Body Insulin Sensitivity Index Research Articles

Beneficial Impact ofZingiber zerumbeton Insulin Sensitivity in Fructose-Fed Rats

Zingiber zerumbet (L) Smith (Zingiberaceae), commonly known as the pinecone or shampoo ginger, is distributed in many parts of Asia. It has been demonstrated that the aqueous extract of Z. zerumbet exerted a potential blood glucose lowering effect in normoglycemic and streptozotocin-induced hyperglycemic rats. The present study was undertaken to clarify whether the ethanol extract of Zingiber zerumbet (EEZZ) is effective in improving insulin resistance. Insulin resistance was induced in rats by feeding a high-fructose diet for six weeks. Thereafter, rats were maintained on the same diet and treated with oral EEZZ or pioglitazone once daily for eight weeks. At the end of treatment, the degree of basal insulin resistance was measured by homeostasis model assessment (HOMA-IR). Insulin sensitivity was calculated using the composite whole body insulin sensitivity index (ISIcomp). Protein expression was evaluated by immunoblotting. Phytochemicals in EEZZ were determined through liquid chromatography-tandem mass. Not only curcumin but also quercetin and kaempferol were abundant in EEZZ. EEZZ (300 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing HOMA-IR and elevating ISIcomp as well as enhancing hepatic glycogen accumulation. Elevated glycosylated hemoglobin levels and hyperinsulinemia were ameliorated by EEZZ. Further, EEZZ enhanced the action of insulin on muscle glucose transporter subtype 4 translocation and attenuated hepatic phosphoenolpyruvate carboxykinase expression. This study suggests that EEZZ may be an ethnomedicine for improving insulin sensitivity.

Aerobic exercise training conserves insulin sensitivity for 1 yr following weight loss in overweight women

The objectives of this study were to 1) identify the independent effects of exercise (aerobic or resistance training) and weight loss on whole body insulin sensitivity and 2) determine if aerobic or resistance training would be more successful for maintaining improved whole body insulin sensitivity 1 yr following weight loss. Subjects were 97 healthy, premenopausal women, body mass index (BMI) 27-30 kg/m(2). Following randomized assignment to one of three groups, diet only, diet + aerobic, or diet + resistance training until a BMI <25 kg/m(2) was achieved, body composition, fat distribution, and whole body insulin sensitivity were determined at baseline, in the weight reduced state, and at 1-yr follow up. The whole body insulin sensitivity index (S(I)) was determined using a frequently sampled intravenous glucose tolerance test. Results of repeated-measures ANOVA indicated a significant improvement in S(I) following weight loss. However, there were no group or group×time interactions. At 1-yr follow up, there were no significant time or group interactions for S(I;) however, there was a significant group×time interaction for S(I). Post hoc analysis revealed that women in the aerobic training group showed a significant increased S(I) from weight reduced to 1-yr follow up (P < 0.05), which was independent of intra-abdominal adipose tissue and %fat. No significant differences in S(I) from weight reduced to 1-yr follow up were observed for diet only or diet + resistance groups. Additionally, multiple linear regression analysis revealed that change in whole body insulin sensitivity from baseline to 1-yr follow up was independently associated with the change in Vo(2max) from baseline to 1-yr follow up (P < 0.05). These results suggest that long-term aerobic exercise training may conserve improvements in S(I) following weight loss and that maintaining cardiovascular fitness following weight loss may be important for maintaining improvements in S(I).

The Triglyceride-to-HDL Cholesterol Ratio

OBJECTIVEWe evaluated whether the triglyceride-to-HDL cholesterol (TG/HDL-C) ratio is associated with insulin resistance (IR) in a large multiethnic cohort of obese youths.RESEARCH DESIGN AND METHODSObese youths (1,452) had an oral glucose tolerance test and a fasting lipid profile. Insulin sensitivity was estimated using the whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA)-IR and evaluated, in a subgroup of 146 obese youths, by the hyperinsulinemic-euglycemic clamp. The cohort was divided by ethnicity (612 whites, 357 Hispanics, and 483 African Americans) and then stratified into ethnicity-specific tertiles of TG/HDL-C ratio. Differences across tertiles were evaluated, and the association between the TG/HDL-C ratio and insulin sensitivity (WBISI) was defined by a multiple stepwise linear regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was determined to calculate the TG/HDL-C ratio cutoff to identify insulin-resistant subjects by ethnicity.RESULTSIn each ethnic group and across rising tertiles of TG/HDL-C ratio, insulin sensitivity (WBISI) progressively decreased, whereas 2-h glucose and the AUC-glucose progressively increased. The cutoff for TG/HDL-C ratio was 2.27, and the odds of presenting with IR, in youths with TG/HDL-C ratio higher than the cutoff, was 6.023 (95% CI 2.798–12.964; P < 0.001) in white girls and boys, whereas for both Hispanics and African Americans the AUC-ROCs were not significant, thus not allowing the calculation of an optimal cutoff TG/HDL-C value.CONCLUSIONSThe TG/HDL-C ratio is associated with IR mainly in white obese boys and girls and thus may be used with other risk factors to identify subjects at increased risk of IR-driven morbidity.

