.8 (±5.9) kg/m2 or usual care (UC) (n = 30) mean BMI 29.4 (±7.4) kg/m2. Metabolic syndrome prevalence was determined, as well as change in criteria and overall metabolic syndrome. Results. At baseline, 55.4% of total women met the criteria for metabolic syndrome. There was no statistically significant change in metabolic syndrome when comparing EX and UC. However, adhering to the exercise intervention (at least 120 mins/week of exercise) resulted in a significant (P = .009) decrease in metabolic syndrome z-score from baseline to 6 months (−0.76 ± 0.36) when compared to those who did not adhere (0.80 ± 0.42). Conclusions. Due to a higher prevalence of metabolic syndrome in breast cancer survivors, lifestyle interventions are needed to prevent chronic diseases associated with obesity. Increasing exercise adherence is a necessary target for further research in obese breast cancer survivors.
PMCID: PMC3844242  PMID: 24319454
18.  Hawai‘i's Multiethnic Adolescent and Young Adult Survivors of Childhood Cancer: Are Their Health Behavior Risks Similar to State and National Samples? 
Due to toxicities associated with their malignancies and treatments, adolescent and young adult survivors of childhood cancer (AYASCC) are at high risk for developing chronic diseases. This can be compounded by a greater prevalence of unhealthy behaviors relative to similarly aged non-cancer peers. Disparities in health behaviors have been noted for Black and Hispanic AYASCC, but data on Asian American (AA) or Native Hawaiian and Other Pacific Islander (NHOPI) minorities are lacking. The purpose of this study was to help bridge these information gaps by gathering data from Hawai‘i AA and NHOPI AYSCC. Telephone surveys were used to collect health behavior data from survivors 13–24 years of age (N=64); 55% of the sample was female, 77% AA or NHOPI, 63% leukemia/lymphoma survivors, and 32% overweight/obese. These were compared to state/national survey data for similarly aged individuals (Youth Risk Behavior Surveillance System data for 13–17 year olds, and Behavioral Risk Factor Surveillance System data for 18–24 year olds). While Hawai‘i AYASCC had significantly lower rates of tobacco/alcohol use, a higher proportion did not eat five fruits/vegetables a day (96%) compared to state (83%) and national (78%) samples (P < .001). Although many met age-specific physical activity recommendations, 44% of <18 year olds and 29% of ≥18 year olds still failed to meet national guidelines. Low intake of fruits/vegetables and suboptimal levels of physical activity place these vulnerable, ethnic minority cancer survivors at higher risk for chronic disease. These findings underscore the need to assess and advise survivors about their diet and exercise habits as part of post-treatment care.
PMCID: PMC3831565  PMID: 24251083
Childhood cancer survivors; Asian and Native Hawaiian/Pacific Islander; Nutrition; Physical activity
19.  The metabolic syndrome and body composition in childhood cancer survivors 
Korean Journal of Pediatrics  2011;54(6):253-259.
Long-term survivors of childhood cancer appear to have an increased risk for the metabolic syndrome, subsequent type 2 diabetes and cardiovascular disease in adulthood compared to healthy children. The purpose of this study was to investigate the frequency of the metabolic syndrome and associated factors in childhood cancer survivors at a single center in Korea.
We performed a retrospective review of medical records of 98 childhood cancer survivors who were diagnosed and completed anticancer treatment at Samsung Medical Center, Seoul, Korea between Jan. 1996 and Dec. 2007. Parameters of metabolic syndrome were evaluated between Jan. 2008 and Dec. 2009. Clinical and biochemical findings including body fat percentage were analyzed.
A total of 19 (19.4%) patients had the metabolic syndrome. The median body fat percentage was 31.5%. The body mass index and waist circumference were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.00, respectively). Sixty-one (62.2%) patients had at least one abnormal lipid value. The triglyceride showed significant positive correlation with the body fat percentage (r=0.26, P=0.03). The high density lipoprotein cholesterol showed significant negative correlation with the percent body fat (r=-0.26, P=0.03).
