ß-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak.

BACKGROUND: In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, ß-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and ß-cell function, measured by the clamp. METHODS: Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and ß-cell function relative to insulin sensitivity. RESULTS: Compared with the Early-peak group, the Late-peak group had impaired ß-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05). CONCLUSIONS: In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished ß-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth.

Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?

OBJECTIVE: Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. METHODS: This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2 H2 ]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. RESULTS: Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. CONCLUSIONS: Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a ß-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.

Differences in ß-cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role?

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated ß-cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined ß-cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2-h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C-peptide concentrations to assess ß-cell glucose sensitivity (ßCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater ßCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened ß-cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in ß-cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.

Early Biomarkers of Subclinical Atherosclerosis in Obese Adolescent Girls with Polycystic Ovary Syndrome.

OBJECTIVES: Because in obese youth, pulse wave velocity (PWV), an early cardiovascular disease marker, is elevated, we tested if obese girls with polycystic ovary syndrome (OB-PCOS) have higher PWV and carotid intima-media thickness (cIMT) compared with obese girls without PCOS (OB-non-PCOS) and normal-weight girls without PCOS (NW-non-PCOS) and whether PWV and cIMT correlate with inflammatory and circulating endothelial function biomarkers. STUDY DESIGN: Cross-sectional study of PWV and cIMT in 91 OB-PCOS, 30 obese controls (OB-non-PCOS), and 19 normal-weight controls (NW-non-PCOS). Body composition, blood pressure, fasting glucose, insulin, lipid concentrations, and endothelial function biomarkers were measured. OB-non-PCOS and OB-PCOS underwent 2-hour oral glucose tolerance testing. RESULTS: PWV was higher in OB-PCOS (664 ± 24 cm/s) and OB-non-PCOS (624 ± 37 cm/s) compared with NW-non-PCOS (468 ± 13 cm/s, P < .001), with no differences in cIMT. Systolic blood pressure, low-density lipoprotein, and non-high-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol and indices of insulin sensitivity were lower in OB-PCOS and OB-non-PCOS compared with NW-non-PCOS. Vascular cell adhesion molecule-1 and high-sensitivity C-reactive protein were higher in OB-PCOS compared with NW-non-PCOS. PWV correlated with adiposity (rs = .46), insulin sensitivity index (homeostatic model assessment-insulin resistance rs = .31), systolic blood pressure (rs = .24; P ≤ .003 for all), and free testosterone (rs = .24; P = .03). In multiple regression analysis with PWV as the dependent variable and age, race, body mass index, PCOS, and dysglycemia as independent variables, only body mass index was an independent contributor to the model (r(2) = 0.068, P = .003). CONCLUSIONS: In adolescent girls, obesity and not PCOS appears to be associated with heightened cardiovascular disease risk. Increased PWV, vascular cell adhesion molecule-1, and high-sensitivity C-reactive protein may be the earliest subclinical atherosclerosis biomarkers in OB-PCOS.

Triglyceride glucose index as a surrogate measure of insulin sensitivity in obese adolescents with normoglycemia, prediabetes, and type 2 diabetes mellitus: comparison with the hyperinsulinemic-euglycemic clamp.

BACKGROUND: There is a need for simple surrogate estimates of insulin sensitivity in epidemiological studies of obese youth because the hyperinsulinemic-euglycemic clamp is not feasible on a large scale. OBJECTIVE: (i) To examine the triglyceride glucose (TyG) index (Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]) and its relationship to in vivo insulin sensitivity in obese adolescents (OB) along the spectrum of glucose tolerance and (ii) to compare TyG index with triglyceride/high-density lipoprotein TG/HDL and 1/fasting insulin (1/IF ), other surrogates of insulin sensitivity. PATIENTS AND DESIGN: Cross-sectional data in 225 OB with normal glucose tolerance (NGT), prediabetes (preDM), and type 2 diabetes (T2DM) who had a 3-h hyperinsulinemic-euglycemic clamp and fasting lipid measurement. RESULTS: Insulin-stimulated glucose disposal (Rd) declined significantly across the glycemic groups from OB-NGT to OB-preDM to OB-T2DM with a corresponding increase in TyG index (8.3 ± 0.5, 8.6 ± 0.5, 8.9 ± 0.6, p < 0.0001). The correlation of TyG index to Rd was -0.419 (p < 0.0001). The optimal TyG index for diagnosis of insulin resistance was 8.52 [receiver operating characteristic-area under the ROC curves (ROC-AUC) 0.750, p < 0.0001]. The ROC-AUC for 1/IF was 0.836. In multiple regression analysis, 64.8% of the variance in Rd was explained by TyG index, 1/IF , body mass index (BMI) z-score, glycemic group, and sex. CONCLUSION: The TyG index affords an easily and widely available simple laboratory method as a surrogate estimate of insulin sensitivity that could be used repeatedly in large-scale observational and/or interventional cohorts of OB. Although not superior to 1/IF , TyG index offers the advantage of having a standardized method of measuring triglyceride and glucose, which is not the case for insulin assays.