Visfatin in juvenile obesity – the effect of obesity intervention and sex

The association of visfatin, an adipocytokine relevant to the development of inflammation and metabolic disorders, with juvenile obesity needs to be re-established as previously used tests occurred to be nonspecific. To evaluate visfatin association with a metabolic profile of 88 overweight/obese and 26 lean children/adolescents as well as changes in its levels following weight reduction programme (diet + enhanced physical activity ± metformin). A case-control and cohort study. Visfatin was higher in obese than lean and overweight individuals (2·07 vs. 1·53 and 1·47 ng mL(-1) , P = 0·034). Of metabolic syndrome components, central obesity combined with either insulin resistance (IR) or hyperinsulinemia (HI) was associated with increases in circulating visfatin. In girls, visfatin correlated with leptin (r = 0·40, P = 0·009) and thiols (r = -0·36, P = 0·009), which explained 24% in visfatin variability. In boys, visfatin correlated with waist circumference (r = 0·36, P = 0·036), BMI% (r = 0·38, P = 0·025), whole body insulin sensitivity index (r = -0·36, P = 0·036), IL-6 (r = 0·38, P = 0·024) and thiobarbituric acid reactive substances (TBARS) (r = 0·52, P = 0·001), of which IL-6 and TBARS were independent predictors of visfatin elevation, explaining 42% in data variability. Visfatin was significantly lower following weight reduction programme than at baseline (1·43 vs. 1·83 ng mL(-1) , P = 0·033). Visfatin reduction correlated neither with changes in metabolic parameters nor was it affected by metformin. ΔVisfatin correlated exclusively with baseline visfatin (r = 0·612, P < 0·0001), which explained 38% in data variability. Central obesity combined with HI/IR contributes to visfatin elevation. Visfatin association with metabolic/biochemical variables is gender dependent. Diet + enhanced physical activity are effective in visfatin reduction, the degree of which depends on baseline visfatin.

Angelica acutiloba Root Attenuates Insulin Resistance Induced by High‐Fructose Diet in Rats

Angelica acutiloba root (Japanese Dong Quai), used for treatment of gynecological disorders, is currently cultivated in Taiwan. The present study evaluated the preventative effect of Angelica acutiloba root (Japanese Dong Quai) on the induction of insulin resistance. Insulin resistance was induced in rats by feeding a high fructose diet for 6 weeks. Thereafter, the rats were maintained on the same diet and treated with oral A. acutiloba root extract or pioglitazone once daily for 8 weeks. At the end of treatment, the degree of basal insulin resistance was measured by homeostasis model assessment (HOMA-IR). Insulin sensitivity was calculated using the composite whole body insulin sensitivity index (ISIcomp). Protein expression was evaluated by immunoblotting. A. acutiloba (300 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing HOMA-IR and elevating ISIcomp. Elevated glycosylated hemoglobin levels and hyperinsulinemia were ameliorated by A. acutiloba treatment without hepatotoxic or nephrotoxic effects. A. acutiloba treatment improved dyslipidemia, induced lipoprotein lipase activity and enhanced hepatic glycogen accumulation. Further, A. acutiloba treatment enhanced the action of insulin on muscle glucose transporter subtype 4 translocation and attenuated hepatic phosphoenolpyruvate carboxykinase expression. The findings suggest that A. acutiloba may be an effective ethnomedicine for improving insulin sensitivity.

