Ovarian Morphology in Girls Longitudinal Cohort Study: Pilot Evaluation of Ovarian Morphology as a Biomarker of Reproductive and Metabolic Features during the First Gynecological Year.

OBJECTIVE: The objective was to establish whether aspects of ovarian morphology correlate with reproductive and metabolic features during the first postmenarcheal year using data from the Ovarian Morphology in Girls (OMG!) cohort study. The feasibility of transabdominal ultrasonography to assess ovarian features was also determined. METHODS: Healthy adolescent females enrolled in a prospective cohort study. Study visits occurred at 6-10, 11-13, 17-19, and 23-25 months postmenarche and entailed a physical exam, transabdominal ultrasound, and fasting blood draw. Participants maintained menstrual diaries throughout the study. The present analysis reflects participants who completed the study visit at 6-10 months postmenarche. Associations between ovarian morphology or average cycle length with reproductive and metabolic features were assessed by Spearman correlations and linear regression. RESULTS: Forty participants enrolled in the OMG! STUDY: Thirty-one participants initiated study procedures at 6-10 months postmenarche, and data were available for analysis for 29 participants. Image quality was judged as partially visible or excellent in 90% of the left and 78% of the right ovaries assessed, with all images collected having sufficient image quality to provide measurements of at least 1 ovarian marker. The follicle number per ovary and ovarian volume were positively associated with anti-Müllerian hormone levels and negatively associated with fasting insulin. The average cycle length was only associated negatively with triglycerides. CONCLUSION: Transabdominal ultrasonography in the early postmenarcheal period provides sufficient resolution to enable estimations of antral follicle count and ovarian size. Ovarian features in early gynecological life may correspond with measures of reproductive and metabolic function.

Sexual function in women with polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common and distressing endocrine disorder associated with lower quality of life, subfertility, diabetes, cardiovascular disease, depression, anxiety, and eating disorders. PCOS characteristics, its comorbidities, and its treatment can potentially influence sexual function. However, studies on sexual function in women with PCOS are limited and contradictory. OBJECTIVE AND RATIONALE: The aim was to perform a systematic review of the published literature on sexual function in women with PCOS and assess the quality of the research and certainty of outcomes, to inform the 2023 International Guidelines for the Assessment and Management of PCOS. SEARCH METHODS: Eight electronic databases were searched until 1 June 2023. Studies reporting on sexual function using validated sexuality questionnaires or visual analogue scales (VAS) in PCOS populations were included. Random-effects models were used for meta-analysis comparing PCOS and non-PCOS groups with Hedges' g as the standardized mean difference. Study quality and certainty of outcomes were assessed by risk of bias assessments and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method according to Cochrane. Funnel plots were visually inspected for publication bias. OUTCOMES: There were 32 articles included, of which 28 used validated questionnaires and four used VAS. Pooled Female Sexual Function Index (FSFI) scores in random-effects models showed worse sexual function across most subdomains in women with PCOS, including arousal (Hedges's g [Hg] [95% CI] = -0.35 [-0.53, -0.17], I2 = 82%, P < 0.001), lubrication (Hg [95% CI] = -0.54 [-0.79, -0.30], I2 = 90%, P < 0.001), orgasm (Hg [95% CI] = -0.37 [-0.56, -0.19], I2 = 83%, P < 0.001), and pain (Hg [95% CI] = -0.36 [-0.59, -0.13] I2 = 90%, P < 0.001), as well as total sexual function (Hg [95% CI] = -0.75 [-1.37, -0.12], I2 = 98%, P = 0.02) and sexual satisfaction (Hg [95% CI] = -0.31 [-0.45, -0.18], I2 = 68%, P < 0.001). Sensitivity and subgroup analyses based on fertility status and body mass index (BMI) did not alter the direction or significance of the results. Meta-analysis on the VAS studies demonstrated the negative impact of excess body hair on sexuality, lower sexual attractiveness, and lower sexual satisfaction in women with PCOS compared to controls, with no differences in the perceived importance of a satisfying sex life. No studies assessed sexual distress. GRADE assessments showed low certainty across all outcomes. WIDER IMPLICATIONS: Psychosexual function appears to be impaired in those with PCOS, but there is a lack of evidence on the related distress scores, which are required to meet the criteria for psychosexual dysfunction. Health care professionals should discuss sexual function and distress and be aware of the multifactorial influences on sexual function in PCOS. Future research needs to assess both psychosexual function and distress to aid in understanding the degree of psychosexual dysfunction in PCOS. Finally, more diverse populations (e.g. non-heterosexual and more ethnically diverse groups) should be included in future studies and the efficacy of treatments for sexual dysfunction should also be assessed (e.g. lifestyle and pharmacological interventions).

