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ims/hypothesis: We determined whether single nucleotide polymorphisms (SNPs) previously associated with diabetogenic traits improve the discriminative power of a type 2 diabetes genetic risk score. Methods: Participants ( n = 2,751) were genotyped for 73 SNPs previously associated with type 2 diabetes, fasting glucose/insulin concentrations, obesity or lipid levels, from which five genetic risk scores (one for each of the four traits and one combining all SNPs) were computed. Type 2 diabetes patients and non-diabetic controls ( n = 1,327/1,424) were identified using medical records in addition to an independent oral glucose tolerance test. Results: Model 1, including only SNPs associated with type 2 diabetes, had a discriminative power of 0.591 ( p < 1.00 × 10 vs null model) as estimated by the area under the receiver operator characteristic curve (ROC AUC). Model 2, including only fasting glucose/insulin SNPs, had a significantly higher discriminative power than the null model (ROC AUC 0.543; p = 9.38 × 10 vs null model), but lower discriminative power than model 1 ( p = 5.92 × 10). Model 3, with only lipid-associated SNPs, had significantly higher discriminative power than the null model (ROC AUC 0.565; p = 1.44 × 10) and was not statistically different from model 1 ( p = 0.083). The ROC AUC of model 4, which included only obesity SNPs, was 0.557 ( p = 2.30 × 10 vs null model) and smaller than model 1 ( p = 0.025). Finally, the model including all SNPs yielded a significant improvement in discriminative power compared with the null model ( p < 1.0 × 10) and model 1 ( p = 1.32 × 10); its ROC AUC was 0.626. Conclusions/interpretation: Adding SNPs previously associated with fasting glucose, insulin, lipids or obesity to a genetic risk score for type 2 diabetes significantly increases the power to discriminate between people with and without clinically manifest type 2 diabetes compared with a model including only conventional type 2 diabetes loci. [ABSTRACT FROM AUTHOR]

Background:High-intensity progressive resistance training (PRT) improves adiposity and metabolic risk in adults, but has not been investigated in children within a randomized controlled trial (RCT).Objective:We hypothesized that high-intensity PRT (8 weeks, twice a week) would decrease central adiposity in children, as assessed via waist circumference.Methods Design/Setting/Participants:Concealed randomization stratified by age and gender was used to allocate rural New Zealand school students to the wait-list control or PRT group.Intervention:Participants were prescribed two sets (eight repetitions per set) of 11 exercises targeting all the major muscle groups at high intensity.Primary Outcome:Waist circumference; secondary outcomes included whole body fat, muscular fitness (one repetition maximum), cardiorespiratory fitness (peak oxygen consumption during a treadmill test), lipids, insulin sensitivity and fasting glucose.Results:Of the 78 children (32 girls and 46 boys; mean age 12.2(1.3) years), 51% were either overweight (33%) or obese (18%). High-intensity PRT significantly improved waist circumference (mean change PRT −0.8 (2.2) cm vs +0.5 (1.7) cm control; F=7.59, P=0.008), fat mass (mean change PRT +0.2 (1.4) kg vs +1.0 (1.2) kg control; F=6.00, P=0.017), percent body fat (mean change PRT –0.3 (1.8)% vs +1.2 (2.1)% control; F=9.04, P=0.004), body mass index (mean change PRT −0.01 (0.8) kg m−2 vs +0.4 (0.7) kg m−2 control; F=6.02, P=0.017), upper body strength (mean change PRT+11.6(6.1) kg vs +2.9(3.7) kg control; F=48.6, P<0.001) and lower body strength (mean change PRT +42.9(26.6) kg vs +28.5(26.6) kg control; F=4.72, P=0.034) compared to the control group. Waist circumference decreased the most in those with the greatest baseline relative strength (r=−0.257, P=0.036), and greatest relative (r=−0.400, P=0.001) and absolute (r=0.340, P=0.006) strength gains during the intervention.Conclusion:Isolated high-intensity PRT significantly improves central and whole body adiposity in association with muscle strength in normal-weight and overweight children. The clinical relevance and sustainability of these changes in adiposity should be addressed in future long-term studies.International Journal of Obesity (2008) 32, 1016–1027; doi:10.1038/ijo.2008.5; published online 19 February 2008 [ABSTRACT FROM AUTHOR]

