Rosiglitazone improves glucose metabolism in obese adolescents with impaired glucose tolerance: a pilot study.

Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor ß-cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and ß-cell function. In a small randomized, double-blind, placebo (PLA)-controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z-score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z-score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, magnetic resonance imaging, and (1)H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short-term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and ß-cell function, two principal pathophysiological abnormalities of IGT.

Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link?

UNLABELLED: Fatty liver is increasingly common in obese adolescents. We determined its association with glucose dysregulation in 118 (37M/81F) obese adolescents of similar age and percent total fat. Fast-magnetic resonance imaging (MRI) and simple MRI were used to quantify hepatic fat content and abdominal fat distribution. All subjects had a standard oral glucose tolerance test. Insulin sensitivity was estimated by the Matsuda Index and homeostasis model assessment of insulin resistance. Baseline total and high molecular weight (HMW)-adiponectin and interleukin (IL)-6 levels were measured. The cohort was stratified according to tertiles of hepatic fat content. Whereas age and %fat were comparable across tertiles, ethnicity differed in that fewer Blacks and more Whites and Hispanics were in the moderate and high category of hepatic fat fraction (HFF). Visceral and the visceral-to-subcutaneous fat ratio increased and insulin sensitivity decreased across tertiles. Two-hour plasma glucose rose with increasing hepatic steatosis (P < 0.008). 73.7% of the subjects in the high HFF had the metabolic syndrome compared to 19.5% and 30.6%, respectively, in the low and moderate categories. Both total and HMW-adiponectin decreased, and IL-6 increased with increasing hepatic steatosis. CONCLUSION: In obese adolescents, independent of total fat, increasing severity of fatty liver is associated with glucose dysregulation, metabolic syndrome, and with a proinflammatory milieu.

Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point dixon and three-point IDEAL.

Hepatic fat fraction (HFF) was measured in 28 lean/obese humans by single-voxel proton spectroscopy (MRS), a two-point Dixon (2PD), and a three-point iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) method (3PI). For the lean, obese, and total subject groups, the range of HFF measured by MRS was 0.3-3.5% (1.1 +/- 1.4%), 0.3-41.5% (11.7 +/- 12.1), and 0.3-41.5% (10.1 +/- 11.6%), respectively. For the same groups, the HFF measured by 2PD was -6.3-2.2% (-2.0 +/- 3.7%), -2.4-42.9% (12.9 +/- 13.8%), and -6.3-42.9% (10.5 +/- 13.7%), respectively, and for 3PI they were 7.9-12.8% (10.1 +/- 2.0%), 11.1-49.3% (22.0 +/- 12.2%), and 7.9-49.3% (20.0 +/- 11.8%), respectively. The HFF measured by MRS was highly correlated with those measured by 2PD (r = 0.954, P < 0.001) and 3PI (r = 0.973, P < 0.001). With the MRS data as a reference, the percentages of correct differentiation between normal and fatty liver with the MRI methods ranged from 68-93% for 2PD and 64-89% for 3PI. Our study demonstrates that the apparent HFF measured by the MRI methods can significantly vary depending on the choice of water-fat separation methods and sequences. Such variability may limit the clinical application of the MRI methods, particularly when a diagnosis of early fatty liver needs to be performed. Therefore, protocol-specific establishment of cutoffs for liver fat content may be necessary.

High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotype.

OBJECTIVE: To explore whether an imbalance between the visceral and subcutaneous fat depots and a corresponding dysregulation of the adipokine milieu is associated with excessive accumulation of fat in the liver and muscle and ultimately with insulin resistance and the metabolic syndrome. RESEARCH DESIGN AND METHODS: We stratified our multi-ethnic cohort of 118 obese adolescents into tertiles based on the proportion of abdominal fat in the visceral depot. Abdominal and liver fat were measured by magnetic resonance imaging and muscle lipid (intramyocellular lipid) by proton magnetic resonance spectroscopy. RESULTS: There were no differences in age, BMI Z score, or fat-free mass across tertiles. However, as the proportion of visceral fat increased across tertiles, BMI and percentage of fat and subcutaneous fat decreased, while hepatic fat increased. In addition, there was an increase in 2-h glucose, insulin, c-peptide, triglyceride levels, and insulin resistance. Notably, both leptin and total adiponectin were significantly lower in tertile 3 than 1, while C-reactive protein and interleukin-6 were not different across tertiles. There was a significant increase in the odds ratio for the metabolic syndrome, with subjects in tertile 3 5.2 times more likely to have the metabolic syndrome than those in tertile 1. CONCLUSIONS: Obese adolescents with a high proportion of visceral fat and relatively low abdominal subcutaneous fat have a phenotype reminiscent of partial lipodystrophy. These adolescents are not necessarily the most severely obese, yet they suffer from severe metabolic complications and are at a high risk of having the metabolic syndrome.

Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state.

OBJECTIVE: Among other metabolic consequences, a dyslipidemic profile often accompanies childhood obesity. In adults, type 2 diabetes and hepatic steatosis have been shown to alter lipoprotein subclass distribution and size; however, these alterations have not yet been shown in children or adolescents. Therefore, our objective was to determine the effect of hepatic steatosis on lipoprotein concentration and size in obese adolescents. RESEARCH DESIGN AND METHODS: Using fast magnetic resonance imaging, we measured intrahepatic fat content in 49 obese adolescents with normal glucose tolerance. The presence or absence of hepatic steatosis was determined by a threshold value for hepatic fat fraction (HFF) of 5.5%; therefore, the cohort was divided into two groups (HFF > or <5.5%). Fasting lipoprotein subclasses were determined using nuclear magnetic resonance spectroscopy. RESULTS: Overall, the high-HFF group had 88% higher concentrations of large VLDL compared with the low-HFF group (P < 0.001). Likewise, the high-HFF group had significantly higher concentrations of small dense LDL (P < 0.007); however, the low-HFF group had significantly higher concentrations of large HDL (P < 0.001). Stepwise multiple regression analysis revealed that high HFF was the strongest single correlate, accounting for 32.6% of the variance in large VLDL concentrations (P < 0.002). CONCLUSIONS: The presence of fatty liver was associated with a pronounced dyslipidemic profile characterized by large VLDL, small dense LDL, and decreased large HDL concentrations. This proatherogenic phenotype was strongly related to the intrahepatic lipid content.

Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat.

BACKGROUND: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. METHODS: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. FINDINGS: Elevated ALT (> 35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18-35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. INTERPRETATION: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.

Development of type 2 diabetes in children and adolescents.

Type 2 diabetes is emerging as a significant health problem in children and adolescents. The disease usually develops in obese insulin-resistant youth with a typical pattern of lipid partitioning characterized by increased lipid deposition in myocytes, the visceral compartment, and the liver. Unfavorable adipocytokine profiles, together with a state of low-grade inflammation, create an additional metabolic burden tightly coupled to other components of the metabolic syndrome. Insufficient beta-cell compensation promotes altered glucose metabolism.

Adiponectin in childhood and adolescent obesity and its association with inflammatory markers and components of the metabolic syndrome.

CONTEXT: Adiponectin levels are lower in obese children and adolescents, whereas markers of inflammation and proinflammatory cytokines are higher. Hypoadiponectinemia may contribute to the low-grade systemic chronic inflammatory state associated with childhood obesity. OBJECTIVE: We investigated whether C-reactive protein (CRP), the prototype of inflammation, is related to adiponectin levels independently of insulin resistance and adiposity. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: In a multiethnic cohort of 589 obese children and adolescents, we administered a standard oral glucose tolerance test and obtained baseline measurements for adiponectin, plasma lipid profile, CRP, IL-6, and leptin. RESULTS: Stratifying the cohort into quartiles of adiponectin levels and adjusting for potential confounding variables, such as age, gender, ethnicity, body mass index z-score, pubertal status, and insulin sensitivity, the present study revealed that low levels of adiponectin are associated not only with higher CRP levels, but also with components of the metabolic syndrome, such as low high-density lipoprotein cholesterol and a high triglyceride-to-high-density-lipoprotein ratio. CONCLUSIONS: The link between adiponectin levels and a strong marker of inflammation, CRP, is independent of insulin resistance and adiposity in obese children and adolescents. Adiponectin may be one of the signals linking inflammation and obesity. Thus, adiponectin may function as a biomarker of the metabolic syndrome in childhood obesity.