Distinct Reproductive Phenotypes Segregate With Differences in Body Weight in Adolescent Polycystic Ovary Syndrome.

Introduction: Polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome defined by hyperandrogenism and irregular menses. In adult women with PCOS, discrete metabolic and reproductive subgroups have been identified. We hypothesize that distinct phenotypes can be distinguished between adolescent girls who are lean (LN-G) and girls with obesity (OB-G) at the time of PCOS diagnosis. Methods: Data were extracted from the CALICO multisite PCOS database. Clinical data collected at the time of diagnosis were available in 354 patients (81% with obesity) from 7 academic centers. Patients with body mass index (BMI) < 85th percentile for age and sex were characterized as lean (LN-G) and those with BMI percentile ≥ 95th percentile as obese (OB-G). We compared metabolic and reproductive phenotypes in LN-G and OB-G. Results: Reproductive phenotypes differed between the groups, with LN-G having higher total testosterone, androstenedione, and LH levels, while OB-G had lower sex hormone binding globulin (SHBG) and higher free testosterone. Metabolic profiles differed as expected, with OB-G having higher hemoglobin A1c, alanine aminotransferase, and serum triglycerides and more severe acanthosis nigricans. Conclusion: LN-G with PCOS had a distinct reproductive phenotype characterized by increased LH, total testosterone, and androstenedione levels, suggesting neuroendocrine-mediated ovarian androgen production. In contrast, phenotypes in OB-G suggest hyperandrogenemia is primarily driven by insulin resistance with low SHBG levels. These observations support the existence of distinct metabolic and reproductive subtypes in adolescent PCOS characterized by unique mechanisms for hyperandrogenemia.

Breaking Boundaries: Toward Consistent Gender-Sensitive Language in Sexual and Reproductive Health Guidelines.

This review assesses gender-sensitive language in sexual and reproductive health (SRH) guidelines, including a guideline for polycystic ovary syndrome. We conducted a systematic search across databases like Medline, EMBASE, and Cochrane until July 31, 2023, using terms related to gender-inclusivity, SRH, and guideline protocols. Criteria for inclusion were gender-sensitive language, SRH focus, and guideline relevance, excluding non-English articles or those without policy considerations. Our search yielded 25 studies, with 6 included for qualitative synthesis. Results showed significant gaps in using gender-sensitive language in SRH guidelines. The debate on this language mirrors broader societal discourse. Recognizing gender diversity is essential for research, clinical practices, and societal norms. While promoting inclusion, drawbacks like unintended erasure or miscommunication should also be addressed. A gender-additive approach balances inclusivity and biological accuracy. Precise and inclusive discourse is crucial. Future research should focus on systemic approaches in the SRH sector.

Bridging the Information Gap in Polycystic Ovary Syndrome: A Narrative Review with Systematic Approach.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy with wide-ranging implications for affected individuals. Literature has shown that patients with PCOS are dissatisfied with the health information provided to them and that healthcare professionals lack adequate knowledge. In this narrative review with systematic approach, we explored the unmet information needs in PCOS care for both patients and healthcare professionals. A comprehensive search of databases yielded 41 relevant studies, predominantly of observational and qualitative design. Adults and adolescents with PCOS desire wide ranging health information and express a keen desire for weight management guidance. Importantly, discussions surrounding weight should be addressed knowledgeably and without weight bias. Therefore, healthcare professionals should facilitate access to comprehensive evidence-based resources. Lack of information drives PCOS-related online searches. Referral to support groups that promote individual agency in the self-management aspects of PCOS can furthermore guide patient resource acquisition. Patients prefer guidance from professionals that understand the psychosocial complexity of PCOS and can empathize with experiences of stigmatization or even marginalization depending on the cultural context of the individual. The findings informed the 2023 International Evidence-Based PCOS Guideline, recommending patient-centered communication, evidence-based information resources, and culturally sensitive approaches to optimize PCOS care.