Hypothalamic Obesity following Craniopharyngioma Surgery: Results of a Pilot Trial of Combined Diazoxide and Metformin Therapy

Objective. To assess the effect of combined diazoxide-metformin therapy in obese adolescents treated for craniopharyngioma. Design. A prospective open-label 6-month pilot treatment trial in 9 obese subjects with craniopharyngioma. Diazoxide (2 mg/kg divided b.i.d., maximum 200 mg/day) and metformin (1000 mg b.i.d.). Whole body insulin sensitivity index (WBISI) and area-under-the-curve insulin (AUC(ins)) were calculated. Results. Seven subjects completed: 4M/3F, mean ± SD age 15.4 ± 2.9 years, weight 99.7 ± 26.3 kg, BMI 35.5 ± 5.6 kg/m(2), and BMI SDS 2.3 ± 0.3. Two were withdrawn due to vomiting and peripheral edema. Of participants completing the study, the mean ± SD weight gain, BMI, and BMI SDS during the 6 months were reduced compared to the 6 months prestudy (+1.2 ± 5.9 versus +9.5 ± 2.7 kg, P = .004; -0.3 ± 2.3 versus +2.2 ± 1.5 kg/m(2), P = .04; -0.04 ± 0.15 versus +0.11 ± 0.08, P = .021, resp.). AUC(ins) correlated with weight loss (r = 0.82, P = .02) and BMI decrease (r = 0.96, P = .009). Conclusion. Combined diazoxide-metformin therapy was associated with reduced weight gain in patients with hypothalamic obesity. AUC(ins) at study commencement predicted effectiveness of the treatment.

12 - Generation of immigration and overweight in canadian youth

aim: Waist/height is a proposed index of cardiovascular and metabolic risk in youth that is simple to calculate and that may be superior to body mass index (BMI). Most studies that have assessed waist/height in youth have done so with a wide range of body sizes. We aimed to compare the waist/height and BMI z-score specifically in overweight youth. Methods: In 41 overweight subjects (16 female; aged 8-18 years), waist, height and weight were measured. Waist/height and BMI z-score were calculated. Blood pressure (BP) and fasting blood work was collected (glucose and lipid metabolism and a two-hour oral glucose tolerance test was performed with sampling of glucose and insulin every 30 minutes. Area-under-the-curve (AUC) insulin, and whole body insulin sensitivity index (WBISI) were calculated. Univariate correlations were performed between cardiometabolic risk factors and both waist/height and BMI z-score. Parameters with non-normally distributed values were log-transformed for analysis. results: BMI z-score had stronger correlations than waist/height with systolic BP (SBP; R=0.55, P=0.0002 and R=0.48, P=0.003, respectively). Waist/height had stronger correlations than BMI z-score with diastolic BP (DBP; R=0.49, P=0.002) and SBPand DBPz-scores (R=0.42, P=0.009 and R=0.49, P=0.002), glucose (R=-0.39, P=0.02), insulin (R=0.62, P<0.0001), AUC insulin (R=0.61, P=0.0001) and WBISI (R=-0.60, P=0.0002), and FFA (R=0.48, P=0.004). Neither correlated significantly with triglycerides, total cholesterol, HDLor LDL-cholesterol. conclusions: Within a group of overweight youth, waist/height provides a superior index than BMI z-score for some cardiometabolic risk factors. Unlike BMI, waist/height does not require adjustments for age and sex, thus this simple calculation may be valuable in the clinical assessment of metabolic risk in overweight youth.

Adipose triglyceride lipase expression in human adipose tissue and muscle. Role in insulin resistance and response to training and pioglitazone