Dietary intake, body image perceptions, and weight concerns of female US International Synchronized Figure Skating Teams.

The objectives of the study were to determine the nutrient intakes and to examine body image perceptions and weight concerns of elite female US international synchronized skaters. One hundred and twenty-three skaters (mean age = 17.0 +/- 2.1 y; BMI = 21.32 +/- 2.13) representing six US international synchronized skating teams from the 1998 competitive season participated in the study. Nutrient intakes were determined from 3-d dietary records. Body image perceptions were assessed from responses to silhouette drawings. Skaters completed an emotional and physical self-appraisal. Weight concerns were assessed using a self-administered validated weight history questionnaire. The reported energy intake was 26 kcal/kg. The contribution of carbohydrate, fat, and protein to total energy intake was 62%, 23%, and 15% for younger (14-18 y) and 62%, 24%, and 14%, respectively, for the older (19-30 y))skaters. Significant differences (P < 0.001) were observed between perceived ideal and current body shapes. The greater the dissatisfaction with physical and emotional self, the larger the discrepancy between current versus desired body shape. Results suggest that sports nutritionists should not only assess nutrition factors but also examine psychosocial and emotional correlates related to body image and weight concerns of synchronized skaters.

Beta-cell function across the spectrum of glucose tolerance in obese youth.

The profile of insulin secretion and the role of proinsulin processing across the spectrum of glucose tolerance in obese youth have not been studied. The aims of this study were to define the role of insulin secretion and proinsulin processing in glucose regulation in obese youth. We performed hyperglycemic clamps to assess insulin secretion, applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration data. Thirty obese youth with normal glucose tolerance (NGT), 22 with impaired glucose tolerance (IGT), and 10 with type 2 diabetes were studied. The three groups had comparable anthropometric measures and insulin sensitivity. The glucose sensitivity of first-phase secretion showed a significant stepwise decline from NGT to IGT and from IGT to type 2 diabetes. The glucose sensitivity of second-phase secretion was similar in NGT and IGT subjects yet was significantly lower in subjects with type 2 diabetes. Proinsulin-to-insulin ratios were comparable during first- and second-phase secretion between subjects with NGT and IGT and were significantly increased in type 2 diabetes. Obese youth with IGT have a significant defect in first-phase insulin secretion, while a defect in second-phase secretion and proinsulin processing is specific for type 2 diabetes in this age-group.

The "obese insulin-sensitive" adolescent: importance of adiponectin and lipid partitioning.

There is a wide interindividual variation in peripheral insulin sensitivity at any given body mass index or percent body fat among obese adolescents with normal glucose tolerance. The goals of this study were to determine whether variability in insulin sensitivity is associated with differences in patterns of lipid partitioning or substrate use under fasting and hyperinsulinemic conditions. We compared 14 obese insulin-resistant adolescents with 14 obese insulin-sensitive controls, pair matched for age, gender, pubertal stage and body composition. Insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp, intramyocellular lipid content by (1)H-nuclear magnetic resonance and visceral fat by magnetic resonance imaging. Obese insulin-sensitive subjects had lower intramyocellular (1.64 +/- 0.68 vs.2.26 +/- 0.62% of water peak, P = 0.017) and visceral lipid deposition (45 +/- 23 vs. 77 +/- 52 cm(2), P = 0.04) and a higher level of adiponectin, compared with their obese-resistant counterparts (8.8 +/- 3.6 vs. 6.5 +/- 1.8 mug/dl, P = 0.015). Glycerol fluxes were similar between the two obese groups yet occurred in the face of different concentrations of insulin. Intramyocellular lipid and visceral fat were negatively related to insulin sensitivity. Obese insulin-sensitive adolescents are characterized by lower lipid deposition in the intramyocellular and visceral compartments and greater levels of adiponectin, despite similar degree of adiposity.

Predictors of changes in glucose tolerance status in obese youth.