Gender diversity in adolescents with polycystic ovary syndrome.

OBJECTIVES: The objective of our study was to describe the prevalence of gender diverse (GD) youth  among adolescents with polycystic ovary syndrome (PCOS). METHODS: We conducted a retrospective chart review on patients who met NIH criteria for PCOS in our Multidisciplinary Adolescent PCOS Program (MAPP). We compared those with PCOS to MAPP patients who did not meet PCOS criteria as well as to non-PCOS patients from the Adolescent Specialty Clinic (ASC). Variables analyzed included gender identity, androgen levels, hirsutism scores, and mood disorders. We used chi-square, Fisher's exact, t-tests, and Wilcoxon rank sum tests to compare groups.  Gender identities self-reported as male, fluid/both or nonbinary  were pooled into the GD category. RESULTS: Within the MAPP, 7.6% (n=12) of PCOS youth self-identified as GD compared to 1.8% (n=3) of non PCOS youth (p=0.01, chi-square). When compared to non-PCOS GD adolescents from ASC (4.4%; n=3), the difference to PCOS youth was no longer significant (p=0.56). Among MAPP patients, gender diversity was associated with higher hirsutism scores (p<0.01), but not higher androgen levels. In PCOS, depression/anxiety was higher in GD vs cisgender youth (100% vs. 37.6%, p<0.01 and 77.8% vs. 35.8%, p=0.03 respectively). CONCLUSIONS: Gender diversity was observed more commonly in those meeting PCOS criteria. PCOS GD youth were more hirsute and reported more depression/anxiety. Routine screening for differences in gender identity in comprehensive adolescent PCOS programs could benefit these patients, as alternate treatment approaches may be desired to support a transmasculine identity.

GnRH Agonist Improves Hyperandrogenism in an Adolescent Girl With an Insulin Receptor Gene Mutation.

Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range <50 ng/dL), free testosterone 2.21 ng/dL (reference range <1.09 ng/dL), normal glucose, and HbA1c of 5.6%. She received a diagnosis of polycystic ovary syndrome (PCOS) and was referred to our Multi-Specialty Adolescent PCOS Program. There, oral glucose tolerance test showed fasting glucose and insulin of 80 mg/dL and 63.1 mIU/mL, respectively. The 2-hour glucose and insulin were 199 mg/dL and 1480 µIU/mL, respectively. Because of hyperandrogenism with severe IR, dysglycemia, and normal lipids, type A IR was considered. Genetic testing revealed a heterozygous mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy improved hyperandrogenism and reduced ovarian size while severe IR persisted. We describe an adolescent with type A IR who experienced resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Given the patient's marked reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropin effect. GnRH agonist therapy should be considered in the treatment of hyperandrogenism in severe cases of IR.

Ovarian Morphology by Transabdominal Ultrasound Correlates With Reproductive and Metabolic Disturbance in Adolescents With PCOS.

