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1.  Effects of Growth Hormone and Pioglitazone in Viscerally Obese Adults with Impaired Glucose Tolerance: A Factorial Clinical Trial 
PLoS Clinical Trials  2007;2(5):e21.
Objective:
Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH-induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time.
Design:
Randomized, double-blind, placebo-controlled, 2 × 2 factorial design.
Setting:
Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States.
Participants:
62 abdominally obese adults aged 40–75 with impaired glucose tolerance.
Interventions:
GH (8 μg/kg/d, or placebo) and pioglitazone (30 mg/d, or placebo) for 40 wk.
Outcome Measures:
Baseline and after 40 wk of treatment, VAT content was quantified by CT scan, glucose tolerance was assessed using a 75-g oral glucose tolerance test, and insulin sensitivity was measured using steady-state plasma glucose levels obtained during insulin suppression test.
Results:
Baseline: body mass index (BMI), plasma glucose, and visceral fat content were similar. 40 wk: visceral fat area declined 23.9 ± 7.4 cm2 in GH group, mean difference from placebo: −28.1 cm2 (95% CI −49.9 to −6.3 cm2; p = 0.02). Insulin resistance declined 52 ± 11.8 mg/dl with PIO, mean difference from placebo of −58.8 mg/dl (95% CI −99.7 to −18.0 mg/dl; p = 0.01). VAT and SSPG declined with GH and PIO combined, mean differences from placebo of −31.4 cm2 (95% CI −56.5 cm2 to −6.3 cm2; p = 0.02) and −55.3 mg/dl (95% CI −103.9 to −6.7 mg/dl; p = 0.02), respectively. Fasting plasma glucose increased transiently in GH group. No significant changes in BMI were observed.
Conclusions:
Addition of PIO to GH attenuated the short-term diabetogenic effect of GH; the drug combination reduced VAT and insulin resistance over time. GH plus PIO may have added benefit on body composition and insulin sensitivity in the metabolic syndrome.
Editorial Commentary
Background: People who are overweight are at higher risk of developing type 2 diabetes, particularly if they have impaired glucose tolerance (IGT). When an individual has IGT, their cells are not able to respond properly to insulin in the blood, which means that blood sugar levels can remain high, and fat cells do not take up fatty acids from blood at the rate they should. The term prediabetes is often used to refer to these linked characteristics. However, if such individuals are able to lose weight they can reduce their chances of becoming diabetic in the future. In particular, loss of a particular type of fat, the visceral fat (packed in around the internal organs, as opposed to fat immediately under the skin), is thought to be beneficial for people at risk of developing type 2 diabetes. Some researchers have suggested that giving human growth hormone (GH) to people who are overweight might help reduce their levels of visceral fat. At the same time, drugs known as thiazolidinediones are currently used, in combination with other drugs, diet, and exercise, as a treatment for type 2 diabetes. The researchers carrying out this study wanted to find out whether combining treatment with human GH and a thiazolidinedione, pioglitazone (PIO), would reduce levels of visceral fat and improve glucose metabolism in overweight adults with IGT. The researchers specifically planned to compare the changes in these primary outcomes amongst people receiving both human GH and PIO for 40 weeks with the changes in individuals receiving placebo only; additional comparisons were also done for individuals receiving either drug alone, as compared to placebo.
What this trial shows: A total of 76 participants were randomized and received the treatment allocated to them, but only 62 participants were included in the final analyses due to losses to follow-up. The primary outcomes being compared at baseline and after 40 weeks of treatment were the change in visceral fat levels and change in individuals' sensitivity to insulin. Individuals receiving GH experienced a drop in visceral fat area over the 40 weeks of the trial, as compared to placebo, whilst PIO alone did not seem to have an effect on visceral fat area. Individuals receiving both GH and PIO, however, also showed a decrease in visceral fat area. When examining the effect on insulin resistance, GH alone did not seem to have an effect on the ability to respond to insulin. However, administration of PIO alone did bring about a decrease in insulin resistance levels, as compared to placebo, and individuals receiving both GH and PIO together also experienced a drop in insulin resistance. The trial was not designed to detect statistically significant differences in side effects between the groups studied, but some side effects, such as build-up of fluid in the limbs and joint stiffness, seemed to be more common in the groups receiving drug treatment than in the placebo group.
Strengths and limitations: Although the trial was small, enough participants were recruited to detect statistically significant changes in the primary outcomes. Strengths of the trial include the use of appropriate techniques to conceal the randomization sequence from investigators recruiting participants into the trial and blinding of both participants and investigators to the treatments that an individual would receive. However, one limitation includes the fact that the likelihood of developing diabetes was not directly measured as an outcome in this trial, and it is therefore not possible to conclude from these results that administration of GH, PIO, or both combined, will help prevent diabetes amongst overweight people with IGT. Finally, this trial compared the drug interventions directly with placebo and not with behavioral interventions such as diet and exercise, which are normally recommended for the prevention of diabetes amongst overweight people. It would be important to further investigate the efficacy, harms, and costs of these drugs directly against nondrug interventions before making any recommendations about their clinical use.
Contribution to the evidence: Other studies have shown that PIO administration has beneficial effects on insulin sensitivity in people with type 2 diabetes. This study adds evidence confirming that PIO is likely to have similar effects in people who are not diabetic but who are overweight and who have IGT. The study also adds data regarding the effect of PIO and GH combined in such populations; giving both drugs together seemed to have beneficial effects on visceral fat area and insulin sensitivity, as compared to placebo.
doi:10.1371/journal.pctr.0020021
PMCID: PMC1865086  PMID: 17479164
2.  Glucose tolerance, insulin resistance and insulin secretion in young south Indian adults; relationships to parental size, neonatal size and childhood body mass index 
Objective
To study the relationship of newborn size and post-natal growth to glucose intolerance in south Indian adults.
Research design and Methods
2,218 men and women (mean age 28 years) were studied from a population-based birth cohort born in a large town and adjacent rural villages. The prevalence of adult diabetes mellitus [DM] and impaired glucose tolerance [IGT], and insulin resistance and insulin secretion (calculated) were examined in relation to BMI and height at birth, and in infancy, childhood and adolescence and changes in BMI and height between these stages.
Results
Sixty-two (2.8%) subjects had type 2 diabetes (DM) and 362 (16.3%) had impaired glucose tolerance (IGT). IGT and DM combined (IGT/DM) and insulin resistance were associated with low childhood body mass index (BMI) (p<0.001 for both) and above-average BMI gain between childhood or adolescence and adult life (p<0.001 for both). There were no direct associations between birthweight or infant size and IGT/DM; however, after adjusting for adult BMI, lower birthweight was associated with an increased risk.
Conclusions
The occurrence of IGT and Type 2 DM is associated with thinness at birth and in childhood followed by accelerated BMI gain through adolescence.
doi:10.1016/j.diabres.2009.11.015
PMCID: PMC3428893  PMID: 20115937
Type 2 diabetes mellitus; impaired glucose tolerance; insulin resistance; childhood body mass index; young adulthood
3.  Adult metabolic syndrome and impaired glucose tolerance are associated with different patterns of body mass index gain during infancy; Data from the New Delhi birth cohort 
Diabetes care  2008;31(12):2349-2356.
Objective:
To describe patterns of infant, childhood and adolescent body mass index (BMI) and weight associated with adult metabolic risk factors for cardiovascular disease.
Research Design and Methods:
We measured waist circumference, blood pressure, glucose, insulin and lipid concentrations, and the prevalence of metabolic syndrome (NCEP-ATPIII definition) in 1,492 men and women aged 26-32 years in Delhi, India, whose weight and height were recorded 6-monthly throughout infancy (0-2 years), childhood (2-11 years) and adolescence (11 years-adult).
Results:
Men and women with metabolic syndrome (29% overall), any of its component features, or higher (>upper quartile) insulin resistance (HOMA) had more rapid BMI or weight gain than the rest of the cohort throughout infancy, childhood and adolescence. Glucose intolerance (impaired glucose tolerance or diabetes) was, like metabolic syndrome, associated with rapid BMI gain in childhood and adolescence, but with lower BMI in infancy.