OBJECTIVE: Type 2 diabetes in obese youth is an emerging problem. The metabolic and anthropometric predictors of change in glucose tolerance status in obese youth are unknown. RESEARCH DESIGN AND METHODS: A total of 117 obese children and adolescents were studied by performing an oral glucose tolerance test (OGTT) at baseline and after approximately 2 years. Data from both OGTTs and changes in weight were examined to identify youth at highest risk for developing diabetes and the factors that have the strongest impact on glucose tolerance. RESULTS: Eighty-four subjects had normal glucose tolerance (NGT) and 33 impaired glucose tolerance (IGT) at baseline. Eight subjects (all of whom had IGT at baseline) developed type 2 diabetes, whereas 15 subjects with IGT reverted to NGT. In this cohort, severe obesity, impaired glucose tolerance, and African-American background emerged as the best predictors of developing type 2 diabetes, whereas fasting glucose, insulin, and C-peptide were nonpredictive. Changes in insulin sensitivity, strongly related to weight change, had a significant impact on the 2-h glucose level on the follow-up study. CONCLUSIONS: Severely obese children and adolescents with IGT, particularly of African-American descent, are at very high risk for developing type 2 diabetes over a short period of time. Parameters derived from an OGTT and not fasting samples can serve as predictors of changes in glucose tolerance.

The normal glucose tolerance continuum in obese youth: evidence for impairment in beta-cell function independent of insulin resistance.

Normal glucose tolerance is expressed over a wide range of glucose concentrations. Whether there is a continuum of risk for developing type 2 diabetes mellitus even when the 2-h plasma glucose is still within this normal range is uncertain. Oral glucose tolerance tests were performed in 407 obese normal glucose tolerance youth (4-20 yr) to examine the relationship between variations in 2-h plasma glucose levels and beta-cell responsiveness. Individuals were grouped by 2-h plasma glucose levels as follows: 1) less than 100 mg/dl, 2) 100-119 mg/dl, and 3) 120-139 mg/dl. Subsequent analysis stratified each 2-h plasma level by insulin sensitivity index. Increased 2-h glucose level was associated with a progressive increase in glucose between 0 and 30 min (P < 0.05). The Delta (0-30 min) insulin did not vary significantly across levels, thus resulting in a decreased insulinogenic index (P < 0.02). This pattern was observed at every level of insulin sensitivity (P < 0.02). These data translated to an unfavorable (leftward) shift in the insulin feedback system for increasing 2-h glucose level (P < 0.005). Increased 2-h plasma glucose within the range of normal glucose tolerance in obese youth is associated with a specific impairment of beta-cell responsiveness distinct from the deterioration of insulin sensitivity.

Obesity and the metabolic syndrome in children and adolescents.

BACKGROUND: The prevalence and magnitude of childhood obesity are increasing dramatically. We examined the effect of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to insulin resistance and to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial cohort of children and adolescents. METHODS: We administered a standard glucose-tolerance test to 439 obese, 31 overweight, and 20 nonobese children and adolescents. Baseline measurements included blood pressure and plasma lipid, C-reactive protein, and adiponectin levels. Levels of triglycerides, high-density lipoprotein cholesterol, and blood pressure were adjusted for age and sex. Because the body-mass index varies according to age, we standardized the value for age and sex with the use of conversion to a z score. RESULTS: The prevalence of the metabolic syndrome increased with the severity of obesity and reached 50 percent in severely obese youngsters. Each half-unit increase in the body-mass index, converted to a z score, was associated with an increase in the risk of the metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95 percent confidence interval, 1.16 to 2.08), as was each unit of increase in insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95 percent confidence interval, 1.07 to 1.18 for each additional unit of insulin resistance). The prevalence of the metabolic syndrome increased significantly with increasing insulin resistance (P for trend, <0.001) after adjustment for race or ethnic group and the degree of obesity. C-reactive protein levels increased and adiponectin levels decreased with increasing obesity. CONCLUSIONS: The prevalence of the metabolic syndrome is high among obese children and adolescents, and it increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters.

Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents.