Adipose triglyceride lipase (ATGL) catalyzes the first step in adipocyte and muscle triglyceride hydrolysis, and comparative gene identification–58 (CGI-58) is an essential cofactor. We studied the expression of ATGL and CGI-58 in human adipose and muscle and examined correlations with markers of muscle fatty acid oxidation. Nondiabetic volunteers were studied. Subjects with impaired glucose tolerance were treated with pioglitazone or metformin for 10 weeks. Subjects with normal glucose tolerance underwent a 12-week training program. We examined changes in ATGL and CGI-58 with obesity and insulin resistance, and effects of exercise and pioglitazone. Adipose triglyceride lipase messenger RNA (mRNA) expression showed no correlation with either body mass index or insulin sensitivity index in either adipose or muscle. However, adipose ATGL protein levels were inversely correlated with body mass index ( r = −0.64, P < .02) and positively correlated with insulin sensitivity index ( r = 0.67, P < .02). In muscle, ATGL mRNA demonstrated a strong positive relationship with carnitine palmitoyltransferase I mRNA ( r = 0.82, P < .0001) and the adiponectin receptors AdipoR1 mRNA ( r = 0.71, P < .0001) and AdipoR2 mRNA ( r = 0.74, P < .0001). Muscle CGI-58 mRNA was inversely correlated with intramyocellular triglyceride in both type 1 ( r = −0.35, P < .05) and type 2 ( r = −0.40, P < .05) fibers. Exercise training resulted in increased muscle ATGL, and pioglitazone increased adipose ATGL by 31% ( P < .05). Pioglitazone also increased ATGL in adipocytes. Adipose ATGL protein is decreased with insulin resistance and obesity; and muscle ATGL mRNA is associated with markers of fatty acid oxidation in muscle, as is CGI-58. The regulation of ATGL and CGI-58 has important implications for the control of lipotoxicity.

The effect of group-based lifestyle interventions on risk factors and insulin resistance in subjects at risk for metabolic syndrome: the Tabaruzaka Study 1

The aim of this study was to evaluate the efficacy of two group-based lifestyle interventions in ameliorating the risk factors of metabolic syndrome (MS) and insulin resistance. Ninety-eight subjects who had at least one component of MS were randomized into standard intervention (SI) (4-month intervention; n = 50) and extended intervention (EI) (10-month intervention; n = 48) groups, and 39 subjects were followed up for a control group. The effects of intervention were evaluated after 10, 22 and 34 months. At month 10, the standard and EI groups showed improved body mass index (BMI) (SI, -0.28; EI, -0.47; control, -0.09), high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and A1c and a decreased mean number of components of MS (SI, -0.37; EI, -0.51; control, 0.08). At month 34, the effects on BMI (SI, -0.66; EI, -0.60; control, -0.05) and HDL-cholesterol were sustained for both the intervention groups. In controls, the increases in fasting plasma glucose and the mean number of components of MS from the baseline to month 34 were greater than those in the standard and EI groups. Whole body insulin sensitivity index and hepatic insulin resistance index were also improved at month 10. Group-based lifestyle intervention could be an efficient way to prevent MS. Its effects were sustainable, at least in part, for 2 years. These effects may be mediated by an improvement in insulin sensitivity.

Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes

To evaluate the clinical and endocrine differences between main polycystic ovary syndrome (PCOS) phenotypes. To evaluate clinical and hormone parameters in a large group of consecutive women with PCOS diagnosed according Rotterdam criteria and divided according their phenotype. University department of medicine. Three hundred eighty-two consecutive women with PCOS and 85 ovulatory controls. Evaluation of clinical and hormone parameters. Blood levels of gonadotropins, testosterone, sex-hormone-binding globulin, dehydroepiandrosterone sulfate, 17α-hydroxyprogesterone, progesterone, glucose, and insulin, and calculation of the free androgen index and insulin sensitivity. The severe PCOS phenotype (hyperandrogenism, chronic anovulation, and polycystic ovaries: type I classic PCOS) was the most common phenotype in 53.9% of the patients. The phenotype of 8.9% of patients was characterized by hyperandrogenism and chronic anovulation but normal ovaries (type II classic PCOS). The two phenotypes of classic PCOS had similar clinical and endocrine characteristics, but the patients with polycystic ovaries had a higher luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio. Ovulatory PCOS was relatively common (28.8% of PCOS patients) and presented milder clinical and endocrine alterations than the classic PCOS phenotypes. The normoandrogenic phenotype was relatively uncommon. These patients had a normal body mass index, insulin sensitivity, and free androgen index but showed increased levels of LH and LH/FSH ratio. Ovulatory PCOS represents the mild form of classic PCOS, but the normoandrogenic phenotype, although part of the spectrum, may represent a different disorder or have a different pathogenetic pathway.