Relationship of adiponectin and leptin with autoimmunity in children with new-onset type 1 diabetes: a pilot study.

AIM: To explore racial differences in adiponectin, and leptin and their relationship with islet autoimmunity in children with new-onset type 1 diabetes (T1D). METHODS: Medical records were reviewed from a cohort of new-onset clinically diagnosed T1D subjects matched by race, age, gender, and year of diagnosis. Sera were available for 156 subjects (77 African American (AA), 79 Caucasian (C), 48% male, age of 11.1 ± 3.8 yr) and assayed for adiponectin and leptin prior to (D0), 3, 5 d, and 2-4 months (M3) after insulin therapy and islet autoantibodies to GAD, IA2, insulin, and ICA were measured at onset. RESULTS: Adiponectin levels increased significantly following insulin therapy by day 5 (D5) (D0: 13.7 ± 7.2 vs. D5: 21.3 ± 9.9 µg/mL, p < 0.0001), but no further significant increase from D5 to M3. At DO, AA had lower adiponectin levels (10.5 vs. 15.7 µg/mL, p = 0.01), were more often overweight than C (55 vs. 18%, BMI ≥ 85th‰) and fewer had positive autoantibodies (72 vs. 87%, p = 0.05). Racial differences in adipocytokines disappeared after adjustment for BMI. At M3, subjects with more number of positive autoantibodies had higher adiponectin levels (p = 0.043) and adiponectin/leptin ratio (ALR) (p = 0.01), and lower leptin levels (p = 0.016). CONCLUSION: Adiponectin levels increased acutely with insulin therapy. Significantly lower adiponectin levels in AA were related to greater adiposity and not race. These pilot data showing those with the fewest autoantibodies had the lowest adiponectin levels, supporting the concept that insulin-resistant subjects may present with clinical T1D at earlier stages of ß-cell damage.

Oral disposition index in obese youth from normal to prediabetes to diabetes: relationship to clamp disposition index.

OBJECTIVE: We sought to assess the glucose disposition index using an oral glucose tolerance test (OGTT; oDI) compared with the glucose disposition index measured from the combination of the euglycemic-hyperinsulinemic and hyperglycemic clamps (cDI) in obese pediatric subjects spanning the range of glucose tolerance. STUDY DESIGN: Overweight/obese adolescents (n = 185) with varying glucose tolerance (87 normal, 54 impaired, 31 with type 2 diabetes, and 13 with type 1 diabetes) completed an OGTT and both a hyperinsulinemic-euglycemic and a hyperglycemic clamp study. Indices of insulin sensitivity and ß-cell function were calculated, and 4 different oDI estimates were calculated as the products of insulin and C-peptide-based sensitivity and secretion indices. RESULTS: Mirroring the differences across groups by cDI, the oDI estimates were greatest in normal glucose tolerance adolescents and lowest in type 2 diabetes mellitus and obese with type 1 diabetes mellitus adolescents. The insulin-based oDI estimates correlated with cDI overall (r ≥ 0.74, P < .001) and within each glucose tolerance group (r ≥ 0.40, P < .001). Also, oDI and cDI predicted 2-hour OGTT glucose similarly. CONCLUSIONS: The oDI is a simple surrogate estimate of ß-cell function relative to insulin sensitivity that can be applied to obese adolescents with varying glucose tolerance in large-scale epidemiological studies where the applicability of clamp studies is limited due to feasibility, cost, and labor intensiveness.

One-hour plasma glucose concentration during the OGTT: what does it tell about ß-cell function relative to insulin sensitivity in overweight/obese children?