Objective:Obese patients with schizophrenia being treated with clozapine and non-psychiatric obese are often assumed to share the same physiological changes in obesity. The aim of this study was to identify possible metabolic and hormonal differences between non-psychiatric obese subjects (OB) and obese patients with schizophrenia being treated with clozapine (OSC).Subjects:Fifty-one normal healthy subjects (Nor, body mass index (BMI):23.2±0.3), 50 OB (BMI:31.7±0.7) and 71 OSC (BMI:30.4±0.5).Measurements:Anthropometric, metabolic and hormonal parameters were determined by anthropometry, enzyme autoanalyzer, immunoassay and enzyme-linked immunosorbent assay.Results:Triglyceride, total cholesterol divided by high-density lipoprotein (HDL) cholesterol (TC/HDL) and leptin levels were significantly higher whereas the HDL and the molar ratio of insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein (IGFBP)-3 levels were significantly lower in both OB and OSC groups than those in the Nor group. Compared to normal subjects, insulin and homeostasis model assessment (HOMA) index levels were significantly higher in OSC, and, in OSC, insulin sensitivity and insulin-like growth factor (IGF)-1 were significantly lower. Although the anthropometric parameters in the OB and OSC groups were similar, in the OSC group the waist-to-hip ratio (WHR), insulin levels and HOMA index were significantly higher, while insulin sensitivity, cholesterol, low-density lipoprotein (LDL) cholesterol, TC/HDL, LDL/HDL, IGF-1 and IGF-1/IGFBP-3 molar ratio were lower, than those of the OB group.Conclusion:Insulin homeostasis and lipid profiles in clozapine-treated schizophrenic obesity were different from those in non-psychiatric obesity with similar anthropometric parameters, body weight and BMI. Among the three groups, the highest fasting insulin, the lowest insulin sensitivity and the highest HOMA index occurred in the OSC group. The OSC group was characterized by impaired glucose–insulin homeostasis, abnormal lipid profiles and hormonal changes in the GH-IGF-IGFBP axis and in leptin.International Journal of Obesity (2008) 32, 436–442; doi:10.1038/sj.ijo.0803750; published online 23 October 2007 [ABSTRACT FROM AUTHOR]

The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFα has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFα-induced insulin resistance in brown adipocytes. Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B ( Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFα and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22 R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting. NR1HR agonists ameliorate TNFα-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFα. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFα. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase ζ and/or the increase of Slc2a4 expression. Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance. [ABSTRACT FROM AUTHOR]

Objective:To compare the value of body fat mass (%FM) to indirect measures of general (body mass index (BMI)) and central adiposity (waist circumference (WC); waist-to-height ratio (WC/ht)) for the prediction of overweight- and obesity-related metabolic risk in a study population with a high prevalence of metabolic syndrome (MSX).Methods:BMI, WC, WC/ht, body composition (by air-displacement plethysmography) and metabolic risk factors: triglycerides, cholesterol, HDL-cholesterol (HDL-C), uric acid, systolic blood pressure (BPsys), insulin resistance by homeostasis model assessment (HOMA-IR) and C-reactive protein (CRP) were measured in 335 adults (191 women, 144 men; mean age 53 ±13.9 years, prevalence of MSX 30%).Results:When compared with BMI and WC, %FM showed weaker associations with metabolic risk factors, except for CRP and BPsys in men. In women, HDL-C and HOMA-IR showed the closest correlations with BMI. For all other risk factors, WC or WC/ht were the best predictors in both sexes. Differences in the strength of correlations between an obesity index and different risk factors exceeded the differences observed between all obesity indices within one risk factor. In stepwise multiple regression analyses, WC/ht was the main predictor of metabolic risk in both sexes combined. However, analysis of the area under receiver operating characteristic curves for prediction of the prevalence of 2 component traits of the MSX revealed a similar accuracy of all obesity indices.Conclusions:At the population level, measurement of body FM has no advantage over BMI and WC in the prediction of obesity-related metabolic risk. Although measures of central adiposity (WC, WC/ht) tended to show closer associations with risk factors than measures of general adiposity, the differences were small and depended on the type of risk factor and sex, suggesting an equivalent value of methods.International Journal of Obesity (2006) 30, 475–483. doi:10.1038/sj.ijo.0803144; published online 1 November 2005 [ABSTRACT FROM AUTHOR]