Comparative Evaluation of Whole Body and Hepatic Insulin Resistance Using Indices from Oral Glucose Tolerance Test in Morbidly Obese Subjects with Nonalcoholic Fatty Liver Disease

Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a marker of Insulin Resistance (IR). Euglycemic-hyperinsulinemic clamp is the gold standard for measuring whole body IR (hepatic + peripheral IR). However, it is an invasive and expensive procedure. Homeostasis Model Assessment Index for Insulin Sensitivity (HOMA-IS), Quantitative Insulin Sensitivity Check Index (QUICKI) for hepatic IR and Insulin Sensitivity Index (ISI0,120), and Whole Body Insulin Sensitivity Index (WBISI) for whole body IR are the indices calculated after Oral Glucose Tolerance Test (OGTT). We used these indices as noninvasive methods of IR (inverse of insulin sensitivity) estimation and compared hepatic/peripheral components of whole body IR in NAFLD. Methods. 113 morbidly obese, nondiabetic subjects who underwent gastric bypass surgery and intraoperative liver biopsy were included in the study. OGTT was performed preoperatively and the indices were calculated. Subjects were divided into closely matched groups as normal, fatty liver (FL) and Non-Alcoholic Steatohepatitis (NASH) based on histology. Results. Whole body IR was significantly higher in both FL and NASH groups (NAFLD) as compared to Normal, while hepatic IR was higher only in NASH from Normal. Conclusions. FL is a manifestation of peripheral IR but not hepatic IR.

Abelmoschus moschatus (Malvaceae), an aromatic plant, suitable for medical or food uses to improve insulin sensitivity

Abelmoschus moschatus (Malvaceae) is an aromatic and medicinal plant, distributed in many parts of Asia, including south Taiwan. The present study was undertaken to clarify whether the herb is effective in improving insulin resistance. Insulin resistance in rats was induced by a diet containing 60% fructose for 6 weeks. The degree of insulin resistance was measured by homeostasis model assessment of basal insulin resistance (HOMA-IR). Insulin sensitivity was calculated using the composite whole body insulin sensitivity index (ISIcomp) during the oral glucose tolerance test. Insulin receptor-related signaling mediators in soleus muscles of rats were evaluated by immunoprecipitation or immunoblotting. The extract of A. moschatus had a higher level of polyphenolic flavonoids. A. moschatus extract (200 mg/kg per day) displayed the characteristics of rosiglitazone (4 mg/kg per day) in reducing the higher HOMA-IR index as well as elevating ISIcomp in fructose chow-fed rats after a 2-week treatment. Treatment with moschatus extract for 2 weeks increased post-receptor insulin signaling mediated by enhancements in insulin receptor substrate-1-associated phosphatidylinositol 3-kinase step and glucose transporter subtype 4 translocation in insulin-resistant soleus muscles. A. moschatus is therefore proposed as potentially useful adjuvant therapy for patients with insulin resistance and/or the subjects wishing to increase insulin sensitivity.

Comparison of composite whole body insulin sensitivity index derived from mixed meal test and oral glucose tolerance test in insulin resistant obese subjects

Apart from fasting blood glucose (FBG) and insulin (FBI), oral glucose tolerance test (OGTT) is also used in calculating insulin sensitivity. During OGTT, insulin secretion may not reflect normal physiological insulin secretion. Based on this idea, hepatic and whole body insulin sensitivity rates were tested during OGTT and mixed meal test (MMT) in obese subjects. Thirty-one women with Quantitative Insulin Sensitivity Check Index (QUICKI) values below 0.350 and body mass index (BMI) >or=30 were included into the study. OGTT with 75-g glucose and MMT 300 kcal were applied to all cases. Data obtained from OGTT and MMT were used in the assessment of insulin sensitivity with Hemostasis of Model Assessment-Insulin Resistance (HOMA-IR) and Matsuda's Composite Whole Body Insulin Sensitivity Index (Matsuda's ISI). Mean BMI, FBG, and FBI were 36.8 +/- 3.9 kg/m(2), 100.5 +/- 0.10 mg/dl, 16.2 +/- 5.3 microg/ml, respectively. QUICKI was 0.31 +/- 0.01 and HOMA-IR was 3.71 +/- 0.88. Matsuda's ISI derived from OGTT was 6.96 +/- 3.35 and from MMT was 11.32 +/- 6.61. In analysis, it was demonstrated that there was a correlation between HOMA-IR, QUICKI, and Matsuda's ISIs derived from OGTT and MMT. Comparing the time periods separately, it was detected that despite similar increment in insulin levels, glucose levels were higher in OGTT than MMT at 15 and 30 min. Consequently, Matsuda's ISI was demonstrated to be effectively used with the data of MMT, as used with OGTT. Moreover, MMT was shown to be in parallel to physiologic insulin secretion and reflect pancreatic functions better compared to OGTT.