Conclusions:
In this Indian population, patterns of infant BMI and weight gain differed for people who developed metabolic syndrome (rapid gain) compared with those who developed glucose intolerance (low infant BMI). Rapid BMI gain during childhood and adolescence was a risk factor for both disorders.
doi:10.2337/dc08-0911
PMCID: PMC2584194  PMID: 18835958
Metabolic syndrome; diabetes; birthweight; infant weight; child growth
4.  Increased incidence of glucose disorders during pregnancy is not explained by pre-pregnancy obesity in London, Canada 
Background
The increasing incidence of impaired glucose tolerance (IGT), gestational diabetes (GDM) and type 2 diabetes (T2D) during pregnancy was hypothesized to be associated with increases in pre-pregnancy body mass index (BMI). The aims were to 1) determine the prevalence of IGT/GDM/T2 D over a 10 year period; 2) examine the relationship between maternal overweight/obesity and IGT/GDM/T2D; and 3) examine the extent to which maternal metabolic complications impact maternal and fetal pregnancy outcomes.
Methods
Data arose from a perinatal database which contains maternal characteristics and perinatal outcome for all singleton infants born in London, Canada between January 1, 2000 and December 31, 2009. Univariable and multivariable odds ratios (OR) were estimated using logistic regression with IGT/GDM/T2 D being the outcome of interest.
Results
A total of 36,597 women were included in the analyses. Population incidence of IGT, GDM and T2 D rose from 0.7%, 2.9% and 0.5% in 2000 to 1.2%, 4.2% and 0.9% in 2009. The univariable OR for IGT, GDM and T2 D were 1.65, 1.52 and 2.06, respectively, over the ten year period. After controlling for maternal age, parity and pre-pregnancy BMI the OR did not decrease. Although there was a positive relationship between pre-pregnancy BMI and prevalence of IGT/GDM/T2 D, this did not explain the time trends in the latter. Diagnosis of IGT/GDM/T2 D increased the risk of having an Apgar score <7 at 5 minutes, which was partially explained by gestational hypertension, high placental ratio, gestational age and large for gestational age babies.
Conclusions
We found a significant increase in the incidence of IGT/GDM/T2 D for the decade between 2000-2009 which was not explained by rising prevalence of maternal overweight/obesity.
doi:10.1186/1471-2393-10-85
PMCID: PMC3022738  PMID: 21184681
5.  Allele Summation of Diabetes Risk Genes Predicts Impaired Glucose Tolerance in Female and Obese Individuals 
PLoS ONE  2012;7(6):e38224.
Introduction
Single nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies. It is not known whether a similar genetic impact on the risk of prediabetes (impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) exists.
Methods
In our cohort of 1442 non-diabetic subjects of European origin (normal glucose tolerance [NGT] n = 1046, isolated IFG n = 142, isolated IGT n = 140, IFG+IGT n = 114), an impact on glucose homeostasis has been shown for 9 SNPs in previous studies in this specific cohort. We analyzed these SNPs (within or in the vicinity of the genes TCF7L2, KCNJ11, HHEX, SLC30A8, WFS1, KCNQ1, MTNR1B, FTO, PPARG) for association with prediabetes.
Results
The genetic risk load was significantly associated with the risk for IGT (p = 0.0006) in a model including gender, age, BMI and insulin sensitivity. To further evaluate potential confounding effects, we stratified the population on gender, BMI and insulin sensitivity. The association of the risk score with IGT was present in female participants (p = 0.008), but not in male participants. The risk score was significantly associated with IGT (p = 0.008) in subjects with a body mass index higher than 30 kg/m2 but not in non-obese individuals. Furthermore, only in insulin resistant subjects a significant association between the genetic load and the risk for IGT (p = 0.01) was found.
Discussion
We found that T2D genetic risk alleles cause an increased risk for IGT. This effect was not present in male, lean and insulin sensitive subjects, suggesting a protective role of beneficial environmental factors on the genetic risk.
doi:10.1371/journal.pone.0038224
PMCID: PMC3387191  PMID: 22768041
6.  Assessment of Insulin Resistance and Impaired Glucose Tolerance in Lean Women with Polycystic Ovary Syndrome 
Journal of Women's Health  2011;20(1):37-43.
Abstract
Objective
To analyze insulin resistance (IR) and determine the need for a 2-hour oral glucose tolerance test (OGTT) for the identification of IR and impaired glucose tolerance (IGT) in lean nondiabetic women with polycystic ovary syndrome (PCOS).
Methods
This was a cross-sectional analysis of treatment-naive women with PCOS who enrolled in a university-based clinical trial. Nondiabetic women with PCOS based on the Eunice Kennedy Shriven National Institute of Child Health and Human Development (NICHD) definition, aged 18–43 years and weighing ≤113 kg, were evaluated. Glucose and insulin levels were assessed at times 0, 30, 60, 90, and 120 minutes after a 75-g glucose load. Lean was defined as body mass index (BMI) <25 kg/m2. Multiple linear regression was performed.
Results
A cohort of 78 women was studied. The prevalence of IR was 0% among lean women vs. 21% among nonlean subjects based on fasting insulin I0 and 40%–68% based on two different homeostatic model assessment (HOMA) cutoff points (p < 0.005). All women with IR had a BMI ≥ 28. Controlling for age and race, BMI explained over 57% of the variation in insulin fasting (Io), glucose fasting/Io (Go/Io), the qualitative insulin sensitivity check index (QUICKI), and HOMA and was a highly significant predictor of these outcomes (p < 0.0001). Only 1 of 31 (3%) of the lean PCOS women had IGT based on a 2-hour OGTT, and no lean subjects had IGT based on their fasting blood glucose.
Conclusions
Diabetes mellitus, IGT, and IR are far less common in young lean women with PCOS compared with obese women with PCOS. These data imply that it is unnecessary to routinely perform either IR testing or 2-hour OGTT in lean women with PCOS; however, greater subject accumulation is needed to determine if OGTT is necessary in lean women with PCOS. BMI is highly predictive of both insulin and glucose levels in women with PCOS.
doi:10.1089/jwh.2010.2053
PMCID: PMC3026650  PMID: 21194310
7.  Metabolic Signatures of Adiposity in Young Adults: Mendelian Randomization Analysis and Effects of Weight Change 
PLoS Medicine  2014;11(12):e1001765.
In this study, Wurtz and colleagues investigated to what extent elevated body mass index (BMI) within the normal weight range has causal influences on the detailed systemic metabolite profile in early adulthood using Mendelian randomization analysis.
Please see later in the article for the Editors' Summary
Background
Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.
Methods and Findings
We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16–39 y; 51% women; mean ± standard deviation BMI 24±4 kg/m2). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%–183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87%±3%; R2 = 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160%±2%; R2 = 0.92).
Conclusions
Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Adiposity—having excessive body fat—is a growing global threat to public health. Body mass index (BMI, calculated by dividing a person's weight in kilograms by their height in meters squared) is a coarse indicator of excess body weight, but the measure is useful in large population studies. Compared to people with a lean body weight (a BMI of 18.5–24.9 kg/m2), individuals with higher BMI have an elevated risk of developing life-shortening cardiometabolic diseases—cardiovascular diseases that affect the heart and/or the blood vessels (for example, heart failure and stroke) and metabolic diseases that affect the cellular chemical reactions that sustain life (for example, diabetes). People become unhealthily fat by consuming food and drink that contains more energy (calories) than they need for their daily activities. So adiposity can be prevented and reversed by eating less and exercising more.
Why Was This Study Done?
Epidemiological studies, which record the patterns of risk factors and disease in populations, suggest that the illness and death associated with excess body weight is partly attributable to abnormalities in how individuals with high adiposity metabolize carbohydrates and fats, leading to higher blood sugar and cholesterol levels. Further, adiposity is also associated with many other deviations in the metabolic profile than these commonly measured risk factors. However, epidemiological studies cannot prove that adiposity causes specific changes in a person's systemic (overall) metabolic profile because individuals with high BMI may share other characteristics (confounding factors) that are the actual causes of both adiposity and metabolic abnormalities. Moreover, having a change in some aspect of metabolism could also lead to adiposity, rather than vice versa (reverse causation). Importantly, if there is a causal effect of adiposity on cardiometabolic risk factor levels, it might be possible to prevent the progression towards cardiometabolic diseases by weight loss. Here, the researchers use “Mendelian randomization” to examine whether increased BMI within the normal and overweight range is causally influencing the metabolic risk factors from many biological pathways during early adulthood. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. Several gene variants are known to lead to modestly increased BMI. Thus, an investigation of the associations between these gene variants and risk factors across the systemic metabolite profile in a population of healthy individuals can indicate whether higher BMI is causally related to known and novel metabolic risk factors and higher cardiometabolic disease risk.
What Did the Researchers Do and Find?