BACKGROUND: In adults 1-h plasma glucose concentration cut-point of 155 mg/dL (8.6 mmol/L) during the oral glucose tolerance test (OGTT) is a strong predictor of future diabetes risk. OBJECTIVE: We tested the hypothesis that a 1-h glucose concentration ≥155 mg/dL is associated with lower ß-cell function in overweight/obese youth. RESEARCH DESIGN AND METHODS: One hundred and thirteen diabetes free overweight/obese youth aged 10-20 yr, underwent evaluation of ß-cell function during a 2 h hyperglycemic clamp ∼225 mg/dL (12.5 mmol/L), and insulin sensitivity during a 3 h hyperinsulinemic-euglycemic clamp, and a standard 2 h OGTT. Body composition and abdominal adiposity were determined by DEXA and CT scan. The disposition index (DI) was calculated as the product of first-phase insulin secretion and insulin sensitivity. Subjects were divided into two categories of 1-h plasma glucose concentration: <155 mg/dL (n=69) and ≥155 mg/dL (n=44). RESULTS: Youth with 1-h glucose ≥155 mg/dL had lower DI than those with 1-h glucose <155 mg/dL (295.1 ± 27.4 vs. 498.6 ± 37.7 mg/kg/min, p<0.001), independent of the glucose tolerance status. In multiple regression models, DI was the strongest contributor to 1-h glucose concentration explaining ∼21% of its variance. CONCLUSIONS: Overweight/obese youth with 1-h glucose ≥155 mg/dL during the oral glucose tolerance test have a significantly lower ß-cell function relative to insulin sensitivity even within the normal glucose tolerance range. Such youth may be at higher risk of future diabetes.

The Shape of the Oral Glucose Tolerance Test-Glucose Response Curve in Islet Cell Antibody-Positive vs. -Negative Obese Youth Clinically Diagnosed with Type 2 Diabetes.

BACKGROUND: The oral glucose tolerance test (OGTT)-glucose response curves (GRCs; incessant increase, monophasic, and biphasic) reflect insulin sensitivity and ß-cell function, being worse in the former and superior in the latter. Here, we examined if the OGTT-GRC pattern is worse in obese antibody (glutamic acid decarboxylase 65-kDa [GAD65] and insulinoma-associated protein-2 [IA-2])-positive (Ab+) vs. -negative (Ab-) youth clinically diagnosed with type 2 diabetes (CDX-T2D). METHODS: Forty-seven obese youth, 15 Ab+ and 32 Ab-, were divided into three OGTT-GRC groups: incessant increase, monophasic, and biphasic. The prevalence of OGTT-GRC, clamp-measured insulin sensitivity, and ß-cell function was compared. RESULTS: Incessant increase OGTT-GRC is the most frequent curve type and is three-fold higher in Ab+ vs. Ab- youth CDX-T2D. In Ab+ youth, there was up to 40% lower second-phase insulin secretion in the incessant increase group vs. the other two groups combined (monophasic and biphasic). In Ab- youth, while first- and second-phase insulin secretion was significantly lower in the incessant increase vs. the other two groups combined, overall ß-cell function was less impaired than in Ab+ youth. In neither Ab- or Ab+ youth was OGTT-GRC related to hepatic or peripheral insulin sensitivity. CONCLUSION: Severe insulin deficiency, a characteristic of type 1 diabetes, seems to be related to higher prevalence of incessant increase in Ab+ vs. Ab- obese youth.

ß-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum.

BACKGROUND/AIMS: In obese youth, it is not clear what degree of ß-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between ß-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance. METHODS: Data from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m2/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp synchronized with a 2-h OGTT were examined. RESULTS: In IGT vs. NGT, 36% lower DI corresponded to 27% higher G-AUC; in type 2 diabetes vs. IGT, 65% lower DI related to 25% higher G-AUC, and in type 2 diabetes vs. NGT, 78% lower DI paralleled 59% higher G-AUC. Although AA vs. AW youth had larger decrements in DI, from NGT to IGT and from NGT to type 2 diabetes, they displayed comparable increments in G-AUC. CONCLUSION: At least ~35-50% recovery in ß-cell function might be needed to have clinically meaningful improvement in G-AUC commensurate with conversion to better glucose tolerance. Mechanism(s) protective against dysglycemia might be operative in AA vs. AW youth despite greater declines in DI. Treatments aiming to improve ß-cell function should focus on degree of change in DI commensurate with clinically meaningful changes in glycemia, reflective of restoration of glucose tolerance.