Given the extreme increase in prediabetes, type 2 diabetes, and the potential for metabolic syndrome in obese youth, identifying simplified indexes for assessing stimulated insulin sensitivity is critical. The purpose of this study was validation of two surrogate indexes of insulin sensitivity determined from the oral glucose tolerance test (OGTT): the composite whole body insulin sensitivity index (WBISI) and the insulin sensitivity index (ISI). An obese population (aged 8-18 yr) of normal and impaired glucose tolerance individuals was studied. One group (n = 38) performed both the euglycemic-hyperinsulinemic clamp and OGTT for comparison of insulin sensitivity measurements as well as (1)H-magnetic resonance spectroscopy estimates of intramyocellular lipid content. Another larger (n = 368) cohort participated only in an OGTT. Both the WBISI and ISI represented good estimates (r = 0.78 and 0.74; P < 0.0005) for clamp-derived insulin sensitivity (glucose disposed, M-value), respectively. In the large cohort, the surrogate indexes demonstrated the shift toward poorer function and increased risk profile as a function of insulin resistance. Additionally, the WBISI and ISI correlated with intramyocellular lipid content (r = -0.74 and -0.71; P < 0.0001), a tissue marker for insulin resistance. Insulin sensitivity can be estimated using plasma glucose and insulin responses derived from the OGTT in obese youth with normal and impaired glucose tolerance.

Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning.

BACKGROUND: Impaired glucose tolerance is common among obese adolescents, but the changes in insulin sensitivity and secretion that lead to this prediabetic state are unknown. We investigated whether altered partitioning of myocellular and abdominal fat relates to abnormalities in glucose homoeostasis in obese adolescents with prediabetes. METHODS: We studied 14 obese children with impaired glucose tolerance and 14 with normal glucose tolerance, of similar ages, sex distribution, and degree of obesity. Insulin sensitivity and secretion were assessed by the euglycaemic-hyperinsulinaemic clamp and the hyperglycaemic clamp. Intramyocellular lipid was assessed by proton nuclear magnetic resonance spectroscopy and abdominal fat distribution by magnetic resonance imaging. FINDINGS: Peripheral glucose disposal was significantly lower in individuals with impaired than in those with normal glucose tolerance (mean 35.4 [SE 4.0] vs 60.6 [7.2] micromoles per kg lean body mass per min; p=0.023) owing to a reduction in non-oxidative glucose disposal metabolism (storage). Individuals with impaired glucose tolerance had higher intramyocellular lipid content (3.04 [0.43] vs 1.99 [0.19]%, p=0.03), lower abdominal subcutaneous fat (460 [47] vs 626 [39] cm2, p=0.04), and slightly higher visceral fat than the controls (70 [11] vs 47 [6] cm2, p=0.065), resulting in a higher ratio of visceral to subcutaneous fat (0.15 [0.02] vs 0.07 [0.01], p=0.002). Intramyocellular and visceral lipid contents were inversely related to the glucose disposal and non-oxidative glucose metabolism and positively related to the 2 h plasma glucose concentration. INTERPRETATION: In obese children and adolescents with prediabetes, intramyocellular and intra-abdominal lipid accumulation is closely linked to the development of severe peripheral insulin resistance.

Low adiponectin levels in adolescent obesity: a marker of increased intramyocellular lipid accumulation.

We examined the impact of adolescent obesity on circulating adiponectin levels and the relationship between adiponectin and insulin sensitivity, intramyocellular (IMCL) lipid content, plasma triglycerides, and free fatty acids. Plasma adiponectin levels were measured in 8 nonobese (percentage fat, 18 +/- 1.8) and 14 obese adolescents (percentage fat, 41 +/- 1.6). Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Intramuscular lipid content was quantified using (1)H-nuclear magnetic resonance spectroscopy, and abdominal fat distribution by magnetic resonance imaging. Adiponectin levels were lower in obese adolescents (9.2 +/- 1 microg/ml, P < 0.001) and were positively related to insulin sensitivity in all subjects (r = 0.531, P < 0.02). Strong inverse relationships were found between adiponectin and triglyceride levels (r = -0.80, P < 0.001) and IMCL (r = -0.73, P < 0.001). Triglycerides (partial r(2) = 0.52; P < 0.0002) and IMCL (partial r(2) = 0.10; P < 0.05) were the most significant predictors of adiponectin levels, explaining 62% of the variation. In conclusion, plasma adiponectin levels are reduced in adolescent obesity and related to insulin resistance, independent of total body fat and central adiposity. There is a strong relationship between adiponectin and IMCL lipid content in this pediatric population. The putative modulatory effects of adiponectin on insulin sensitivity may, in part, be mediated via its effects on IMCL lipid content.