The measurement of fat balance (fat input minus fat output) involves the accurate estimation of both metabolizable fat intake and total fat oxidation. This is possible mostly under laboratory conditions and not yet in free-living conditions. In the latter situation, net fat retention/mobilization can be estimated based on precise and accurate sequential body composition measurements. In case of positive balance, lipids stored in adipose tissue can originate from dietary (exogenous) lipids or from nonlipid precursors, mainly from carbohydrates (CHOs) but also from ethanol, through a process known as de novo lipogenesis (DNL). Basic equations are provided in this review to facilitate the interpretation of the different subcomponents of fat balance (endogenous vs exogenous) under different nutritional circumstances. One difficulty is methodological: total DNL is difficult to measure quantitatively in man; for example, indirect calorimetry only tracks net DNL, not total DNL. Although the numerous factors (mostly exogenous) influencing DNL have been studied, in particular the effect of CHO overfeeding, there is little information on the rate of DNL in habitual conditions of life, that is, large day-to-day fluctuations of CHO intakes, different types of CHO ingested with different glycemic indexes, alcohol combined with excess CHO intakes, etc. Three issues, which are still controversial today, will be addressed: (1) Is the increase of fat mass induced by CHO overfeeding explained by DNL only, or by decreased endogenous fat oxidation, or both? (2) Is DNL different in overweight and obese individuals as compared to their lean counterparts? (3) Does DNL occur both in the liver and in adipose tissue? Recent studies have demonstrated that acute CHO overfeeding influences adipose tissue lipogenic gene expression and that CHO may stimulate DNL in skeletal muscles, at least in vitro. The role of DNL and its importance in health and disease remain to be further clarified, in particular the putative effect of DNL on the control of energy intake and energy expenditure, as well as the occurrence of DNL in other tissues (such as in myocytes) in addition to hepatocytes and adipocytes.International Journal of Obesity (2004) 28, S3-S11. doi:10.1038/sj.ijo.0802852 [ABSTRACT FROM AUTHOR]

Aims/hypothesis. This study compared the long-term weight loss and health outcomes at 1-year follow-up, after a 12-week intensive intervention consisting of two low-Pat, weight-loss diets, which differed in protein content. Methods. We randomly assigned 66 obese patients (BMI: 27-40 kg/m2) with Type 2 diabetes to either a low-protein (15% protein, 55% carbohydrate) or high-protein diet (30% protein, 40% carbohydrate) !br 8 weeks of energy restriction (-6.7 MJ/day) and 4 weeks of energy balance. Subjects were asked to maintain the same dietary pattern !br a further 12 months of follow-up. Results. The study was completed by 38 of the subjects, with equal dropouts in each group. At Week 64, weight reductions against baseline were -2.2±1.1 kg (low protein) and -3.7±1.0 kg (high protein), p<0.01, with no diet effect. Fat mass was not different from baseline in either group. At Week 12, both diets reduced systolic and diastolic blood pressure by 6 and 3 mm Hg respectively, hut blood pressure increased more with weight regain during follow-up in the low- protein group (p≤0.04). At Week 64, both diets significantly increased HDL cholesterol and lowered C-reactive protein concentrations. There was no difference in the urinary urea : creatinine ratio at baseline between the two groups, hut this ratio increased at Week 12 (in the high-protein group only, p<0.001, diet effect), remaining stable during follow-up in both diets. Conclusions/interpretation. A high-protein weight- reduction diet may in the long term have a more favourable cardiovascular risk profile than a low- protein diet with similar weight reduction in people with Type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVES:: To estimate the prevalence of insulin resistance syndrome (IRS) in a representative sample of youth. To test for the independent contribution of insulin resistance (IR) and adiposity to clustering of metabolic risk factors. To identify the underlying components of IRS. To examine the relationship between adiposity and fasting plasma levels of free fatty acids (FFA). METHODS:: In 1999, we conducted a school-based survey of a representative sample of youth aged 9, 13 and 16?y in Quebec, Canada. Age-specific questionnaire data, standardized clinical measurements and a fasting blood sample were available for 2244 subjects. Fasting insulin and HOMA were used as surrogate measures of IR. RESULTS:: In all age-sex groups, adiposity indices, blood pressure (BP), plasma glucose and triglycerides (TG) increased significantly with increasing insulin quartiles while HDL cholesterol (HDL-C) decreased. The