PURPOSE: To determine whether ovarian morphology imaged using transabdominal ultrasonography reflects clinical and metabolic features in adolescents with polycystic ovary syndrome (PCOS). METHODS: A retrospective pilot study was conducted in 33 adolescents (12-18 years) with PCOS as defined by hyperandrogenism and irregular cycles. Adolescents underwent the following assessments at a random time during the menstrual cycle: transabdominal ultrasonography, physical examination (height, weight, and systolic and diastolic blood pressure), fasting hormonal tests (free, percent free, and total testosterone, androstenedione, follicle stimulating hormone, luteinizing hormone), and metabolic tests (including an oral glucose tolerance test, fasting and 2-hour insulin and glucose, homeostatic model assessment of insulin resistance, and whole-body insulin sensitivity index). Ultrasound images were analyzed offline for ovarian area (OA), ovarian volume (OV), follicle number per cross section (FNPS), and follicle distribution pattern. Associations among endocrine and metabolic variables with sonographic features were assessed by Spearman's rank correlation coefficients and stepwise multiple linear regression. RESULTS: Total testosterone and androstenedione, but not free testosterone, or percent free testosterone, positively correlated with OA (ρ = .515, ρ = .422, respectively), OV (ρ = .451, ρ = .382), and FNPS (ρ = .394, ρ = .474). Luteinizing hormone:follicle stimulating hormone ratio also positively correlated with ovarian size (OA, ρ = .520 and OV, ρ = .409). Unexpectedly, body mass index (ρ = -.503) and fasting glucose levels (ρ = -.393) were inversely correlated with FNPS. Total testosterone was an independent predictor of FNPS, OA, and OV as judged by stepwise multiple regression analyses. CONCLUSIONS: Some aspects of ovarian morphology in adolescents with PCOS using transabdominal ultrasonography associate with markers of reproductive dysfunction and provide rationale to further investigate how ovarian morphology may reflect concurrent metabolic dysfunction.

Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI.

CONTEXT: Polycystic ovary syndrome (PCOS) is a chronic condition with metabolic manifestations spanning the reproductive years. OBJECTIVE: We sought to examine glucose metabolism, irrespective of the presence of obesity in a cohort of adolescent girls with PCOS. DESIGN: One hundred adolescents were assessed for PCOS in a multi-specialty adolescent PCOS program. PCOS was diagnosed by Androgen Excess Society criteria. Oral glucose tolerance testing (OGTT), homeostatic model assessment of insulin resistance, and androgen and lipid profiles were performed for those meeting criteria. RESULTS: Sixty-six adolescents (mean age 15.8 ± 0.2 yrs, range 13.0-18.6) had confirmed PCOS, and were eligible for inclusion in our analysis. Abnormal glucose metabolism was present in 12 of 66 (18.2%) subjects: 2 (3.0%) impaired fasting glucose, 10 (15.2%) impaired glucose tolerance (IGT), and 1 (1.5%) type 2 diabetes. IGT was the most common abnormality, occurring with equal frequency in obese (OB, mean body mass index (BMI) 36.9 ± 0.8 kg/m(2) ) and non-obese (NOB, mean BMI 24.5 ± 0.6 kg/m(2) ) adolescents (p = 0.3). In a subgroup analysis, NOB adolescents with IGT (NOB-IGT) had similar mean 2-h insulin, high density lipoprotein, C-reactive protein, and testosterone levels to the OB cohort despite marked differences in BMI (p < 0.001) and % body fat (p = 0.002). However, the NOB-IGT group had a lower mean fasting insulin level than the OB cohort (p = 0.04). CONCLUSION: Abnormal glucose metabolism is highly prevalent in adolescents with PCOS. In particular, IGT occurs across the spectrum of BMI. A screening OGTT should be considered for adolescents diagnosed with PCOS, independently of their BMI.

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

OBJECTIVE: 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). METHODS: 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). RESULTS: 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). CONCLUSION: 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.

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.

Effects of a weight management program on body composition and metabolic parameters in overweight children: a randomized controlled trial.