Adipose Tissue Insulin Resistance in Youth on the Spectrum From Normal Weight to Obese and From Normal Glucose Tolerance to Impaired Glucose Tolerance to Type 2 Diabetes.

OBJECTIVE: Adipose tissue insulin resistance is one of the pathophysiological components of type 2 diabetes. Herein we investigated: 1) adipose insulin resistance index (Adipose-IR) (calculated as fasting insulin × free fatty acids [FFAs]) in youth across the spectrum of adiposity from normal weight to obese and the spectrum from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes, 2) the relationship of Adipose-IR with physical and metabolic characteristics, and 3) the predictive power of Adipose-IR for determining dysglycemia in youth. RESEARCH DESIGN AND METHODS: A total of 205 youth had fasting glucose, insulin, FFA, Adipose-IR, body composition, visceral adipose tissue (VAT), leptin, and adiponectin evaluated. RESULTS: Adipose-IR was 2.2-fold higher in obese NGT, 4.3-fold higher in IGT, and 4.6-fold higher in type 2 diabetes compared with that in normal-weight peers (all P < 0.05). Females with dysglycemia (IGT and type 2 diabetes) had higher Adipose-IR than their male counterparts (P < 0.001). Adipose-IR correlated positively with total body and visceral adiposity, fasting glucose, HOMA-IR, and leptin and negatively with adiponectin. Receiver operating characteristic curve analysis yielded an optimal cutoff for Adipose-IR of 9.3 µU/mL × mmol/L for determining dysglycemia with 80% predictive power. CONCLUSIONS: Adipose-IR is a simple surrogate estimate that reflects pathophysiological alterations in adipose tissue insulin sensitivity in youth, with progressive deterioration from normal weight to obese and from NGT to IGT to type 2 diabetes. Adipose-IR can be applied in large-scale epidemiological/observational studies of the natural history of youth-onset type 2 diabetes and its progression or reversal with intervention strategies.

Menstrual health and the metabolic syndrome in adolescents.

The metabolic syndrome, a constellation of interrelated risk factors for cardiovascular disease and type 2 diabetes mellitus, has become a major public health concern against the backdrop of increasing rates of obesity. Insulin resistance plays a pivotal role as the underlying pathophysiological linchpin of the various components of the syndrome. The metabolic syndrome is well recognized in adults, and there is convincing evidence that it starts in childhood, with progressive clustering of the various components over time and tracking through adulthood. Adult women and adolescents with polycystic ovary syndrome (PCOS) have higher prevalence rates of the metabolic syndrome compared with the general population. Several anthropometric (obesity, particularly abdominal obesity), metabolic (insulin resistance/hyperinsulinemia, dyslipidemia) and hormonal (low IGFBP1, IGFBP2 and low sex hormone binding globulin) features of adolescents with PCOS are also features of the metabolic syndrome. Insulin resistance, believed to be a key pathogenic factor in both PCOS and the metabolic syndrome, may be the thread that links the two conditions. Menstrual health in adolescents could be viewed as yet another component in the evaluation of the metabolic syndrome. Careful assessment of menstrual history and appropriate laboratory work-up could reveal the presence of PCOS in obese at-risk adolescent girls with a family history of the metabolic syndrome.

Higher Incidence Rates of Hypothyroidism and Late TSH Rise in Preterm Very-Low-Birth-Weight Infants at a Tertiary Care Center.

BACKGROUND/AIMS: Preterm newborns with a very low birth weight (VLBW) of < 1,500 g have an atypical form of hypothyroidism with a delayed rise in TSH, necessitating a second newborn screening specimen collection. The aims of this study were to survey the compliance with second newborn screening to detect delayed TSH rise in VLBW preterm infants at a tertiary care center, and to determine the rate of atypical hypothyroidism. METHODS: Retrospective review of the records of 104 preterm VLBW infants. Late TSH rise was defined as an increase in TSH concentration after 14 days of age in the presence of a normal initial screen. RESULTS: The compliance rate was 92% for the second screening. High rates of hypothyroidism (16.3%) and of late TSH rise (4.8%) were detected. Patients with hypothyroidism had a significantly lower birth weight (p = 0.01) and longer hospital stay (p = 0.004). Patients with late versus those with early TSH rise had a significantly lower mean birth weight (851 ± 302 vs. 1,191 ± 121 g, p = 0.004). CONCLUSION: The rates of early and late TSH rise in this VLBW population were higher than those in the literature and could be due to the use of povidone-iodine disinfectants. The yield of a second TSH screening in this study was high indicating the need for vigilance in screening VLBW preterm infants.