The researchers measured the BMI of 12,664 adolescents and young adults (average BMI 24.7 kg/m2) living in Finland and the blood levels of 82 metabolites in these young individuals at a single time point. Statistical analysis of these data indicated that elevated BMI was adversely associated with numerous cardiometabolic risk factors. For example, elevated BMI was associated with raised levels of low-density lipoprotein, “bad” cholesterol that increases cardiovascular disease risk. Next, the researchers used a gene score for predisposition to increased BMI, composed of 32 gene variants correlated with increased BMI, as an “instrumental variable” to assess whether adiposity causes metabolite abnormalities. The effects on the systemic metabolite profile of a 1-kg/m2 increment in BMI due to genetic predisposition closely matched the effects of an observed 1-kg/m2 increment in adulthood BMI on the metabolic profile. That is, higher levels of adiposity had causal effects on the levels of numerous blood-based metabolic risk factors, including higher levels of low-density lipoprotein cholesterol and triglyceride-carrying lipoproteins, protein markers of chronic inflammation and adverse liver function, impaired insulin sensitivity, and elevated concentrations of several amino acids that have recently been linked with the risk for developing diabetes. Elevated BMI also causally led to lower levels of certain high-density lipoprotein lipids in the blood, a marker for the risk of future cardiovascular disease. Finally, an examination of the metabolic changes associated with changes in BMI in 1,488 young adults after a period of six years showed that those metabolic measures that were most strongly associated with BMI at a single time point likewise displayed the highest responsiveness to weight change over time.
What Do These Findings Mean?
These findings suggest that increased adiposity has causal adverse effects on multiple cardiometabolic risk markers in non-obese young adults beyond the effects on cholesterol and blood sugar. Like all Mendelian randomization studies, the reliability of the causal association reported here depends on several assumptions made by the researchers. Nevertheless, these findings suggest that increased adiposity has causal adverse effects on multiple cardiometabolic risk markers in non-obese young adults. Importantly, the results of both the causal effect analyses and the longitudinal study suggest that there is no threshold below which a BMI increase does not adversely affect the metabolic profile, and that a systemic metabolic profile linked with high cardiometabolic disease risk that becomes established during early adulthood can be reversed. Overall, these findings therefore highlight the importance of weight reduction as a key target for metabolic risk factor control among young adults.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001765.
The Computational Medicine Research Team of the University of Oulu has a webpage that provides further information on metabolite profiling by high-throughput NMR metabolomics
The World Health Organization provides information on obesity (in several languages)
The Global Burden of Disease Study website provides the latest details about global obesity trends
The UK National Health Service Choices website provides information about obesity, cardiovascular disease, and type 2 diabetes (including some personal stories)
The American Heart Association provides information on all aspects of cardiovascular disease and diabetes and on keeping healthy; its website includes personal stories about heart attacks, stroke, and diabetes
The US Centers for Disease Control and Prevention has information on all aspects of overweight and obesity and information about heart disease, stroke, and diabetes
MedlinePlus provides links to other sources of information on heart disease, vascular disease, and obesity (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001765
PMCID: PMC4260795  PMID: 25490400
8.  Different Pathophysiology of Impaired Glucose Tolerance in First Degree Relatives of Individuals with Type 2 Diabetes 
To assess whether an increased genetic predisposition for type 2 diabetes (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an OGTT and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) that had normal glucose homeostasis and no first degree T2DM relative (NGH; N=133), IGT with a first degree T2DM relative (IGT/FH+; N=74) or IGT without a first degree T2DM relative (IGT/FH−; N=50). Compared to NGH, first and second phase plasma insulin responses were reduced ~45% and 30%, respectively (both P<0.001) in IGT/FH+, whereas insulin sensitivity was only ~20% reduced (P=0.011). In contrast, in IGT/FH−, first phase plasma insulin responses were only ~20% reduced (P=0.016), second phase plasma insulin responses were not reduced, but insulin sensitivity was ~40% reduced (P<0.001). IGT/FH+ differed significantly from IGT/FH− by having 25–30% lower first phase plasma insulin responses (P=0.026) and 25–30% greater insulin sensitivity (P=0.027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first phase plasma insulin responses were ~30% lower in IGT/FH+ with a BMI ≥27 kg/m2 (P=0.018) but similar in IGT/FH+ with a BMI <27 kg/m2 compared to the corresponding IGT/FH− subgroups. We conclude that in IGT an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity.
doi:10.1016/j.metabol.2008.12.004
PMCID: PMC2713184  PMID: 19375581
impaired glucose tolerance; insulin resistance; insulin secretion
9.  Adult Metabolic Syndrome and Impaired Glucose Tolerance Are Associated With Different Patterns of BMI Gain During Infancy 
Diabetes Care  2008;31(12):2349-2356.
OBJECTIVE—The purpose of this study was to describe patterns of infant, childhood, and adolescent BMI and weight associated with adult metabolic risk factors for cardiovascular disease.
RESEARCH DESIGN AND METHODS—We measured waist circumference, blood pressure, glucose, insulin and lipid concentrations, and the prevalence of metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III definition) in 1,492 men and women aged 26–32 years in Delhi, India, whose weight and height were recorded every 6 months throughout infancy (0–2 years), childhood (2–11 years), and adolescence (11 years–adult).
RESULTS—Men and women with metabolic syndrome (29% overall), any of its component features, or higher (greater than upper quartile) insulin resistance (homeostasis model assessment) had more rapid BMI or weight gain than the rest of the cohort throughout infancy, childhood, and adolescence. Glucose intolerance (impaired glucose tolerance or diabetes) was, like metabolic syndrome, associated with rapid BMI gain in childhood and adolescence but with lower BMI in infancy.
CONCLUSIONS—In this Indian population, patterns of infant BMI and weight gain differed for individuals who developed metabolic syndrome (rapid gain) compared with those who developed glucose intolerance (low infant BMI). Rapid BMI gain during childhood and adolescence was a risk factor for both disorders.
doi:10.2337/dc08-0911
PMCID: PMC2584194  PMID: 18835958
10.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
11.  Pregnancy Weight Gain and Childhood Body Weight: A Within-Family Comparison 
PLoS Medicine  2013;10(10):e1001521.
David Ludwig and colleagues examine the within-family relationship between pregnancy weight gain and the offspring's childhood weight gain, thereby reducing the influence of genes and environment.
Please see later in the article for the Editors' Summary
Background
Excessive pregnancy weight gain is associated with obesity in the offspring, but this relationship may be confounded by genetic and other shared influences. We aimed to examine the association of pregnancy weight gain with body mass index (BMI) in the offspring, using a within-family design to minimize confounding.
Methods and Findings
In this population-based cohort study, we matched records of all live births in Arkansas with state-mandated data on childhood BMI collected in public schools (from August 18, 2003 to June 2, 2011). The cohort included 42,133 women who had more than one singleton pregnancy and their 91,045 offspring. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted her children's BMI and odds ratio (OR) of being overweight or obese (BMI≥85th percentile) at a mean age of 11.9 years, using a within-family design. For every additional kg of pregnancy weight gain, childhood BMI increased by 0.0220 (95% CI 0.0134–0.0306, p<0.0001) and the OR of overweight/obesity increased by 1.007 (CI 1.003–1.012, p = 0.0008). Variations in pregnancy weight gain accounted for a 0.43 kg/m2 difference in childhood BMI. After adjustment for birth weight, the association of pregnancy weight gain with childhood BMI was attenuated but remained statistically significant (0.0143 kg/m2 per kg of pregnancy weight gain, CI 0.0057–0.0229, p = 0.0007).
Conclusions
High pregnancy weight gain is associated with increased body weight of the offspring in childhood, and this effect is only partially mediated through higher birth weight. Translation of these findings to public health obesity prevention requires additional study.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Childhood obesity has become a worldwide epidemic. For example, in the United States, the number of obese children has more than doubled in the past 30 years. 7% of American children aged 6–11 years were obese in 1980, compared to nearly 18% in 2010. Because of the rising levels of obesity, the current generation of children may have a shorter life span than their parents for the first time in 200 years.
Childhood obesity has both immediate and long-term effects on health. The initial problems are usually psychological. Obese children often experience discrimination, leading to low self-esteem and depression. Their physical health also suffers. They are more likely to be at risk of cardiovascular disease from high cholesterol and high blood pressure. They may also develop pre-diabetes or diabetes type II. In the long-term, obese children tend to become obese adults, putting them at risk of premature death from stroke, heart disease, or cancer.