Effect of the rs997509 Polymorphism on the Association between Ectonucleotide Pyrophosphatase Phosphodiesterase 1 and Metabolic Syndrome and Impaired Glucose Tolerance in Childhood Obesity

Variants on the nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP-1) gene have been associated with obesity and insulin resistance. Because insulin resistance is a pivotal factor in the development of metabolic syndrome (MS) and impaired glucose tolerance (IGT), we aimed to test the association between the K121Q and rs997509 ENPP-1 variants with obesity, MS and IGT in obese children and adolescents. We screened 809 children, 409 obese and 400 lean controls. Obese subjects underwent a standard oral glucose tolerance test, whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) were calculated. No difference in prevalence for K121Q and rs997509 polymorphisms between obese and controls (P > 0.05) were observed. Obese children carrying the rs997509 rare allele showed higher insulin (P = 0.001), HOMA (P < .001) and lower WBISI values (P = 0.04) compared with common allele homozygous. A similar observation was done for K121Q variant, with 121Q allele carriers showing higher insulin (P = 0.03) and HOMA (P = 0.04) values than 121K homozygotes. Moreover, subjects carrying the rs997509 rare allele had higher risk of MS (odds ratio 2.4, 95% confidence interval: 1.3-4.3) and IGT (odds ratio 4.7, 95% confidence interval: 1.9-11.4) than common allele homozygotes. Evaluating combined effects of both polymorphisms, which are in strong linkage disequilibrium, we showed that the effect on insulin sensitivity was due to the rs997509 T variant. We conclude that the ENPP1 rs997509T allele can predispose obese children to MS and IGT and that this variant might drive the association between the ENPP1 121Q allele and insulin resistance.

Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance

Although metformin (MET) is an insulin sensitizer currently used as an adjunct to the treatment of some of the complications of childhood obesity besides type 2 diabetes mellitus, few studies have comprehensively examined its metabolic and clinical effects in obese children with normal glucose tolerance (NGT). We therefore conducted a 4-month double-blind clinical trial in 28 obese [mean body mass index (BMI): 40.3 +/- 5.7 kg/m(2)], insulin-resistant [homeostasis model assessment - insulin resistance: 7.6 +/- 2.8 and whole body insulin sensitivity index (WBISI): 1.5 +/- 0.7] adolescents (age 15.0 +/- 1.3 yr) randomized to MET (n = 15, dose 1500 mg daily) or placebo (n = 13). The treatment with MET was well tolerated. MET treatment was associated with a decreased BMI (p = 0.02) as well as with a reduction in subcutaneous fat (p = 0.03), particularly the deep subcutaneous fat (p = 0.04) as assessed by magnetic resonance imaging. Postintervention, the MET group had a 35% improvement in insulin sensitivity (WBISI) compared with the placebo group (p = 0.008). However, significance was lost with adjustments for differences in baseline insulin sensitivity (p = 0.09). While there was no change in inflammatory cytokines or lipid parameters, cardiovascular function as assessed by heart rate recovery after exercise improved with MET and worsened in placebo (p = 0.03). Short-term use of MET is well tolerated by obese children with NGT and has a beneficial effect on BMI and autonomic control of the heart as well as a trend toward improved insulin sensitivity. Thus, long-term treatment with MET may provide a means to ameliorate the cardio-metabolic consequences of adolescent obesity.

Liver Steatosis in Obese Prepubertal Children: A Possible Role of Insulin Resistance

To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis. Cross-sectional study evaluating the prevalence of liver steatosis in 100 severely obese prepubertal children and comparing IR indexes between children with (group 1) and without steatosis (group 2). Furthermore, IR indexes were compared to values of 50 normal weight children. Fasting blood samples were collected for the evaluation of liver function tests, lipid profile, plasma glucose, and insulin levels. All children underwent an oral glucose tolerance test and anthropometric measurements. Hepatic ultrasound was performed according to international criteria and by one single operator. Analysis was performed by Mann-Whitney U-test, Pearson correlation, and logistic regression. Liver steatosis was found in 52% obese children and was equally distributed between the two sexes. Obese children were more insulin resistant when compared to controls (homeostasis model assessment of IR (HOMA-IR): P = 0.0001; whole body insulin sensitivity index (WBISI): P = 0.0005; fasting glucose/fasting insulin ratio (G/I): P = 0.0001), and group 1 presented an even higher degree of IR when compared to group 2 (HOMA-IR P = 0.0001; WBISI P = 0.0004; G/I P = 0.0001). The area under the curve (AUC) for insulin was significantly higher in group 1 when compared to group 2, while no difference was found in the AUC for glucose. There was no association between IR and adiposity indexes (P >0.05). The role of IR as a predictor for the development of steatosis was analyzed by multiple logistic regression, which documented that IR indexes were significantly related to steatosis independently of BMI-SDS. Liver steatosis is an emerging problem in prepubertal severely obese children, and it appears to be an association between liver steatosis and IR in these subjects.