CONTEXT: Pediatric obesity has escalated to epidemic proportions, leading to an array of comorbidities, including type 2 diabetes in youth. Since most overweight children become overweight adults, this chronic condition results in serious metabolic complications by early adulthood. To curtail this major health issue, effective pediatric interventions are essential. OBJECTIVE: To compare effects of a weight management program, Bright Bodies, on adiposity and metabolic complications of overweight children with a control group. DESIGN: One-year randomized controlled trial conducted May 2002-September 2005. SETTING: Recruitment and follow-up conducted at Yale Pediatric Obesity Clinic in New Haven, Conn, and intervention at nearby school. PARTICIPANTS: Random sample of 209 overweight children (body mass index [BMI] >95th percentile for age and sex), ages 8 to 16 years of mixed ethnic groups were recruited. A total of 135 participants (60%) completed 6 months of study, 119 (53%) completed 12 months. INTERVENTION: Participants were randomly assigned to either a control or weight management group. The control group (n = 69) received traditional clinical weight management counseling every 6 months, and the weight management group (n = 105) received an intensive family-based program including exercise, nutrition, and behavior modification. Intervention occurred biweekly the first 6 months, bimonthly thereafter. The second randomization within the weight management group assigned participants (n = 35) to a structured meal plan approach (dieting), but this arm of the study was discontinued while enrollment was ongoing due to a high dropout rate. MAIN OUTCOME MEASURES: Change in weight, BMI, body fat, and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 and 12 months. RESULTS: Six-month improvements were sustained at 12 months in weight management vs control, including changes in the following (mean [95% confidence interval]): weight (+0.3 kg [-1.4 to 2.0] vs +7.7 kg [5.3 to 10.0]); BMI (-1.7 [-2.3 to -1.1] vs +1.6 [0.8 to 2.3]); body fat (-3.7 kg [-5.4 to -2.1] vs +5.5 kg [3.2 to 7.8]); and HOMA-IR (-1.52 [-1.93 to -1.01] vs +0.90 [-0.07 to 2.05]). CONCLUSION: The Bright Bodies weight management program had beneficial effects on body composition and insulin resistance in overweight children that were sustained up to 12 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00409422.

Degree of obesity and glucose allostasis are major effectors of glucose tolerance dynamics in obese youth.

OBJECTIVE: One of the signals for the beta-cell to maintain an adequate response to worsening insulin sensitivity is elevated ambient glycemia, namely the concept of "glucose allostasis." We examined whether glucose allostasis can be demonstrated using oral glucose tolerance tests (OGTTs) and the effects of the dynamics of beta-cell demand on longitudinal changes of glucose tolerance in obese youth. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of 784 OGTTs of obese youth was used to demonstrate the concept of allostasis, and a longitudinal assessment of 181 subjects was used to examine the effects of changes in beta-cell demand and the degree of obesity on glucose tolerance. RESULTS: Glucose allostasis can be demonstrated using indexes derived from an OGTT. Increasing beta-cell demand and the degree of obesity at baseline were independently related to elevations in ambient glycemia over time. Baseline BMI Z score was a significant contributor to elevated glucose levels on the second OGTT, while the change in degree of obesity during follow-up was not. CONCLUSIONS: Increasing beta-cell demand related to worsening insulin sensitivity and the degree of obesity per se have independent roles in the development of elevated glucose levels over time. This implicates that peripheral insulin sensitization and/or beta-cell enhancement alongside a significant reduction in obesity may be needed to prevent the development of altered glucose metabolism in obese youth.

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.

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.

Glucose and insulin metabolism in obese youth.

As the prevalence of childhood obesity increases, its health implications are becoming evident to pediatricians around the country. Most striking is the unprecedented epidemic of abnormalities in glucose metabolism, with the diagnosis of type 2 diabetes (T2DM) outnumbering the diagnosis of type 1 diabetes mellitus in many Pediatric Endocrine Clinics. Furthermore, the "Metabolic Syndrome" may be present in as many as 30% of obese adolescents and is manifested by the typical coexistence of central obesity, dyslipidemia, hypertension and impaired glucose tolerance or pre-diabetes. For the past ten years, our laboratory has focused on the metabolic consequences of obesity in youth. We have observed that alterations in the partitioning of fat in both muscle and abdominal tissues in these individuals is closely linked to insulin resistance and abnormalities in glucose homeostasis. Furthermore, we have been able to examine metabolic factors that predict the development of T2DM in obese children. We are currently examining the effect of impaired glucose tolerance on the vascular health of obese youth and have found that subtle shifts in glucose metabolism are associated with microalbuminuria, a surrogate marker of endothelial function and premature cardiovascular mortality.

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.