Childhood cancer survivors should have thorough metabolic evaluation including measurement of body fat percentage even if they are not obese. A better understanding of the determinants of the metabolic syndrome during adolescence might provide preventive interventions for improving health outcomes in adulthood.
PMCID: PMC3174361  PMID: 21949520
Cancer survivor; Metabolic syndrome; Body composition; Fat percentage
20.  Metabolic Syndrome in Mexican Women Survivors of Breast Cancer: A Pilot Study at a General Hospital 
Medical Archives  2014;68(1):19-21.
According to developed countries’ studies, in breast cancer survivors there is a high prevalence of metabolic syndrome; however, in Mexico data is lacking about this issue.
To explore if metabolic syndrome occurs in Mexican women survivors of breast cancer.
Material and methods:
At a second-level general hospital, women with breast cancer with a surviving >2 years were studied. The analysis involved their demographic and anthropometric features, blood pressure measurement, time of surviving, besides fasting blood levels of lipids and glucose.
The sample consisted of 100 women; 42% were obese (body mass index ≥30 kg/m2). The sample´s mean age was 60 years with a mean surviving time of 6.5 years. Their mean glucose level was 122 mg/dL and triglycerides 202 mg/dL. There were 33% with blood pressure ≥130/85mm Hg or diagnosis of hypertension. Fifty-seven percent had glucose >99 mg/dL or diagnosis of diabetes mellitus, and 58% had triglycerides >149 mg/dL. Metabolic syndrome occurred in 57% of obese women.
Our results suggest that metabolic syndrome occurs in more than 50% of obese Mexican women survivors of breast cancer.
PMCID: PMC4272473  PMID: 24783905
Body Mass Index; Cancer; Metabolic Syndrome; Mexico/Epidemiology; Obesity
21.  Prevalence and association between obesity and metabolic syndrome among Chinese elementary school children: a school-based survey 
BMC Public Health  2010;10:780.
China has experienced an increase in the prevalence of childhood overweight/obesity over the last decades. The purpose of this study was to examine the prevalence of obesity and metabolic syndrome among Chinese school children and determine if there is a significant association between childhood obesity and metabolic syndrome.
A cross-sectional study was conducted among 1844 children (938 males and 906 females) in six elementary schools at Guangzhou city from April to June 2009. The body mass index (BMI), waist circumference, blood pressure, Tanner stage, lipids, insulin and glucose levels were determined. Criteria analogous to ATPIII were used for diagnosis of metabolic syndrome in children.
Among 1844 children aged 7-14 years, 205 (11.1%) were overweight, and 133 (7.2%) were obese. The prevalence of metabolic syndrome was 6.6% overall, 33.1% in obese, 20.5% in overweight and 2.3% in normal weight children. Multiple logistic regression analysis showed that BMI (3rd quartile)(OR 3.28; 95%CI 0.35-30.56), BMI (4th quartile)(OR 17.98; 95%CI 1.75-184.34), homeostasis model assessment (HOMA-IR) (2nd quartile) (OR2.36; 95% CI 0.46-12.09), HOMA-IR (3rd quartile) (OR 2.46; 95% CI 0.48-12.66), HOMA-IR (4th quartile) (OR3.87; 95% CI 0.72-20.71) were significantly associated with metabolic syndrome.
The current epidemic of obesity with subsequent increasing cardiovascular risk factors has constituted a threat to the health of school children in China. HOMA-IR and BMI were strong predictors of metabolic syndrome in children. Therefore, rigorous obesity prevention programs should be implemented among them.
PMCID: PMC3022853  PMID: 21176200
22.  Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome 
To investigate risk factors for metabolic syndrome in prepubertal boys with Klinefelter syndrome.