There are many factors that lead to childhood obesity and they often act in combination. A major risk factor, especially for younger children, is having at least one obese parent. The challenge lies in unravelling the complex links between the genetic and environmental factors that are likely to be involved.
Why Was This Study Done?
Several studies have shown that a child's weight is influenced by his/her mother's weight before pregnancy and her weight gain during pregnancy. An obese mother, or a mother who puts on more pregnancy weight than average, is more likely to have an obese child.
One explanation for the effects of pregnancy weight gain is that the mother's overeating directly affects the baby's development. It may change the baby's brain and metabolism in such a way as to increase the child's long-term risk of obesity. Animal studies have confirmed that the offspring of overfed rats show these kinds of physiological changes. However, another possible explanation is that mother and baby share a similar genetic make-up and environment so that a child becomes obese from inheriting genetic risk factors, and growing up in a household where being overweight is the norm.
The studies in humans that have been carried out to date have not been able to distinguish between these explanations. Some have given conflicting results. The aim of this study was therefore to look for evidence of links between pregnancy weight gain and children's weight, using an approach that would separate the impact of genetic and environmental factors from a direct effect on the developing baby.
What Did the Researchers Do and Find?
The researchers examined data from the population of the US state of Arkansas recorded between 2003 and 2011. They looked at the health records of over 42,000 women who had given birth to more than one child during this period. This gave them information about how much weight the women had gained during each of their pregnancies. The researchers also looked at the school records of the children, over 91,000 in total, which included the children's body mass index (BMI, which factors in both height and weight). They analyzed the data to see if there was a link between the mothers' pregnancy weight gain and the child's BMI at around 12 years of age. Most importantly, they looked at these links within families, comparing children born to the same mother. The rationale for this approach was that these children would share a similar genetic make-up and would have grown up in similar environments. By taking genetics and environment into account in this manner, any remaining evidence of an impact of pregnancy weight gain on the children's BMI would have to be explained by other factors.
The results showed that the amount of weight each mother gained in pregnancy predicted her children's BMI and the likelihood of her children being overweight or obese. For every additional kg the mother gained during pregnancy, the children's BMI increased by 0.022. The children of mothers who put on the most weight had a BMI that was on average 0.43 higher than the children whose mothers had put on the least weight.
The study leaves some questions unanswered, including whether the mother's weight before pregnancy makes a difference to their children's BMI. The researchers were not able to obtain these measurements, nor the weight of the fathers. There may have also been other factors that weren't measured that might explain the links that were found.
What Do These Findings Mean?
This study shows that mothers who gain excessive weight during pregnancy increase the risk of their child becoming obese. This appears to be partly due to a direct effect on the developing baby.
These results represent a significant public health concern, even though the impact on an individual basis is relatively small. They could contribute to several hundred thousand cases of childhood obesity worldwide. Importantly, they also suggest that some cases could be prevented by measures to limit excessive weight gain during pregnancy. Such an approach could prove effective, as most mothers will not want to damage their child's health, and might therefore be highly motivated to change their behavior. However, because inadequate weight gain during pregnancy can also adversely affect the developing fetus, it will be essential for women to receive clear information about what constitutes optimal weight gain during pregnancy.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001521.
The US Centers for Disease Control and Prevention provide Childhood Obesity Facts
The UK National Health Service article “How much weight will I put on during my pregnancy?” provides information on pregnancy and weight gain and links to related resources
doi:10.1371/journal.pmed.1001521
PMCID: PMC3794857  PMID: 24130460
12.  Earlier Mother's Age at Menarche Predicts Rapid Infancy Growth and Childhood Obesity 
PLoS Medicine  2007;4(4):e132.
Background
Early menarche tends to be preceded by rapid infancy weight gain and is associated with increased childhood and adult obesity risk. As age at menarche is a heritable trait, we hypothesised that age at menarche in the mother may in turn predict her children's early growth and obesity risk.
Methods and Findings
We tested associations between mother's age at menarche, mother's adult body size and obesity risk, and her children's growth and obesity risk in 6,009 children from the UK population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who had growth and fat mass at age 9 y measured by dual-energy X-ray absorptiometry. A subgroup of 914 children also had detailed infancy and childhood growth data. In the mothers, earlier menarche was associated with shorter adult height (by 0.64 cm/y), increased weight (0.92 kg/y), and body mass index (BMI, 0.51 kg/m2/y; all p < 0.001). In contrast, in her children, earlier mother's menarche predicted taller height at 9 y (by 0.41 cm/y) and greater weight (0.80 kg/y), BMI (0.29 kg/m2/y), and fat mass index (0.22 kg/m2/year; all p < 0.001). Children in the earliest mother's menarche quintile (≤11 y) were more obese than the oldest quintile (≥15 y) (OR, 2.15, 95% CI 1.46 to 3.17; p < 0.001, adjusted for mother's education and BMI). In the subgroup, children in the earliest quintile showed faster gains in weight (p < 0.001) and height (p < 0.001) only from birth to 2 y, but not from 2 to 9 y (p = 0.3–0.8).
Conclusions
Earlier age at menarche may be a transgenerational marker of a faster growth tempo, characterised by rapid weight gain and growth, particularly during infancy, and leading to taller childhood stature, but likely earlier maturation and therefore shorter adult stature. This growth pattern confers increased childhood and adult obesity risks.
Earlier age at menarche may be a transgenerational marker of faster growth, particularly during infancy, leading to taller childhood stature but earlier maturation and hence shorter adult stature.
Editors' Summary
Background.
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. Overweight and obese children—those having a higher than average body mass index (BMI; weight divided by height squared) for their age and sex—are at increased risk of becoming obese adults. Such people are more likely to develop heart disease, diabetes, and other health problems than lean people. Many factors are involved in the burgeoning size of children. Parental obesity, for example, predisposes children to being overweight. In part, this is because parents influence the eating habits of their offspring and the amount of exercise they do. In addition, though, children inherit genetic factors from their parents that make them more likely to put on weight.
Why Was This Study Done?
To prevent childhood obesity, health care professionals need ways to predict which infants are likely to become obese so that they can give parents advice on controlling their children's weight. In girls, early menarche (the start of menstruation) is associated with an increased risk of childhood and adult obesity and tends to be preceded by rapid weight gain in the first two years of life. Because age at menarche is inherited, the researchers in this study have investigated whether mothers' age at menarche predicts rapid growth in infancy and childhood obesity in their offspring using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). In 1991–1992, this study recruited nearly 14,000 children born in Bristol, UK. Since then, the children have been regularly examined to investigate how their environment and genetic inheritance interact to affect their health.
What Did the Researchers Do and Find?
The researchers measured the growth and fat mass of 6,009 children from ALSPAC at 9 years of age. For 914 of these children, the researchers had detailed data on their growth during infancy and early childhood. They then looked for any associations between the mother's age at menarche (as recalled during pregnancy), mother's adult body size, and the children's growth and obesity risk. In the mothers, earlier menarche was associated with shorter adult height and increased weight and BMI. In the children, those whose mothers had earlier menarche were taller and heavier than those whose mothers had a later menarche. They also had a higher BMI and more body fat. The children whose mothers had their first period before they were 11 were twice as likely to be obese as those whose mothers did not menstruate until they were 15 or older. Finally, for the children with detailed early growth data, those whose mothers had the earliest menarche had faster weight and height gains in the first two years of life (but not in the next seven years) than those whose mothers had the latest menarche.
What Do These Findings Mean?
These findings indicate that earlier mother's menarche predicts a faster growth tempo (the speed at which an individual reaches their adult height) in their offspring, which is characterized by rapid weight and height gain during infancy. This faster growth tempo leads to taller childhood stature, earlier sexual maturity, and—because age at puberty determines adult height—shorter adult stature. An inherited growth pattern like this, the researchers write, confers an increased risk of childhood and adult obesity. As with all studies that look for associations between different measurements, these findings will be affected by the accuracy of the measurements—for example, how well the mothers recalled their age at menarche. Furthermore, because puberty, particularly in girls, is associated with an increase in body fat, a high BMI at age nine might indicate imminent puberty rather than a risk of long-standing obesity—further follow-up studies will clarify this point. Nevertheless, the current findings provide a new factor—earlier mother's menarche—that could help health care professionals identify which infants require early growth monitoring to avoid later obesity.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040132.