overall prevalence of IRS defined as hyperinsulinaemia combined with two or more risk factors including overweight, high systolic BP, impaired fasting glucose, high TG and low HDL-C, was 11.5% (95% CI: 10.2-12.9). There were no significant differences in the prevalence of IRS across ages or between sexes. The independent contribution of adiposity to clustering of risk factors was stronger than that of fasting insulin (or HOMA-IR). Factor analysis revealed three factors (BMI/insulin/lipids, BMI/insulin/glucose and diastolic/systolic BP) consistent across ages suggesting that more than one pathophysiologic process underlies IRS. Although elevation of FFA might be in the causal pathway linking obesity to IR, we did not detect any consistent association between measures of fatness and fasting plasma FFA. CONCLUSION:: IRS is highly prevalent in youth, even among children as young as age 9?y. Factor analysis identifies three physiologic domains within IRS with a unifying role for markers of IR and adiposity.International Journal of Obesity (2004) 28, 833-841. doi:10.1038/sj.ijo.0802694 Published online 1 June 2004 [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate whether postprandial abnormalities of energy expenditure and/or lipid oxidation are present in healthy, normal-weight subjects with a strong family history of obesity and thus at high risk to become obese. DESIGN: Case-control study. SUBJECTS: A total of 16 young healthy men participated in the study. Eight subjects had both parents overweight (father's and mother's body mass index (BMI) > 25 kg/m[SUP2]) and eight had both parents with normal body weight (father's and mother's BMI < 25 kg/m[SUP2], respectively). The group of subjects with overweight parents was similar to that with normal-weight parents (control group) in terms of BMI (23.7 ± 1.7 vs 22.7 ± 1.1 kg/m[SUP2]) (M ± s.d.) and fat-free body mass (FFM) (60.5 ± 4.9 vs 58.4 ± 2.0 kg), but was slightly older than the control group (25.4 ± 3.3 vs 22.7 ± 2.4 y; P< 0.05). MEASUREMENTS: Energy expenditure (EE) was measured by indirect calorimetry, and blood samples were taken for the evaluation of metabolic variables in the fasting state and every hour for 8 h after a standard fat-rich meal (protein 15%, carbohydrate 34%, fat 51%, 4090 kJ). RESULTS: Fasting plasma glucose, cholesterol, HDL-cholesterol, triglyceride, free fatty acid (FFA) and leptin concentrations were similar in both groups of participants, but subjects with overweight parents has significantly lower plasma insulin concentrations (5.11 ± 0.51 vs 7.07 ± 1.56 μU/ml; P<0.007) and HOMA index of insulin resistance (1.1 ± 0.1 vs 1.6 ± 0.4; P<0.01). Postprandial plasma glucose, triglyceride, FFA and leptin concentrations were similar in the two groups, whereas insulin levels were significantly lower in the group with both parents overweight at 3, 5, 6, 7 and 8 h. Fasting and postprandial EE, and fasting lipid and carbohydrate oxidation were similar in both groups. On the contrary, postprandial carbohydrate oxidation (incremental area... [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Phospholipid transfer protein plays a key role in lipoprotein metabolism by catalysing the transfer of phospholipids from triglyceride-rich lipoproteins to high-density lipoproteins and, also, within the high-density lipoprotein family, from particle to particle. This transfer results in a change of HDL particle size and the generation of pre-β-high-density lipoproteins which function as initial lipid acceptors in the process of reverse cholesterol transport. Because adipose tissue is a source of phospholipid transfer protein we investigated the influence of obesity and insulin sensitivity on phospholipid transfer protein activity. Methods: Using an exogenous substrate assay phospholipid transfer protein activity was measured in plasma specimens of 190 normolipidaemic, non-diabetic subjects with BMI ranging from 19 to 43 kg/m2. Insulin sensitivity was measured by the short insulin tolerance test. Results: Phospholipid transfer protein activity was associated with BMI (r = 0.46, p < 0.01), body fat mass (r = 0.39, p < 0.01), subcutaneous fat area (r = 0.32, p < 0.01) and plasma leptin concentration (r = 0.24, p < 0.01) but not with insulin sensitivity expressed as the ks of the insulin tolerance test (kITT value) (r = –0.14, p = 0.40). Accordingly, phospholipid transfer protein activity was higher in obese than in non-obese subjects. As determined by linear regression analysis, BMI was the sole predictor of phospholipid transfer protein activity in plasma explaining 22.2 % of the activity (p< 0.01). Conclusions/interpretations: This data suggests that increased phospholipid transfer protein activity in obese subjects is a consequence of obesity itself without the contribution of insulin resistance and can be explained by increased synthesis of phospholipid transfer protein from the enlarged mass of adipose tissue. [Diabetologia (2001) 44: 1111–1117] [ABSTRACT FROM AUTHOR]

