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Background: The risk of type 2 diabetes is increasing in teenage girls, and is associated with their greater insulin resistance (IR)., Hypothesis: We hypothesized that the adverse metabolic profile of girls (compared with boys) would persist from childhood through adolescence., Patients and Methods: Community-based longitudinal cohort of 292 children (147 boys) studied annually from 9 to 16 years., Measures: IR (homeostasis-model-assessment-2), high-density lipoprotein-cholesterol (HDL-C), triglycerides, % body-fat (dual-energy x-ray absorptiometry), pubertal stage (age at peak height velocity), physical activity (accelerometry). Multi-level modelling established the age-related trends in IR and lipids and the influence of covariates., Results: Each year from 9 to 15 years, girls had 21% to 63% higher IR than boys (girls mean IR 0.73-1.33, boys 0.51-0.89, P < .005). At 16 years the gender difference was not significant (girls IR 0.60, boys 0.56, P = .45). Girls had lower HDL-C from 9 to 12 years, higher triglycerides from 9 to 14 years, greater adiposity throughout, and earlier puberty, but boys were more active than girls (all P < .05). After adjustment for %-fat, puberty and activity, the gender difference in IR between girls and boys aged 9 to 15 years became non-significant (IR girls 0.66-1.01, boys 0.65-1.04, P > .07). However, after adjustment at 16 years, girls' IR was 25% lower than boys' (girls 0.44, boys 0.63, P = .001), and they had 22% higher HDL-C (P < .001) and 20% lower triglycerides (P = .003)., Conclusions: The higher IR of prepubertal and early pubertal girls diminishes during late puberty, and boys begin to exhibit greater metabolic risk. Despite being leaner and more active, boys at 16 years have higher IR than girls, suggesting future higher risk for diabetes, thus we reject our hypothesis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m(2)). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min(-1).m(-2).), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.

Background: Primary hyperparathyroidism (PHPT) is associated with insulin resistance and an increased cardiovascular mortality. We aimed to see if parathyroidectomy improved insulin resistance., Methods: Twelve PHPT patients undergoing parathyroidectomy and ten control patients undergoing non-neck surgery were recruited to the study. Fasting venous blood samples were collected immediately pre-operatively and again at five to six weeks post-operatively. Samples were assayed for plasma glucose, serum insulin, total cholesterol, triglycerides, calcium, alkaline phosphatase, magnesium, parathyroid hormone (PTH), and haemoglobin A1c (HbA1c). Insulin resistance was calculated from fasting insulin and glucose values using Homeostasis Model Assessment (HOMA)., Results: Parathyroidectomy decreased serum calcium (mean pre-op = 2.85 mmol/L, post-op 2.28 mmol/L, P < 0.001) and PTH concentrations (mean pre-op = 23.33 pmol/L, post-op = 10.23 pmol/L, P < 0.001) and increased phosphate concentration. However, there was no improvement in insulin resistance in the PHPT group at between 5 and 6 weeks post-operatively (geometric mean; pre-op = 0.88 (95% CI 0.59 - 1.33) vs. post-op = 0.88 (0.66 - 1.17) P = 0.95). In the control group, an increase in serum calcium was observed post-operatively (mean pre-op = 2.29 mmol/L, post-op = 2.35 mmol/L, P = 0.03). No change in insulin resistance was observed (geometric mean; pre-op = 1.37 (95% CI 0.89 - 2.11) vs. post-op = 1.38 (0.72 - 2.67) P = 0.96)., Conclusion: In summary, no significant change in insulin resistance post-parathyroidectomy in patients with PHPT was observed. This indicates that surgical treatment of PHPT does not improve insulin resistance for patients currently selected for parathyroidectomy.