The Avon Longitudinal Study of Parents and Children has a description of the study and results to date
The US Centers for Disease Control and Prevention provides information on overweight and obesity (in English and Spanish)
US Department of Health and Human Services's program, Smallstep Kids, is an interactive site for children about healthy eating (in English and Spanish)
The International Obesity Taskforce has information on obesity and its prevention
The World Heart Federation's Global Prevention Alliance provides details of international efforts to halt the obesity epidemic and its associated chronic diseases
The Child Growth Foundation has information on childhood growth and its measurement
doi:10.1371/journal.pmed.0040132
PMCID: PMC1876410  PMID: 17455989
13.  High prevalence of undiagnosed diabetes and abnormal glucose tolerance in the Iranian urban population: Tehran Lipid and Glucose Study 
BMC Public Health  2008;8:176.
Background
To estimate the prevalence of diagnosed and undiagnosed diabetes mellitus, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG/IGT in a large urban Iranian population aged ≥ 20 years.
Methods
The study population included 9,489 participants of the Tehran Lipid and Glucose Study with full relevant clinical data. Age-standardized prevalence of diabetes and glucose intolerance categories were reported according to the 2003 American Diabetes Association definitions. Age-adjusted logistic regression models were used to estimate the numbers needed to screen (NNTS) to find one person with undiagnosed diabetes.
Results
The prevalence of diagnosed and undiagnosed diabetes, isolated IFG, isolated IGT, and combined IFG/IGT were 8.1%, 5.1%, 8.7%, 5.4% and 4.0% in men and 10%, 4.7%, 6.3%, 7.6%, and 4.5% in women respectively. Participants with undiagnosed diabetes had higher age, body mass index (BMI), waist circumference, systolic and diastolic blood pressures, triglycerides (all p values <0.001) and lower HDL-cholesterol (only in women, p < 0.01) compared to normoglycemic subjects. Undiagnosed diabetes was associated with family history of diabetes, increased BMI (≥ 25 kg/m2), abdominal obesity, hypertriglyceridemia, hypertension and low HDL-cholesterol levels. Among men, a combination of increased BMI, hypertension, and family history of diabetes led to a NNTS of 1.6 (95% CI: 1.57–1.71) and among women a combination of family history of diabetes and abdominal obesity, yielded a NNTS of 2.2 (95% CI: 2.1–2.4).
Conclusion
In conclusion, about one third of Tehranian adults had disturbed glucose tolerance or diabetes. One- third of total cases with diabetes were undiagnosed. Screening individuals with BMI ≥ 25 kg/m2 (men), hypertension (men), abdominal obesity (women) and family history of diabetes may be more efficient.
doi:10.1186/1471-2458-8-176
PMCID: PMC2413226  PMID: 18501007
14.  Patterns of Obesity Development before the Diagnosis of Type 2 Diabetes: The Whitehall II Cohort Study 
PLoS Medicine  2014;11(2):e1001602.
Examining patterns of change in body mass index (BMI) and other cardiometabolic risk factors in individuals during the years before they were diagnosed with diabetes, Kristine Færch and colleagues report that few of them experienced dramatic BMI changes.
Please see later in the article for the Editors' Summary
Background
Patients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis.
Methods and Findings
We studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991–2009 for a median of 14.1 years (interquartile range [IQR]: 8.7–16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the “stable overweight” group (n = 604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of “progressive weight gainers” (n = 15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The “persistently obese” (n = 26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations.
Conclusions
Three patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 350 million people have diabetes, a metabolic disorder characterized by high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes, which was previously called adult-onset diabetes, can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. Long-term complications, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. The number of people with diabetes is expected to increase dramatically over the next decades, coinciding with rising obesity rates in many countries. To better understand diabetes development, to identify people at risk, and to find ways to prevent the disease are urgent public health goals.
Why Was This Study Done?
It is known that people who are overweight or obese have a higher risk of developing diabetes. Because of this association, a common assumption is that people who experienced recent weight gain are more likely to be diagnosed with diabetes. In this prospective cohort study (an investigation that records the baseline characteristics of a group of people and then follows them to see who develops specific conditions), the researchers tested the hypothesis that substantial weight gain precedes a diagnosis of diabetes and explored more generally the patterns of body weight and composition in the years before people develop diabetes. They then examined whether changes in body weight corresponded with changes in other risk factors for diabetes (such as insulin resistance), lipid profiles and blood pressure.
What Did the Researchers Do and Find?
The researchers studied participants from the Whitehall II study, a prospective cohort study initiated in 1985 to investigate the socioeconomic inequalities in disease. Whitehall II enrolled more than 10,000 London-based government employees. Participants underwent regular health checks during which their weight and height were measured, blood tests were done, and they filled out questionnaires for other relevant information. From 1991 onwards, participants were tested every five years for diabetes. The 6,705 participants included in this study were initially free of diabetes, and most of them were followed for at least 14 years. During the follow-up, 645 participants developed diabetes, while 6,060 remained free of the disease.
The researchers used a statistical tool called “latent class trajectory analysis” to study patterns of changes in body mass index (BMI) in the years before people developed diabetes. BMI is a measure of human obesity based on a person's weight and height. Latent class trajectory analysis is an unbiased way to subdivide a number of people into groups that differ based on specified parameters. In this case, the researchers wanted to identify several groups among all the people who eventually developed diabetes each with a distinct pattern of BMI development. Having identified such groups, they also examined how a variety of tests associated with diabetes risk, and risks for heart disease and stroke changed in the identified groups over time.
They identified three different patterns of BMI changes in the 645 participants who developed diabetes. The vast majority (606 individuals, or 94%) belonged to a group they called “stable-overweight.” These people showed no dramatic change in their BMI in the years before they were diagnosed. They were overweight when they first entered the study and gained or lost little weight during the follow-up years. They showed only minor signs of insulin-resistance, starting five years before they developed diabetes. A second, much smaller group of 15 people gained weight consistently in the years before diagnosis. As they were gaining weight, these people also had raises in blood pressure and substantial gains in insulin resistance. The 26 remaining participants who formed the third group were persistently obese for the entire time they participated in the study, in some cases up to 18 years before they were diagnosed with diabetes. They had some signs of insulin resistance in the years before diagnosis, but not the substantial gain often seen as the hallmark of “pre-diabetes.”
What Do These Findings Mean?
These results suggest that diabetes development is a complicated process, and one that differs between individuals who end up with the disease. They call into question the common notion that most people who develop diabetes have recently gained a lot of weight or are obese. A substantial rise in insulin resistance, another established risk factor for diabetes, was only seen in the smallest of the groups, namely the people who gained weight consistently for years before they were diagnosed. When the scientists applied a commonly used predictor of diabetes called the “Framingham diabetes risk score” to their largest “stably overweight” group, they found that these people were not classified as having a particularly high risk, and that their risk scores actually declined in the last five years before their diabetes diagnosis. This suggests that predicting diabetes in this group might be difficult.
The researchers applied their methodology only to this one cohort of white civil servants in England. Before drawing more firm conclusions on the process of diabetes development, it will be important to test whether similar results are seen in other cohorts and among more diverse individuals. If the three groups identified here are found in other cohorts, another question is whether they are as unequal in size as in this example. And if they are, can the large group of stably overweight people be further subdivided in ways that suggest specific mechanisms of disease development? Even without knowing how generalizable the provocative findings of this study are, they should stimulate debate on how to identify people at risk for diabetes and how to prevent the disease or delay its onset.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001602.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes; it includes people's stories about diabetes
The charity Diabetes UK also provides detailed information about diabetes for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the charity Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
More information about the Whitehall II study is available
doi:10.1371/journal.pmed.1001602
PMCID: PMC3921118  PMID: 24523667
15.  Gestational Glucose Tolerance and Maternal Metabolic Profile at 3 Years Postpartum 
Obstetrics and Gynecology  2011;118(5):1065-1073.
OBJECTIVE
To estimate the independent effect of gestational impaired glucose tolerance, defined as a single abnormal oral glucose tolerance test (OGTT) value, on metabolic dysfunction at 3 years postpartum.
METHODS
We used multiple linear regression to measure associations between glucose testing during pregnancy and metabolic markers at 3 years postpartum in Project Viva, a prospective cohort study of maternal and infant health. We compared metabolic measures at 3 years postpartum among four groups: normal glucose challenge test (less than 140 mg/dL, n=461); abnormal glucose challenge test but normal glucose tolerance test (GTT) (n=39); impaired glucose tolerance (IGT) (a single abnormal GTT value, n=21); and gestational diabetes mellitus (GDM) (n=16).