Eighty-nine boys with Klinefelter syndrome, ages 4–12.9 years, and 34 age-matched control boys had height, weight, waist circumference and blood pressure measured and their parents completed a questionnaire about physical activity. The boys with Klinefelter syndrome also had measurement of lipids, fasting glucose and insulin. Insulin-glucose homeostasis model assessment was calculated, and the boys were evaluated for childhood metabolic syndrome.
The Klinefelter syndrome and control groups were similar ages (7.5 ± 2.4 vs. 8.1 ± 2.3 years). Body mass index measurements were similar, but waist circumference was >90‰ in 30% of boys with Klinefelter syndrome versus 21% of controls. The mean daily time spent running was 42 min less in the Klinefelter syndrome versus control groups (p < 0.01). About 37% of the boys with Klinefelter syndrome had elevated LDL cholesterol, 24% had insulin resistance, and 7% met the three criteria for diagnosis of metabolic syndrome.
Truncal obesity, insulin resistance and metabolic syndrome are present in boys as young as 4–12 years with Klinefelter syndrome, and these occur in association with reduced running-type activity.
PMCID: PMC4164507  PMID: 21251059
47; XXY; Insulin resistance; Karyotype; Klinefelter syndrome; Metabolic syndrome; Testicular failure
23.  The prevalence of metabolic syndrome and insulin resistance according to the phenotypic subgroups of polycystic ovary syndrome in a representative sample of Iranian females* 
Polycystic ovary syndrome (PCOS) is associated with metabolic abnormalities which are also parts of metabolic syndrome (MetS). It is debated whether all women with PCOS should be screened for MetS and Insulin resistance (IR), since they may vary in terms of PCOS phenotype, ethnicity and age. This large scale study aimed to determine the prevalence of MetS among Iranian women diagnosed with different phenotypic subgroups of PCOS based on the Rotterdam criteria.
This study was conducted from January 2006 to June 2008 in Isfahan, Iran. The study population comprised females diagnosed with PCOS referred to the infertility clinic. The subjects were divided into for subgroups according to different phenotypes of PCOS based on the Rotterdam criteria. They underwent metabolic screening according to NCEP ATP III guidelines and IR screening based on homeostasis model assessment (HOMA) of insulin resistance.
The prevalence of MetS and IR were 24.9% and 24.3%, respectively. A significant difference in the prevalence of MetS was documented between anovulatory women having PCOS with or without hyperandrogenism (23.1% and 13.9%, respectively; P = 0.001). Likewise, in PCOS women with hyperandrogenism, the MetS prevalence differed among those with or without polycystic ovary (23.1% and 63.8%, respectively; P = 0.001).
The prevalence of MetS and IR varies between the phenotypic subgroups of PCOS. Hyperandrogenemia PCOS phenotypes of Iranian women, in particular those without sonographic polycystic ovary, are highly at risk of MetS and IR.
PMCID: PMC3214394  PMID: 22091305
Polycystic Ovary Syndrome; Rotterdam Criteria; Metabolic Syndrome; Insulin Resistance
24.  Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity  
PLoS Medicine  2008;5(3):e51.
The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.
Methods and Findings
We used a special study design of “clonal controls,” rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean ± standard deviation (SD) age 25.8 ± 1.4 y and a body mass index (BMI) difference 5.2 ± 1.8 kg/m2. Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.
Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
Leena Peltonen and colleagues uncover the metabolic changes that result from obesity through an analysis of genetically identical twin pairs in which one was obese and the other was not.
Editors' Summary
Around the world, the proportion of people who are obese (people with an unhealthy amount of body fat) is increasing. In the US, for example, 1 adult in 7 was obese in the mid 1970s. That is, their body mass index (BMI)—their weight in kilograms divided by their height in meters squared—was more than 30. Nowadays, 1 US adult in 3 has a BMI this high and, by 2025, it is predicted that 1 in 2 will be obese. This obesity epidemic is being driven by lifestyle changes that encourage the over-consumption of energy-rich foods and discourage regular physical activity. The resultant energy imbalance leads to weight gain (the excess energy is stored as body fat or adipose tissue) and also triggers numerous metabolic changes, alterations in the chemical processes that convert food into the energy and various substances needed to support life. These obesity-related metabolic changes increase a person's risk of developing adverse health conditions such as diabetes, a condition in which dangerously high levels of sugar from food accumulate in the blood.