Impaired Lipolysis, Diminished Fat Oxidation, and Metabolic Inflexibility in Obese Girls With Polycystic Ovary Syndrome.

Context: Metabolic flexibility reflects the ability to switch from lipid to carbohydrate oxidation during insulin stimulation manifested in increased respiratory quotient (RQ). Little is known about adipose tissue metabolism and metabolic flexibility in adolescent girls with polycystic ovary syndrome (PCOS). Objective: We investigated whole-body lipolysis, substrate oxidation, and metabolic flexibility in obese girls with PCOS vs obese girls without PCOS. Patients/Design: Twenty-one obese girls with PCOS and 21 obese girls without PCOS were pair-matched for age and race. Body composition, abdominal visceral adipose tissue (VAT), sex hormones, lipid profile, and adiponectin were measured. Whole-body lipolysis ([2H5]glycerol turnover), RQ, and substrate oxidation (indirect calorimetry) were evaluated during fasting and a hyperinsulinemic-euglycemic clamp together with assessment of insulin sensitivity (IS). Results: Despite similar body mass index and percent body fat, girls with PCOS vs girls without PCOS had lower fasting lipolysis and fat oxidation, less increase in RQ during hyperinsulinemia with impaired suppression in lipolysis and lipid oxidation, and lower IS. In multiple regression, the best predictors of metabolic flexibility were [using clinical parameters: adiponectin, fasting triglycerides, and insulin (R2 = 0.618, P < 0.0001); using research parameters: IS, VAT, and baseline RQ (R2 = 0.756, P < 0.0001)]. Conclusions: Obese girls with PCOS vs obese girls without PCOS have decreased lipid mobilization, diminished fat oxidation, and metabolic inflexibility. Whether this metabolic phenotype of adipose tissue dysfunction, which is conducive to fat accretion, plays a role in the induction and maintenance of obesity in adolescent girls with PCOS remains to be determined.

Anti-Müllerian Hormone in Obese Adolescent Girls With Polycystic Ovary Syndrome.

PURPOSE: Anti-Müllerian hormone (AMH) is proposed as a biomarker of polycystic ovary syndrome (PCOS). This study investigated: (1) AMH concentrations in obese adolescents with PCOS versus without PCOS; (2) the relationship of AMH to sex steroid hormones, adiposity, and insulin resistance; and (3) the optimal AMH value and the multivariable prediction model to determine PCOS in obese adolescents. METHODS: AMH levels were measured in 46 obese PCOS girls and 43 obese non-PCOS girls. Sex steroid hormones, clamp-measured insulin sensitivity and secretion, body composition, and abdominal adiposity were evaluated. Logistic regression and receiver-operating characteristic curve analyses were used, and multivariate prediction models were developed to test the utility of AMH for the diagnosis of PCOS. RESULTS: AMH levels were higher in obese PCOS versus non-PCOS girls (8.3 ± .6 vs. 4.3 ± .4 ng/mL, p < .0001), of comparable age and puberty. AMH concentrations correlated positively with age in both groups, total and free testosterone in PCOS girls only, abdominal adipose tissue in non-PCOS girls, with no correlation to in vivo insulin sensitivity and secretion in either groups. A multivariate model including AMH (cutoff 6.26 ng/mL, area under the curve .788) together with sex hormone-binding globulin and total testosterone exhibited 93.4% predictive power for diagnosing PCOS. CONCLUSIONS: AMH may be a useful biomarker for the diagnosis of PCOS in obese adolescent girls.

Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and Impaired ß-Cell Function Relative to Adipose Tissue Insulin Sensitivity in Obese Youth With Impaired Glucose Tolerance.

Despite evidence of insulin resistance and ß-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and ß-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and ß-cell function relative to ATIS (adipose disposition index [DI]) in obese youth with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa], [2H5]glycerol at baseline and during a hyperinsulinemic-euglycemic clamp), lipid oxidation (indirect calorimetry), insulin secretion (2-h hyperglycemic clamp), and body composition (dual-energy X-ray absorptiometry) were examined. Adipose DI was calculated as ATIS: (1/GlyRa × fasting insulin) × first-phase insulin secretion. Despite similar percent body fat, youth with IGT versus NGT had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ∼43% lower in youth with IGT and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT versus NGT is in line with the compromised glucose metabolism reflected in impaired ß-cell function relative to peripheral insulin resistance. We conclude that youth with IGT manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by ß-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes.