RESULTS
Adjusting for age, race, parity, parental history of diabetes, and maternal BMI at 3 years postpartum, we found women with GDM had lower adiponectin (11.2 ng/mL vs. 20.7 ng/mL) and higher homeostatic model assessment – insulin resistance (3.1 vs. 1.3) and waist circumference (91.3 cm vs. 86.2 cm) compared with women with IGT or normal glucose tolerance. Women in both the IGT and GDM groups had lower high-density lipoprotein (GDM: 44.7 mg/dL; IGT: 45.4/dL vs normal glucose tolerance 55.8 mg/dL) and higher triglycerides (GDM: 136.1 mg/dL; IGT: 140.1 mg/dL, vs. normal glucose tolerance: 78.3), compared with women in the normal glucose tolerance group. We found the highest values for Hemoglobin A1c (GDM: 5.1%; IGT 5.3%, normal glucose tolerance 5.1%) and high-sensitivity c reactive protein (GDM 1.4 mg/dL IGT: 2.2 mg/dL; NGT 1.0 mg/dL) among women with IGT.
CONCLUSION
GDM and IGT during pregnancy are associated with persistent metabolic dysfunction at 3 years postpartum, independent of other clinical risk factors.
doi:10.1097/AOG.0b013e3182325f5a
PMCID: PMC3268071  PMID: 22015874
16.  Prevalence and determinants of diabetes mellitus among Iranian patients with chronic liver disease 
Background
Alterations in carbohydrate metabolism are frequently observed in cirrhosis. We conducted this study to define the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) in Iranian patients with chronic liver disease (CLD), and explore the factors associated with DM in these patients.
Methods
One hundred and eighty-five patients with CLD were enrolled into the study. Fasting plasma glucose and two-hour plasma glucose were measured in patients' sera. DM and IGT were diagnosed according to the latest American Diabetes Association criteria.
Results
The subjects included 42 inactive HBV carriers with a mean age of 42.2 ± 12.0 years, 102 patients with HBV or HCV chronic hepatitis with a mean age of 41.2 ± 10.9 years, and 41 cirrhotic patients with a mean age of 52.1 ± 11.4 years. DM and IGT were diagnosed in 40 (21.6%) and 21 (11.4%) patients, respectively. Univariate analysis showed that age (P = 0.000), CLD status (P = 0.000), history of hypertension (P = 0.007), family history of DM (P = 0.000), and body mass index (BMI) (P = 0.009) were associated with DM. Using Multivariate analysis, age (OR = 4.7, 95%CI: 1.8–12.2), family history of DM (OR = 6.6, 95%CI: 2.6–17.6), chronic hepatitis (OR = 11.6, 95%CI: 2.9–45.4), and cirrhosis (OR = 6.5, 95%CI: 2.4–17.4) remained as the factors independently associated with DM. When patients with cirrhosis and chronic hepatitis were analyzed separately, higher Child-Pugh's score in cirrhotic patients (OR = 9.6, 95%CI: 1.0–88.4) and older age (OR = 7.2, 95%CI: 1.0–49.1), higher fibrosis score (OR = 59.5, 95%CI: 2.9–1211.3/ OR = 11.9, 95%CI: 1.0–132.2), and higher BMI (OR = 30.3, 95%CI: 3.0–306.7) in patients with chronic hepatitis were found to be associated with higher prevalence of DM.
Conclusions
Our findings indicate that patients with cirrhosis and chronic hepatitis are at the increased risk of DM occurrence. Older age, severe liver disease, and obesity were associated with DM in these patients.
doi:10.1186/1472-6823-4-4
PMCID: PMC538272  PMID: 15555059
17.  Elevated 1 h postload plasma glucose levels identify adults with normal glucose tolerance but increased risk of non-alcoholic fatty liver disease 
Objective
To determine the ability of the proposed diagnostic value of a 1-h OGTT glucose ≥155mg/dL to identify individuals with non-alcoholic fatty liver disease (NAFLD) diagnosed by ultrasonography in a cohort of adult white individuals.
Design
The study group comprised 710 white individuals participating to the CATAnzaro MEtabolic RIsk factors (CATAMERI) Study, a cross-sectional study assessing cardio-metabolic risk factors in individuals carrying at least one risk factor including dysglycemia, overweight/obesity, hypertension, dyslipidemia. a 75 g oral Oral Glucose Tolerance Test (OGTT) was performed with 0, 30, 60, 90 and 120 min sampling for plasma glucose and insulin measurements. Cardio-metabolic risk factors including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were assessed in the whole cohort.
Results
Of the 710 participants examined, 295 had normal glucose tolerance (NGT) with 1-hour post-load plasma glucose <155 mg/dL (NGT 1h-low), 109 individuals had NGT 1h-high, 104 had isolated impaired fasting glucose (IFG), and 202 had impaired glucose tolerance (IGT). As compared with NGT 1h-low, NGT 1h-high and IGT subjects exhibited significantly higher body mass index (BMI), triglycerides, high sensitivity C reactive protein, ALT, GGT, and hepatic insulin resistance (IR), assessed by the liver IR index, as well as lower high density lipoprotein, and insulin-like growth factor-1 (IGF-1) levels. In a logistic regression analysis adjusted for age, gender, and BMI, NGT 1h-high participants had a 1.5-fold increased risk of having NAFLD and an even increased risk was observed in subjects with IGT (1.8-fold), but not in the isolated IFG group (1.01-fold).
Conclusions
These data suggest that the value of a 1-hour OGTT glucose ≥155 mg/dL may be helpful to identify a subset of NGT individuals at risk for NAFLD.
doi:10.1136/bmjdrc-2014-000016
PMCID: PMC4212569  PMID: 25452862
NAFLD; IGT; OGTT
18.  Prevalence of non-insulin-dependent diabetes mellitus and impaired glucose tolerance in two Algonquin communities in Quebec. 
OBJECTIVE: To assess and compare the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in two native Indian communities. DESIGN: Population-based study. SETTING: Two Algonquin communities in Quebec: River Desert and Lac Simon. PARTICIPANTS: All native Indian residents aged at least 15 years were eligible; 621 (59%) of them volunteered to enroll in the study. The participation rate was 49% in River Desert and 76% in Lac Simon. MAIN OUTCOME MEASURES: Fasting blood glucose level and serum glucose level 2 hours after 75-g oral glucose tolerance test, as described by the World Health Organization, in all subjects except those with confirmed diabetes. Other measures included body mass index (BMI), fat distribution and blood pressure. MAIN RESULTS: The age-sex standardized prevalence rate of NIDDM was 19% in Lac Simon (95% confidence interval [CI] 16% to 21%); this was more than twice the rate of 9% in River Desert (95% CI 7% to 11%). The IGT rates were comparable in the two communities (River Desert 5%, Lac Simon 6%). NIDDM and IGT were uncommon under the age of 35 years. Only in Lac Simon was the NIDDM prevalence rate significantly higher among the women than among the men (23% v. 14%); almost half of the women aged 35 years or more had diabetes. In Lac Simon the rate of marked obesity (BMI greater than 30) was significantly higher among the women than among the men (37% v. 19%; p < 0.001); this sex-related difference was not found in River Desert (rates 31% and 23% respectively). Previously undiagnosed NIDDM accounted for 25% of all the cases. NIDDM and IGT were significantly associated with high BMI, sum of skinfold thicknesses and waist:hip circumference ratio (p < 0.001). The subscapular:triceps skinfold ratio, however, did not display such an association, nor did the age-adjusted systolic blood pressure. CONCLUSIONS: The prevalence of NIDDM is high in Algonquin communities and may vary markedly between communities. Although widespread, particularly in women, obesity cannot entirely explain the much higher rate of NIDDM in Lac Simon. Family and lifestyle risk factors, in particular diet and activity patterns, are being analysed in the two communities.
PMCID: PMC1488604  PMID: 8439889
19.  Skin Autofluorescence Based Decision Tree in Detection of Impaired Glucose Tolerance and Diabetes 
PLoS ONE  2013;8(6):e65592.
Aim
Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We compared SAF and a SAF-based decision tree (SAF-DM) with fasting plasma glucose (FPG) and HbA1c, and additionally with the Finnish Diabetes Risk Score (FINDRISC) questionnaire±FPG for detection of oral glucose tolerance test (OGTT)- or HbA1c-defined IGT and diabetes in intermediate risk persons.
Methods
Participants had ≥1 metabolic syndrome criteria. They underwent an OGTT, HbA1c, SAF and FINDRISC, in adition to SAF-DM which includes SAF, age, BMI, and conditional questions on DM family history, antihypertensives, renal or cardiovascular disease events (CVE).
