Objective: To look for same-sex (gender assortative) association of body mass index (BMI) in healthy trios (mother, father and child) from a contemporary birth cohort, which might imply shared environment rather than shared genes because selective mother-daughter and father-son gene transmission is not a common Mendelian trait. Design: Prospective (longitudinal) cohort study with four annual time points, from 5 to 8 years. Subjects: 226 healthy trios from a 1995 to 1996 birth cohort randomly selected in the city of Plymouth, UK. Measurements: Average BMI of the two parents and maternal/paternal BMI separately related to the BMI-SDS (standard deviation score) of all offspring and to the BMI-SDS of the sons and the daughters separately. Results: There were big differences in BMI-SDS among the daughters grouped according to mothers' category of BMI (effect size 1.37 SDS), but not their sons (effect size 0.16 SDS, gender interaction Po0.004), and among the sons grouped according to their fathers' BMI (effect size 1.28 SDS), but not their daughters (effect size 0.17, gender interaction P ¼ 0.02). Children whose same-sex parents were of normal weight, weighed either close to (girls þ 0.20 BMI-SDS) or less than (boys,À0.34 BMI-SDS) children of 20 years ago, and did not change from 5 to 8 years. In contrast, the risks of obesity at 8 years were 10-fold greater (girls 41%, Po0.001) or sixfold greater (boys 18%, Po0.05) if the same-sex parent was obese. Longitudinal linear mixed effects (multilevel) modelling showed a marked influence of maternal and paternal BMI on the rate of weight gain, which was unaffected by birth weight of the child. We report perhaps the largest effect sizes so far recorded in childhood obesity. Conclusions: Childhood obesity today seems to be largely confined to those whose same-sex parents are obese, and the link does not seem to be genetic. Parental obesity, like smoking, might be targeted in the interests of the child.

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

Objective To establish whether metformin has a significant action in reducing visceral fat and improving other metabolic parameters in women with polycystic ovary syndrome (PCOS).Design Randomised, double-blind, placebo-controlled trial.Setting Reproductive medicine clinic.Population Forty women with anovulatory PCOS.Methods Participants were randomised into receiving metformin 500 mg three times a day or placebo for 3 months.Main outcome measures Fat distribution was measured by computed tomography scan. Secondary outcome measures included serum indices of the metabolic syndrome and evidence of ovulation.Results We found no significant differences in any of the measures of fat distribution between the placebo and metformin groups. The metformin group had significantly lower total cholesterol (P = 0.02), low-density lipoprotein cholesterol (P = 0.02) and cholesterol:high-density lipoprotein cholesterol ratio (P = 0.05), but there was no statistically significant treatment effect on androgens, insulin, insulin resistance, triglycerides, ovulation or pregnancy.Conclusions Metformin has no clinically significant effect in reducing visceral fat mass, although it does have a beneficial effect on lipids. This trial lends support to the growing evidence that metformin is not a weight loss drug. Metformin might therefore be used as an adjunct to lifestyle modification in women with PCOS, but not as a substitute for it.Keywords Fat distribution, metabolic syndrome, metformin, polycystic ovary syndrome, visceral fat.Please cite this paper as: Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome-a randomised, double-blind, placebo-controlled trial. BJOG 2006; 113:817-824.

Physical activity is perceived as important to children's health, and concern has been expressed at the increasing use of motorised transport to school-the "school run."1 We have measured the activity cost of the school run in young children in the EarlyBird study. 2 Participants, methods, and resultsWe analysed data from 154 boys and 121 girls in their first year at 53 urban primary schools. The children wore uniaxial accelerometers (Manufacturing Technology, Florida) during waking hours for five consecutive schooldays and the weekend to measure physical activity. 3 We considered activity during the journey to and from school (8 to 9 am and 3 to 4 pm weekdays), school time (9 am to 3 pm weekdays), non-school time (before 8 am and after 4 pm weekdays), the total school week (weekdays), the weekend, and the total week. We measured height, weight, and body fat as the mean of five skinfolds. We found mode of transport and school journey time by questionnaire and distance to school with the RAC's online route planner. We used the National Statistics Socio-economic Classification to find socioeconomic status. Our study had 80% power to detect a significant difference (P < 0.05) of at least 12% in activity during the journey to or from school and at least 8% in total weekly activity.Twice as many children walked to school (185/275; 67%) as were driven by car, with no significant gender bias (97/154 (63%) boys; 88/121 (73%) girls; Pearson 2 test P = 0.12). The median time taken to walk to school was 6 (interquartile range 5 to 10) minutes and the median distance was 0.7 (0.4 to 1.2) km with 155/ 185 (84%) children walking less than a mile (1.6 km), comparable with the national figure of 82%. 4 Mean activity recorded during the 10 journeys to and from school was significantly higher during that period (0.75 units or 18% higher; P < 0.001) among those who walked than those who travelled by car (table). However, total weekly activity was identical (difference 0.04 units or 0.1%; P = 0.97). Crucially, the additional activity recorded by walkers during the school journey was only 2% (0.75/37.6) of the children's total weekly activity.Although the proportion of walkers was highest in the lowest socioeconomic group (C 65/82 (78%); B 49/78 (63%); A 71/115 (62%); P = 0.02), the pattern of results was unchanged when we analysed each social group in turn (data not given). Analysis of only moderate and high intensity activity gave consistent results. The two groups did not differ significantly in either body mass index (walk 16.1 kg/m 2 v car 16.2 kg/m 2 ;

Girls are born lighter than boys. The consistency of this observation across different populations is striking, suggesting that it may have fundamental significance for those conditions linked with lower birth weight, such as diabetes. Previous hypotheses relating low birth weight to subsequent diabetes have addressed differences in insulin resistance within the sexes, not between them. Here, we propose that gender-specific genes affecting insulin sensitivity are responsible for the gender difference in birth weight -the genetically more insulin resistant female fetus is less responsive to the trophic effects of insulin and is therefore smaller. These genes also render female subjects more susceptible to diabetes, explaining why reports of type 2 diabetes (T2D) in younger populations show a female preponderance. Consistent with our proposal, concentrations of insulin and/or its propeptides are higher at birth in female populations and they are intrinsically more insulin resistant throughout life, with attendant impact on their metabolism, and the regressions describing the relationship between insulin resistance and adiposity in female and male subjects have similar gradients, but different constants. These gender-specific genes have a demonstrable impact on fetal growth and insulin resistance. Diabetes and cardiovascular disease are thought to be driven by insulin resistance, and the observations reported here may help to focus the search for genes that control it.

We conclude that the systemic immunoregulatory state at diagnosis of T1D is predictive of clinical improvement during the remission phase. There was no general change in systemic immune reactivity in the months after diagnosis and initiation of insulin therapy.

Plasminogen activator inhibitor-1 activity is not raised in women with PCOS independent of obesity and these results do not support the hypothesis that it may contribute to their anovulatory infertility, or increase their risk of thrombosis. The only significant metabolic features of the PCOS independent of obesity are insulin resistance, hyperinsulinaemia and lower HDL/total cholesterol ratio. The higher frequency of a positive family history of thrombosis in these women nevertheless requires further explanation.

The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. There is general consensus that the presence of multiple Aab (> or = 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.