Distinguishing characteristics of metabolically healthy versus metabolically unhealthy obese adolescent girls with polycystic ovary syndrome.

OBJECTIVE: To investigate the key physical, metabolic, hormonal and cardiovascular characteristics of metabolically healthy obese (MHO) versus unhealthy obese (MUHO) girls with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional study. SETTING: Research center. PATIENT(S): Seventy obese girls with PCOS were divided into 19 MHO and 51 MUHO based on cutoff points for in vivo insulin sensitivity (within and < 2 SDs of the mean of the insulin sensitivity of the normal-weight girls, respectively). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Body composition, abdominal fat, in vivo insulin sensitivity and secretion (hyperinsulinemic-euglycemic and hyperglycemic clamps respectively), hormonal profile, and cardiovascular disease risk markers. RESULT(S): MUHO-PCOS girls had higher waist circumference, visceral adipose tissue, leptin, and free testosterone, lower SHBG and E2, higher non-high-density lipoprotein (HDL) cholesterol and atherogenic lipoprotein particle concentrations, smaller HDL particle size, and higher high-sensitivity C-reactive protein compared with MHO-PCOS girls. Hepatic and peripheral insulin sensitivity were lower with higher first- and second-phase insulin secretion, but ß-cell function relative to insulin sensitivity was lower in MUHO versus MHO. Pair matching of MHO and MUHO regarding age and body mass index revealed similar findings. MUHO-PCOS girls had larger visceral adiposity, lower insulin sensitivity and ß-cell function, worse hormonal profile, and severely atherogenic lipoprotein concentrations compared with MHO-PCOS girls. CONCLUSION(S): MHO-PCOS girls have favorable physical, metabolic, hormonal, and cardiovascular disease (CVD) characteristics and lower risk biomarkers for type 2 diabetes compared with their MUHO-PCOS peers. A greater understanding of the contrast in this risk phenotype in obese girls with PCOS may have important implications for therapeutic interventions, their outcomes, and their durability.

The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth.

OBJECTIVE: The shape of the glucose response curve during an oral glucose tolerance test (OGTT), monophasic versus biphasic, identifies physiologically distinct groups of individuals with differences in insulin secretion and sensitivity. We aimed to verify the value of the OGTT-glucose response curve against more sensitive clamp-measured biomarkers of type 2 diabetes risk, and to examine incretin/pancreatic hormones and free fatty acid associations in these curve phenotypes in obese adolescents without diabetes. RESEARCH DESIGN AND METHODS: A total of 277 obese adolescents without diabetes completed a 2-h OGTT and were categorized to either a monophasic or a biphasic group. Body composition, abdominal adipose tissue, OGTT-based metabolic parameters, and incretin/pancreatic hormone levels were examined. A subset of 106 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and ß-cell function relative to insulin sensitivity. RESULTS: Despite similar fasting and 2-h glucose and insulin concentrations, the monophasic group had significantly higher glucose, insulin, C-peptide, and free fatty acid OGTT areas under the curve compared with the biphasic group, with no differences in levels of glucagon, total glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pancreatic polypeptide. Furthermore, the monophasic group had significantly lower in vivo hepatic and peripheral insulin sensitivity, lack of compensatory first and second phase insulin secretion, and impaired ß-cell function relative to insulin sensitivity. CONCLUSIONS: In obese youth without diabetes, the risk imparted by the monophasic glucose curve compared with biphasic glucose curve, independent of fasting and 2-h glucose and insulin concentrations, is reflected in lower insulin sensitivity and poorer ß-cell function, which are two major pathophysiological biomarkers of type 2 diabetes in youth.

Liver disease and other comorbidities in Wolcott-Rallison syndrome: different phenotype and variable associations in a large cohort.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients. AIMS: To describe a cohort of WRS patients and discuss the pattern and management of their liver disease. METHODS: Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients. RESULTS: Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different EIF2AK3 mutations were detected, of which 2 were novel. The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented before 25 months with diabetes with variation in the frequency and severity of 10 other features. Liver disease, first manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28). 22/24 had at least one episode of acute hepatic failure which was the cause of death in all deceased patients (13/28). One child was treated by liver transplantation and had no liver disease and better diabetes control for the following 6 years. CONCLUSIONS: Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.