Association between Genetic Polymorphisms of β-Cell Differentiation Genes and Insulin Resistance (β-Cell Dysfunction) in Childhood Acute Lymphoblastic Leukemia (ALL) Survivors.

Background: The purposes of the study were to determine β-cell function and insulin sensitivity after ALL therapy cessation and the association between genetic polymorphisms of β-cell differentiation genes, TCF7L2 and PAX4, with insulin resistance (β-cell dysfunction) in childhood ALL survivors.Methods: Childhood ALL patients diagnosed during 1997–2004 finished the treatment for at least 6 months. The oral glucose tolerance test and lipid screening were performed. Impaired glucose tolerance and diabetes mellitus (DM) were defined according to WHO criteria. β-cell function was estimated by homeostasis model assessment β-cell (HOMA β-cell) and insulinogenic index (IGI) and insulin sensitivity was estimated by whole body insulin sensitivity index (WBISI). The polymorphisms of TCF7L2 (rs12255372 and rs7903146) and PAX4 (A1186C) were genotyped and assessed for the association between these polymorphisms and the β-cell function and the insulin sensitivity.Results: 126 patients were studied (52 females, 74 males and age at the time of study; 4–20 yrs). 116 patients (92%) had normal glucose tolerance (NGT) while the others 10 patients (8%) had impaired glucose tolerance (IGT). Comparing between IGT and NGT groups respectively, we found statistically significant differences in age at the diagnosis (7.5 and 5.2 yrs, p=0.041), age at the study (14 and 10.3 yrs, p=0.001), the duration of post ALL therapy cessation (43 and 26 months, p=0.015), and insulin sensitivity index (WBISI) (5.75 and 9.52, p<0.001). HOMA β-cell and IGI were not different between NGT and IGT group (190.8 and 139.5, p=0.332; 23.6 and 15.8, p=0.310, respectively). Moreover, 32 of 126 patients (25%) had insulin resistance (modified from the criteria of WBISI in obese children and adolescents). These 32 patients who had insulin resistance demonstrated significant pictures of metabolic syndrome i.e. hypertriglyceridemia (116.6 and 85.4 mg/dL, p=0.036), low HDL-C (43.0 and 48.3 mg/dL, p=0.015), obesity (BMI SDS 1.03 and 0.38, p=0.044) and were also older age at the study (12.8 and 9.9 yrs, p<0.001). The genotype frequencies and allele frequencies of polymorphisms of TCF7L2 and PAX4 genes between IGT and NGT groups and between insulin resistance and nonresistance were not difference (p>0.05).Conclusion: The childhood ALL survivors who had IGT were associated with the longer duration of ALL therapy cessation, the older age at diagnosis and at the time of study, and insulin resistance while β-cell function was still relatively preserved. Long-term childhood ALL survivors have potential risks of IGT, insulin resistance and metabolic syndrome. Our findings with such small representatives are not yet applicable to associate TCF7L2 and PAX4 polymorphisms with the insulin resistance (β-cell dysfunction) in the childhood ALL survivors.