Elevated levels of butyrylcholinesterase activity occur under a number of hypertriglyceridemic conditions, including diabetes and obesity. This study examines whether butyrylcholinesterase activity has a direct effect on triglyceride production, using Caco-2 cells, a human intestinal adenocarcinoma cell line. Caco-2 cells were incubated with 500 μM oleate to stimulate triglyceride production, and butyrylcholinesterase activity was measured in the cellular homogenate. Butyrylcholinesterase activity was approximately 3 × 10-3 mmol/min per milligram protein. Although triglyceride production increased by almost five-fold after 18 h of stimulation with oleate, butyrylcholinesterase activity was not increased. Furthermore, inhibition of butyrylcholinesterase activity using 1 mM tetraisopropylpyrophosphoramide did not significantly affect triglyceride production or secretion. Human insulin (100 μU/ml) increased the production of butyrylcholinesterase without increasing triglyceride production. This demonstrates that stimulation of fatty acid production and butyrylcholinesterase activity occur by independent mechanisms and suggests that their correlation in hyperlipidemic conditions is not due to a direct relationship in production in situ. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Information on the association of hyperinsulinaemia with coronary heart disease (CHD) in patients with Type II (non-insulin-dependent) diabetes is limited and controversial. Therefore, we carried out a prospective study to examine the predictive value of fasting plasma insulin and “hyperinsulinaemia cluster” with regard to the risk of CHD mortality.¶Methods. At baseline risk factors for CHD were determined in 902 patients aged 45 to 64 years with Type II diabetes not treated by insulin (499 men and 403 women). These patients were followed up to 7 years for CHD mortality.¶Results. Coronary heart disease mortality (16.2 % in men, 9.2 % in women) increased significantly in men with increasing plasma insulin tertiles (p = 0.006) and in both sexes combined (p = 0.010) but not in women (p = 0.090). The predictive value of hyperinsulinaemia with regard to death from CHD was independent of conventional cardiovascular risk factors but not of risk factors clustering with hyperinsulinaemia. By applying factor analysis and principal component analysis we showed that “hyperinsulinaemia cluster” (a factor having high positive loadings for body mass index, triglycerides and insulin; and a high negative loading for high-density lipoprotein cholesterol) was predictive of death from CHD in patients with Type II diabetes (hazard ratio with 95 % confidence intervals 1.43 (1.18, 1.73), p < 0.001).¶Conclusion/interpretation. Our results support the notion that cardiovascular risk factors clustering with endogenous hyperinsulinaemia increase the risk of death from CHD in patients with Type II diabetes not treated with insulin. [Diabetologia (2000) 43: 148–155] [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the effect of exercise training (ET) on components of the insulin resistance syndrome (IRS) in obese children. DESIGN: Randomized, modified cross-over study, with subjects assigned to one of two conditions: (1) 4 months of ET followed by 4 months of no-ET; or (2) 4 months of no-ET followed by 4 months of ET. Measurements were made at three time points: 0, 4 and 8 months. SUBJECTS: 79 obese, but otherwise healthy children (age: 7-11 y, percent fat (%fat) 27-61%). MEASUREMENTS: Plasma lipid and lipoprotein concentrations, plasma insulin and glucose concentrations; %fat; submaximal heart rate (HR) as an index of fitness. EXERCISE TRAINING: ET was offered 5 d/week 40 min/d. For the 73 children who completed 4 months of ET, the mean attendance was 80% (that is, 4d/week) and the average HR during ET was 157 bpm. RESULTS: Significant (P<0.05) group x time interactions were found for plasma triglyceride (TG) and insulin concentrations and %fat. The average change for both groups, from just before ET to just after the 4 month ET was -0.24 mmol. I[sup -1] for TG, -25.4 pmol. I[sup -1] for insulin and -1.6 units for %fat. When Group I ceased ET, over the following 4 month period the average change for insulin was +26.6 pmol. I[sup -1] and for %fat +1.3 units. CONCLUSION: Some components (plasma TG, insulin, %fat) of the IRS are improved as a result of 4 months of ET in obese children. However, the benefits of ET are lost when obese children become less active. [ABSTRACT FROM AUTHOR]