Background: The emergence of type 2 diabetes in young populations has mirrored a rising prevalence of obesity and insulin resistance during childhood and adolescence. At the same time, the role of adipokines as links between obesity and insulin resistance is becoming more appreciated. We sought to establish age- and sex-specific distributions of metabolic correlates of insulin resistance in healthy prepubertal children., Methods: We collected fasting blood samples from a contemporary cohort of 307 British children at ages 5, 6, 7, and 8 years and measured insulin, glucose, triglycerides, total and HDL cholesterol, urate, glycohemoglobin, sex hormone-binding globulin (SHBG), leptin, and adiponectin. We used homeostasis model assessment (HOMA 2) to estimate insulin sensitivity (HOMA-%S) and beta-cell function (HOMA-%B). Anthropometric measures included body mass index., Results: Body mass index increased from age 5 to 8 years (P < 0.001). HOMA-%B decreased (P < 0.001) and HOMA-%S increased (P < 0.05), but glucose also increased (P < 0.001) whereas glycohemoglobin decreased (P < 0.001). Consistent with the rise in insulin sensitivity, HDL cholesterol increased (P < 0.001) and triglycerides decreased (NS), whereas adiponectin decreased (P = 0.02). The patterns were similar in boys and girls, although girls were less insulin sensitive throughout. Accordingly, triglycerides tended to be higher in the girls, and HDL cholesterol and SHBG lower., Conclusions: The metabolic disturbances associated with insulin resistance appear to be more advanced in girls. Markers of metabolic health improve in both sexes from 5 to 8 years, despite rising adiposity.

Objective: The aim of this study was to evaluate whether adaptive responses made to the uterine or very early infant environment are affecting the current metabolic health of young children in the United Kingdom., Methods: Participants were 300 healthy children and their parents from the EarlyBird Diabetes Study cohort. Children were recruited from randomly selected schools at 5 years of age. Retrospective measures were maternal prepregnancy weight (n = 230), maternal fasting glucose levels at 28 weeks of pregnancy (n = 27), birth weight, and infant weight at ages 3 and 6 weeks. Prospective measures were insulin resistance, height, weight, and percentage of body fat (sum of 5 skinfold measurements) at ages 5, 6, 7, and 8 years., Results: Maternal third-trimester fasting glucose levels were associated positively with birth weight but were not associated with either weight or insulin resistance for the same children at 8 years. Birth weight was unrelated to insulin resistance at 8 years. There were no relationships between weight change in the first weeks of life and weight, percentage of fat, or insulin resistance at 8 years. Longer breastfeeding correlated inversely, although weakly, with percentage of body fat for boys only. Current weight was correlated with insulin resistance at 8 years., Conclusions: For these contemporary children, neither the gestational environment nor early postnatal growth predicted insulin resistance, which was best predicted by current weight. There was no evidence that predictive adaptive responses made by the fetus or infant affected the child's weight or insulin resistance later in childhood.

Objective: Recent studies of type 2 diabetes in young populations consistently show a predominance of affected girls over boys. Girls are more insulin resistant than boys. We aimed in the present report to establish how much of the sex difference in insulin resistance is intrinsic., Methods: EarlyBird is a community-based, nonintervention cohort study of 307 healthy children from school entry at age 5 years. It asks the question: which children are insulin resistant and why? Anthropometric measures, physical activity, resting energy expenditure, and insulin resistance and its metabolic correlates were measured., Results: At 5 years, insulin resistance was 35% higher in girls than in boys. Girls carried 26% more subcutaneous fat despite similar body weights. However, after correcting for anthropometric variables and physical activity, girls remained 33% more insulin resistant than boys. Triglycerides were significantly higher in girls, and high-density lipoprotein cholesterol and sex hormone-binding globulin were significantly lower., Conclusions: Sex-linked genes may account for the intrinsic sex difference observed. These genes may have an important impact on the development of insulin resistance and the metabolic syndrome and may help to explain the female preponderance of type 2 diabetes in children. Their identification may also help in understanding the pathogenesis of insulin resistance.

For a decade or more, poor nutrition during gestation, expressed as low weight at birth, was held to be the factor responsible for insulin resistance later in life. Birth weights, however, are rising and insulin resistant states, such as diabetes mellitus, faster still. Alternative explanations are needed to explain insulin resistance in contemporary industrialised populations. EarlyBird is a non-intervention prospective cohort study that asks the question 'Which children develop insulin resistance, and why?' It is unique in taking serial blood samples from a young age with which to monitor the behaviour of insulin resistance and its metabolic correlates. This, the baseline report of the EarlyBird Study, describes the rationale, design and methodology of the study, and the profile of the population at entry. It situates the anthropometric, physical activity and dietary status of the EarlyBird children and provides a detailed metabolic profile of the British 5 year-old in the year 2000.