Results
218 persons, age 56 yr, 128M/90F, 97 with previous CVE, participated. With OGTT 28 had DM, 46 IGT, 41 impaired fasting glucose, 103 normal glucose tolerance. SAF alone revealed 23 false positives (FP), 34 false negatives (FN) (sensitivity (S) 68%; specificity (SP) 86%). With SAF-DM, FP were reduced to 18, FN to 16 (5 with DM) (S 82%; SP 89%). HbA1c scored 48 FP, 18 FN (S 80%; SP 75%). Using HbA1c-defined DM-IGT/suspicion ≥6%/42 mmol/mol, SAF-DM scored 33 FP, 24 FN (4 DM) (S76%; SP72%), FPG 29 FP, 41 FN (S71%; SP80%). FINDRISC≥10 points as detection of HbA1c-based diabetes/suspicion scored 79 FP, 23 FN (S 69%; SP 45%).
Conclusion
SAF-DM is superior to FPG and non-inferior to HbA1c to detect diabetes/IGT in intermediate-risk persons. SAF-DM’s value for diabetes/IGT screening is further supported by its established performance in predicting diabetic complications.
doi:10.1371/journal.pone.0065592
PMCID: PMC3672176  PMID: 23750268
20.  The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach 
PLoS Medicine  2012;9(5):e1001212.
A Mendelian randomization analysis conducted by Børge G. Nordestgaard and colleagues using data from observational studies supports a causal relationship between body mass index and risk for ischemic heart disease.
Background
Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal.
Methods and Findings
In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19–1.34) for every 4 kg/m2 increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m2 (95 CI% 0.20–0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01–1.05) (corresponding to an average 1.68 kg/m2 BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m2 increase in BMI was 1.52 (95% CI 1.12–2.05).
Conclusions
For every 4 kg/m2 increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Ischemic heart disease (IHD; also known as coronary heart disease) is the leading cause of death among adults in developed countries. In the US alone, IHD kills nearly half a million people every year. With age, fatty deposits (atherosclerotic plaques) build up in the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant reduction in the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions). Risk factors for IHD include smoking, high blood pressure (hypertension), abnormal amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes, and being overweight or obese (having excess body fat). Treatments for IHD include lifestyle changes (for example, losing weight) and medications that lower blood pressure and blood cholesterol levels. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Prospective observational studies have shown an association between a high body mass index (BMI, a measure of body fat that is calculated by dividing a person's weight in kilograms by their height in meters squared; a BMI greater than 30 kg/m2 indicates obesity) and an increased risk of IHD. Observational studies, which ask whether people who are exposed to a suspected risk factor develop a specific disease more often than people who are not exposed to the risk factor, cannot prove, however, that changes in BMI/adiposity cause IHD. Obese individuals may share other characteristics that cause both IHD and obesity (confounding) or, rather than obesity causing IHD, IHD may cause obesity (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether elevations in BMI across the lifecourse have a causal impact on IHD risk. Three common genetic variants—FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238)—which have the largest single genetic variant associations with BMI were used in this study. Given that gene variants are inherited essentially randomly with respect to conventional confounding factors and are not subject reverse causation, use of these as instruments (or proxy measures) for variation in BMI as a risk factor (as opposed to measuring BMI directly) allows researchers to comment on whether obesity is causally involved in IHD.
What Did the Researchers Do and Find?
The researchers analyzed data from two population-based studies in which adults were physically examined and answered a lifestyle questionnaire before being followed to see how many developed IDH. They also analyzed data from a case-control study on IDH (in a case-control study, people with a disease are matched with similar people without the disease and the occurrence of risk factors in the patients and controls is compared). Overall, the researchers measured the BMI of 75,627 white individuals, among whom 11,056 already had IDH or developed it, and determined which of the BMI-increasing genetic variants each participant carried. On the basis of the observational data, every 4 kg/m2 increase in BMI increased the odds of IDH by 26% (an odds ratio of 1.26). Using a score derived from the combination of the three genetic variants, the researchers confirmed an association between each BMI increasing allele and both BMI (as expected) and IHD (0.28 kg/m2 and an odds ratio for IHD of 1.03, respectively). On average, compared to people carrying no BMI-increasing gene variants, people carrying six BMI-increasing gene variants had a 1.68 kg/m2 increase in BMI and an 18% increase in IHD risk. To extend this and to essentially reassess the original, observational, relationship between BMI and IHD risk, an “instrumental variable analysis” was used to examine the causal effect of a lifetime change in BMI on the risk of IDH. In this, it was found that for every 4 kg/m2 increase in BMI increased the odds of IDH by 52%.
What Do These Findings Mean?
These findings support a causal link between increased BMI and IDH risk, although it may be that BMI affects IDH through intermediate factors such as hypertension, dyslipidemia, and diabetes. The findings also show that observational studies into the impact of elevated BMI on IHD risk were consistent with this, but also that the inclusion of genetic data increases the value of observational studies by making it possible to avoid issues such as confounding and reverse causation. Finally, these findings and those of recent, observational studies have important implications for public-health policy because they show that the association between BMI (which is modifiable by lifestyle changes) and IHD is continuous. That is, any increase in BMI increases the risk of IHD; there is no threshold below which a BMI increase has no effect on IDH risk. Thus, public-health policies that aim to reduce BMI by even moderate levels could substantially reduce the occurrence of IDH in populations.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001212.
The American Heart Association provides information about IHD and tips on keeping the heart healthy, including weight management; it also provides personal stories about IHD
The UK National Health Service Choices website provides information about IHD, including information on prevention and personal stories about IHD
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute also provides information on IHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on IHD (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001212
PMCID: PMC3341326  PMID: 22563304
21.  Association of Alanine Aminotransferase Levels (ALT) with the Hepatic Insulin Resistance Index (HIRI): a cross-sectional study 
Background
The association between serum alanine aminotransferase (ALT) levels and hepatic insulin resistance (IR) has been evaluated with the hyperinsulinemic-euglycemic clamp. However, there is no information about the association of ALT with the Hepatic Insulin Resistance Index (HIRI). The aim of this study was to evaluate the association between serum ALT levels and HIRI in subjects with differing degrees of impaired glucose metabolism.
Methods
This cross-sectional study included subjects that had an indication for testing for type 2 diabetes mellitus (T2DM) with an oral glucose tolerance test (OGTT). Clinical and biochemical evaluations were carried out including serum ALT level quantification. HIRI was calculated for each participant. Correlation analyses and lineal regression models were used to evaluate the association between ALT levels and HIRI.
Results
A total of 324 subjects (37.6% male) were included. The mean age was 40.4 ± 14.3 years and the mean body mass index (BMI) was 32.0 ± 7.3 kg/m2. Individuals were divided into 1 of 5 groups: without metabolic abnormalities (n = 113, 34.8%); with the metabolic syndrome (MetS, n = 179, 55.2%), impaired fasting glucose (IFG, n = 85, 26.2%); impaired glucose tolerance (IGT, n = 91, 28.0%), and T2DM (n = 23, 7.0%). The ALT (p < 0.001) and HOMA2-IR (p < 0.001) values progressively increased with HIRI quartiles, while ISI-Matsuda (p < 0.001) progressively decreased. After adjustment for sex, age, and BMI, we identified a significant correlation between HIRI and ALT in persons with the MetS (r = 0.22, p = 0.003), IFG (r = 0.33, p < 0.001), IGT (r = 0.37, p < 0.001), and T2DM (r = 0.72, p < 0.001). Lineal regression analysis adjusting for age, HDL-C, TG and waist circumference (WC) showed an independent association between ALT and HIRI in subjects with the MetS (beta = 0.07, p = 0.01), IFG (beta = 0.10, p = 0.02), IGT (beta = 0.09, p = 0.007), and T2DM (beta = 0.31, p = 0.003). This association was not identified in subjects without metabolic abnormalities.
Conclusions
ALT levels are independently associated with HIRI in subjects with the MetS, IFG, IGT, and T2DM. The ALT value in these subjects may be an indirect parameter to evaluate hepatic IR.
doi:10.1186/1472-6823-12-16
PMCID: PMC3515498  PMID: 22947097
Alanine aminotransferase; ALT; Hepatic insulin resistance; HIRI
22.  Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study 
Background
Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure.
Methods
In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc).
Results
100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period.