Several mutations in the melanocortin 4 receptor gene are associated with obesity in Chinese children and adolescents

To screen mutations in the melanocortin 4 receptor (MC4R) in obese and normal-weight Chinese children and adolescents. Three hundred Chinese children and adolescents, including 200 obese and 100 healthy non-obese individuals, were evaluated. The coding region of the MC4R gene was amplified by polymerase chain reaction (PCR) and sequenced. In obese individuals, we detected two novel heterozygous non-synonymous mutations (c.496G>A, resulting in Val166Ile; c.929G>A, resulting in Arg310Lys) and a novel heterozygous non-sense mutation (c.831T>A, resulting in a premature stop codon Cys277Stop). In both obese individuals and controls, a novel heterozygous non-synonymous mutation (c.68T>G, resulting in Leu23Arg, 0.5 and 1%, respectively) and the Val103Ile polymorphism (c.307G>A, 3 and 2%, respectively) were found. There was no difference in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), cholesterol (CHOL) and whole body insulin sensitivity index (WBISI) between obese individuals with and without mutation. The prevalence for heterozygous MC4R mutations was 1.5% in the obese. Two novel heterozygous non-synonymous mutations (Val166Ile; Arg310Lys) and a novel heterozygous non-sense mutation (Cys277Stop) were detected in Chinese obese individuals. Leu23Arg variant might be a polymorphism in the Chinese population. There were no differences between clinical and biochemical profiles in the heterozygous mutations and the wild type.

Usefulness of Insulin Sensitivity Indexes derived from Oral Glucose Tolerance Test in Women with Polycystic Ovary Syndrome

- Abstract Background: Insulin resistance is prevalent in women with polycystic ovary syndrome (PCOS), and it makes them to have high risk for development of type 2 diabetes. Evaluation of insulin sensitivity would be important to predict their risks. Although the euglycemic-hyperinsulinemic clamp technique is the gold standard for measuring insulin sensitivity, it is too hard to practice in large epidemiologic studies. The aim of this study is to verify the validity of various insulin sensitivity indexes f rom oral glucose tolerance test (OGTT) in women with PCOS. Methods: We performed euglycemic-hyperinsulinemic clamp (target glucose; 90 mg/dL, insulin ;~1 mU/kg․min) to obtain insulin-mediated glucose disposal rate (M-value) in 62 non-diabetic women with PCOS (BMI < 23 kg/m 2 ; n = 37, BMI ≥ 23 kg/m 2 ; n = 25). Homeostasis model assessment [HOMA(IR)], quantitative insulin sensitivity check index (QUICKI), glucose to insulin ratio (G/I ratio), whole body insu lin sensitivity index [ISI (COMP)], metabolic clearance rate of glucose [MCRest-OGTT 1,2 ], and insulin sensitivity indexes [ISIest-OGTT 1,2 ] were calculated from plasma glucose and insulin levels from standard 75-g OGTT. The correlations of various insulin sensitivity indexes f rom OGTT with M-value were evaluated. Results: In lean women with PCOS (BMI < 23 kg/m 2 , n = 37), ISI(COMP) (r = 0.36, P < 0.05), MCRest-OGTT 1 (r = 0.49, P < 0.01), ISIest-OGTT 1 (r = 0.50, P < 0.01), MCRest-OGTT 2 (r = 0.45, P < 0.01) and ISIest-OGTT 2 (r = 0.40, P < 0.05) were significantly correlated with M-value. In overweight and obese women with PCOS (BMI ≥ 23 kg/m 2 , n = 25), HOMA(IR) (r = -0.40, P < 0.05), QUICKI (r = 0.40, P < 0.05), MCRest-OGTT 1 (r = 0.76, P < 0.001), ISI est-OGTT 1 (r = 0.63, P < 0.001), MCRest-OGTT 2

Comparison of methods to detect insulin resistance in obese children and adolescents

To explore the practical and sensitive index for insulin resistance in obese children and adolescents. An oral glucose tolerance test and insulin releasing test were performed in 126 obese (divided into 3 groups according their BMI) and 25 normal children. The ratio of fasting plasma glucose to fasting plasma insulin (FBG/FINS), homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model assessment-insulin activity index (IAI), whole body insulin sensitivity index (WBISI) and area under curve of glucose and insulin (AUCBG, AUCINS) were calculated. There were no significant differences in fasting plasma glucose levels, while significant differences existed in fasting plasma insulin, the ratio of fasting plasma glucose to fasting plasma insulin,homeostasis model assessment-insulin resistance, homeostasis model assessment-insulin activity index, whole body insulin sensitivity index, area under curve of glucose, area under curve of insulin and AUCINS/AUCBG among these four groups. Whole body insulin sensitivity index (WBISI) reflected the sensitiveness of the insulin earlier than that of homeostasis model assessment-insulin resistance and homeostasis model assessment-insulin activity index. Whole body insulin sensitivity index seems to be a better index for insulin resistance for obese children.