For more than a decade, the fetal programming hypothesis has taught that insulin resistance and its associated metabolic disturbances result from poor gestational environment, for which low birth weight is a surrogate. Low birth weight, however, is now uncommon in industrialized societies. We have investigated the relevance of birth weight, "catch-up" weight, and current weight to insulin resistance in 300 contemporary British children. Insulin resistance at 5 years was not related to birth weight but was correlated with current weight and weight catch-up in both sexes, more strongly so in girls (r = 0.33, P < 0.001 vs. r = 0.18, P = 0.03), who were intrinsically more insulin-resistant than boys. Weight change merely co-correlated with current weight (r = 0.67, P < 0.01 in both sexes) and did not improve on the prediction of insulin resistance. Most important, insulin resistance at 5 years was the same in children of heavier birth weight, whose weight SD score had not changed, as in those of lighter birth weight, matched for current weight, who had experienced so-called catch-up (boys 0.89 and 0.88 units, respectively, P = 0.96; girls 1.26 and 1.13 units, P = 0.41). Insulin resistance in contemporary children seems to be a function of excess current weight rather than of low birth weight or change in weight.

Adiponectin, a hormone produced and secreted by adipocytes, is present in circulation in high circulating concentrations, suggesting an important physiological role. An indirect regulator of glucose metabolism, adiponectin increases insulin sensitivity, improves glucose tolerance and inhibits inflammation. Plasma adiponectin relates inversely to adiposity and, importantly, reflects the sequelae of accumulation of excess adiposity. The role of adiponectin in adults has been explored in detail. Studies in children are now available and, given the increasing rates of childhood obesity, it is important to establish the role of adiponectin in mediating insulin resistance and cardiovascular disease in this age group. This paper reviews the regulation of adiponectin, its effect on body mass, glucose metabolism and cardiovascular risk in infants, children and adolescents. It demonstrates clear links between adiponectin and features of the metabolic syndrome in obese children and adolescents. However, adiponectin's role as a predictor of metabolic dysfunction in healthy, normal-weight youngsters is less clear. [ABSTRACT FROM AUTHOR]

Background: High birth weight predicts subsequent obesity, but paradoxically, a reduced risk of subsequent cardiovascular disease compared with low birth weight. This apparent paradox might be explained if high birth weight programmed a greater proportion of subsequent lean mass, which carries less cardiovascular risk than fat tissue. Aim: The aim of this study was to test the hypothesis that the direct correlation between birth weight and subsequent body mass index (BMI) represents an association between birth weight and lean tissue, and to assess the metabolic impact of this relationship. Methods: A total of 234 healthy prepubertal children (133 boys, 101 girls, mean age 5.9 yr ± 0.3 standard deviation) were studied. Birth weights were obtained from maternity records. Lean mass was measured by bioelectrical impedance. Anthropometric measures included height, weight (BMI), waist circumference, and subcutaneous fat mass (FM). Insulin resistance was assessed by the homeostasis model method. Metabolic correlates of insulin resistance included total and high-density lipoprotein cholesterol, triglycerides, and sex-hormone-binding globulin. Results: Birth weight correlated significantly with lean mass in boys (r = 0.41, p < 0.001) and girls (r = 0.27, p < 0.01). Adjusting for BMI did not improve the correlation further. After adjustment for FM, lean mass correlated inversely with triglycerides in boys only (r = −0.41, p < 0.01). Birth weight correlated inversely with triglycerides in boys (r = −0.18, p < 0.05); after adjustment for lean mass, this correlation was not significant. Interpretation: In boys, the relationships between birth weight, triglycerides, and lean mass are consistent with the hypothesis. Overall, our findings provide limited evidence in support of the argument that higher birth weight predicts lower metabolic risk because it marks programming of more lean mass. [ABSTRACT FROM AUTHOR]