Conclusions
Our study suggests that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-diabetes with only slight risk of mild side-effects.
doi:10.1186/1472-6882-14-203
PMCID: PMC4227038  PMID: 24968966
23.  Resistin - the link between adipose tissue dysfunction and insulin resistance in patients with obstructive sleep apnea 
Background
Resistin is an adipocytokine, associated with obesity and inflammation. Its exact role in insulin resistance and diabetes in the general population is still controversial. The relation between resistin plasma levels, insulin resistance and risk of impaired glucose metabolism in OSA patients has not been investigated.
Materials and methods
Plasma levels of resistin were measured in 67 patients with OSA and impaired glucose metabolism. 34,7% (23/67) had diabetes; 40% (27/67) patients had impаired glucose tolerance(IGT); 25,3%(17/67) had normal glucose metabolism (NGM). The association between resistin, BMI, obesity, markers of insulin resistance, oxidative stress and sleep study characteristics was analysed. The different groups of patients were compared in regards to glucometabolic parameters and biomarkers of oxidative stress – isoprostanes and insulin resistance – free fatty acids (FFA).
Results
Plasma levels of resistin were higher in patients with diabetes (6,12 ±5,93ng/ml), compared to those with IGT (3,85±2,81ng/ml, p-0,021) and NGM (3,77±3,23, p-0,043). Resistin did not differ between patients with IGT and NGM (p-0,954). In OSA patients with BMI>40 resistin plasma levels correlated neither to the clinical parameters (BMI, IRI, HOMA-I, HbA1C, AHI, desaturation index), nor to the biomarkers of oxidative stress and insulin resistance. Free fatty acids (0,232>0,177mmol/l, p-0,037) were higher in diabetics in comparison to NGM.
Conclusions
Plasma resistin levels in OSA patients with BMI>40 are independent of insulin resistance and are not associated with the parameters, characterising the oxidative stress or severity of OSA. Resistin could be used in a multiple panel of clinical and biomarkers to discern patients with diabetes from those with IGT; in OSA patients with BMI >40 resistin together with HbA1C could discern patients with diabetes from those with NGM. In OSA patients with BMI >40 FFA and HbA1C are useful clinical markers in assessing the risk of dysglycaemia among patients with normal and IGT.
doi:10.1186/2251-6581-12-5
PMCID: PMC3598160  PMID: 23497617
Resistin; Insulin resistance; OSA; Diabetes; Normal glucose metabolism; Impaired glucose tolerance
24.  Insulin‐secretion capacity in normal glucose tolerance, impaired glucose tolerance, and diabetes in obese and non‐obese Japanese patients 
Abstract
Aims/Introduction:  Pronounced reduction of insulin secretion in response to a rise in glucose level has been reported in Japanese patients compared with Caucasian patients, but the mean body mass index (BMI) is also lower in Japanese patients. As BMI is a determinant of insulin secretion, we examined insulin‐secretion capacity in obese and non‐obese Japanese patients.
Materials and Methods:  Using the oral glucose tolerance test (OGTT), we estimated the insulin‐secreting capacity in obese (BMI ≥ 25) and non‐obese (BMI < 25) Japanese patients, including 1848 patients with normal glucose tolerance (NGT), 321 patients with impaired glucose tolerance (IGT) and 69 diabetes (DM) patients.
Results:  The insulinogenic index (I.I.), calculated by dividing the increment in serum insulin by the increment in plasma glucose from 0 to 30 min during OGTT, decreased from NGT to IGT and to DM in patients with and without obesity. In patients with NGT, IGT and DM, the I.I. values of obese patients were higher than those of the non‐obese patients. The peak of insulin concentration in OGTT appeared at 60 min in NGT and at 120 min in IGT in both obese and non‐obese patients, but in DM it was observed at 120 min in obese patients and at 60 min in non‐obese patients.
Conclusions:  These results show that early‐phase insulin secretion in obese Japanese patients is higher than in non‐obese patients in all stages of glucose tolerance, and delayed insulin‐secretion capacity is also conserved in obese Japanese patients, even in IGT and DM, which is similar to Caucasian patients. (J Diabetes Invest, doi:10.1111/j.2040‐1124.2011.00180.x, 2011)
doi:10.1111/j.2040-1124.2011.00180.x
PMCID: PMC4014949  PMID: 24843576
Insulin secretion; Non‐obese Japanese; Obese Japanese
25.  Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(3):e1001618.
Here, Timpson and colleagues performed a Mendelian Randomization analysis to determine whether childhood adiposity causally influences levels of physical activity. The results suggest that increased adiposity causes a reduction in physical activity in children; however, this study does not exclude lower physical activity also leading to increasing adiposity.
Please see later in the article for the Editors' Summary
Background
Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose–response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.
Methods and Findings
The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity.
In observational analysis, a 3.3 kg/m2 (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10−16), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10−29), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10−4). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.
Conclusions
Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that globally at least 42 million children under the age of five are obese. The World Health Organization recommends that all children undertake at least one hour of physical activity daily, on the basis that increased physical activity will reduce or prevent excessive weight gain in children and adolescents. In practice, while numerous studies have shown that body mass index (BMI) shows a strong inverse correlation with physical activity (i.e., active children are thinner than sedentary ones), exercise programs specifically targeted at obese children have had only very limited success in reducing weight. The reasons for this are not clear, although environmental factors such as watching television and lack of exercise facilities are traditionally blamed.
Why Was This Study Done?
One of the reasons why obese children do not lose weight through exercise might be that being fat in itself leads to a decrease in physical activity. This is termed reverse causation, i.e., obesity causes sedentary behavior, rather than the other way around. The potential influence of environmental factors (e.g., lack of opportunity to exercise) makes it difficult to prove this argument. Recent research has demonstrated that specific genotypes are related to obesity in children. Specific variations within the DNA of individual genes (single nucleotide polymorphisms, or SNPs) are more common in obese individuals and predispose to greater adiposity across the weight distribution. While adiposity itself can be influenced by many environmental factors that complicate the interpretation of observed associations, at the population level, genetic variation is not related to the same factors, and over the life course cannot be changed. Investigations that exploit these properties of genetic associations to inform the interpretation of observed associations are termed Mendelian randomization studies. This research technique is used to reduce the influence of confounding environmental factors on an observed clinical condition. The authors of this study use Mendelian randomization to determine whether a genetic tendency towards high BMI and fat mass is correlated with reduced levels of physical activity in a large cohort of children.
What Did the Researchers Do and Find?
The researchers looked at a cohort of children from a large long-term health research project (the Avon Longitudinal Study of Parents and Children). BMI and total body fat were recorded. Total daily activity was measured via a small movement-counting device. In addition, the participants underwent genotyping to detect the presence of several SNPs known to be linked to obesity. For each child a total BMI allelic score was determined based on the number of obesity-related genetic variants carried by that individual. The association between obesity and reduced physical activity was then studied in two ways. Direct correlation between actual BMI and physical activity was measured (observational data). Separately, the link between BMI allelic score and physical activity was also determined (Mendelian randomization or instrumental variable analysis). The observational data showed that boys were more active than girls and had lower BMI. Across both sexes, a higher-than-average BMI was associated with lower daily activity. In genetic analyses, allelic score had a positive correlation with BMI, with one particular SNP being most strongly linked to high BMI and total fat mass. A high allelic score for BMI was also correlated with lower levels of daily physical activity. The authors conclude that children who are obese and have an inherent predisposition to high BMI also have a propensity to reduced levels of physical activity, which may compound their weight gain.
What Do These Findings Mean?
This study provides evidence that being fat is in itself a risk factor for low activity levels, separately from external environmental influences. This may be an example of “reverse causation,” i.e., high BMI causes a reduction in physical activity. Alternatively, there may be a bidirectional causality, so that those with a genetic predisposition to high fat mass exercise less, leading to higher BMI, and so on, in a vicious circle. A significant limitation of the study is that validated allelic scores for physical activity are not available. Thus, it is not possible to determine whether individuals with a high allelic score for BMI also have a propensity to exercise less, or whether it is simply the circumstance of being overweight that discourages activity. This study does suggest that trying to persuade obese children to lose weight by exercising more is likely to be ineffective unless additional strategies to reduce BMI, such as strict diet control, are also implemented.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001618.
The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States
A more worldwide view is given by the World Health Organization
The UK National Health Service website gives information on physical activity guidelines for different age groups
The International Obesity Task Force is a network of organizations that seeks to alert the world to the growing health crisis threatened by soaring levels of obesity
MedlinePlus—which brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations—has a page on obesity
Additional information on the Avon Longitudinal Study of Parents and Children is available
The British Medical Journal has an article that describes Mendelian randomization
doi:10.1371/journal.pmed.1001618
PMCID: PMC3958348  PMID: 24642734

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