Why Was This Study Done?
The changes in human fat in obesity have not been completely understood, although the abnormal metabolism of adipose tissue is increasingly seen as playing a critical part in excessive weight gain. It has been very difficult to decipher which molecular and metabolic changes associated with obesity are the result of becoming obese, and which might contribute towards the acquisition of obesity in humans in the first place. To discover more about the influence of environment on obesity-induced metabolic changes, the researchers in this study have investigated these changes in pairs of genetically identical twins.
What Did the Researchers Do and Find?
The researchers recruited 14 pairs of genetically identical Finnish twins born between 1975 and 1979 who were “obesity discordant”—that is, one twin of each pair had a BMI of about 25 (not obese); the other had a BMI of about 30 (obese). The researchers took fat and blood samples from each twin, determined the insulin sensitivity of each, and measured the body composition and various fat stores of each. They found that the obese twins had more subcutaneous, intra-abdominal, and liver fat and were less insulin sensitive than the non-obese twins. Insulin sensitivity correlated with the amount of liver fat. Analysis of gene expression in the fat samples showed that 19 gene pathways (mainly inflammatory pathways) were expressed more strongly (up-regulated) in the obese twins than the non-obese twins, whereas seven pathways were down-regulated. The most highly down-regulated pathway was a mitochondrial pathway involved in amino acid breakdown, but mitochondrial energy metabolism pathways were also down-regulated. Finally, mitochondrial DNA copy number in fat was reduced in the obese twins by nearly half, a novel observation that could partly account for the obesity-induced metabolic defects of these individuals.
What Do These Findings Mean?
These and other findings identify several pathways that are involved in the development of obesity and insulin resistance. In particular, they suggest that changes in mitochondrial energy production pathways and in mitochondrial amino acid metabolism pathways could play important roles in the development of obesity and of insulin resistance and in the accumulation of liver fat even in young obese people. The study design involving identical twins has here produced some evidence for aberrations in molecules critical for acquired obesity. The results suggest that careful management of obesity by lifestyle changes has the potential to correct the obesity-related metabolic changes in fat that would otherwise lead to diabetes and other adverse health conditions in obese individuals. In addition, they suggest that the development of therapies designed to correct mitochondrial metabolism might help to reduce the illnesses associated with obesity.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has pages on obesity and diabetes (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of obesity (in English and Spanish)
The UK National Health Service's health Web site (NHS Direct) provides information about obesity
The International Obesity Taskforce provides information about preventing obesity and on diabetes and obesity
The UK Foods Standards Agency and the United States Department of Agriculture provide online tools and useful advice about healthy eating for adults and children
Information is available for patients and carers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance
PMCID: PMC2265758  PMID: 18336063
25.  Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2012;118(23):5920-5928.
Although reductions in bone mineral density are well-documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The aim of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).
Analyses included 7414 5+ year survivors of childhood cancer diagnosed between 1970-86 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings.
The median ages at follow-up among survivors and siblings were 36.2, (range: 21.2-58.8) and 38.1 years (range: 18.4-62.6), respectively with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥1 fractures during their lifetime. The prevalence of fractures was lower among survivors than siblings, both in males (prevalence ratio=0.87, 95%CI=0.81-0.94, p<0.001) and females (prevalence ratio=0.94, 95%CI=0.86-1.04, p=0.22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment and balance difficulties were associated with increased prevalence of fractures among female survivors (p=0.05). Among males, only smoking history and white race were associated with an increased prevalence of fracture (p<0.001).
Findings from this study indicate that the prevalence of fractures among adult survivors is not increased compared to that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.
PMCID: PMC3439597  PMID: 22605509

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