Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes.

BACKGROUND: The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. METHODS: In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. RESULTS: A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. CONCLUSIONS: Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).

Estimating insulin sensitivity and ß-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and ß-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and ß-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

Precision and accuracy of hyperglycemic clamps in a multicenter study.

Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers.NEW & NOTEWORTHY The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers.

Withdrawal of medications leads to worsening of OGTT parameters in youth with impaired glucose tolerance or recently-diagnosed type 2 diabetes.

BACKGROUND: The RISE Pediatric Medication Study compared strategies for preserving ß-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability. OBJECTIVE: Evaluate OGTT measures of glucose and ß-cell response through 12 months of intervention and 9 months of medication washout. PARTICIPANTS: Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). METHODS: A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated ß-cell response. RESULTS: At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in ß-cell response. CONCLUSIONS: G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and ß-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.

ß-cells in youth with impaired glucose tolerance or early type 2 diabetes secrete more insulin and are more responsive than in adults.

OBJECTIVE: Glycemic control deteriorates more rapidly in youth vs adults. We compared model-derived measures of ß-cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a ß-cell defect differentiates these age groups. METHODS: This is a cross-sectional analysis of baseline data from the Restoring Insulin Secretion (RISE) Study. Youth (54 Y-IGT, 33 Y-D) and adults (250 A-IGT, 104 A-D) underwent 3-hour oral glucose tolerance tests for modeling of insulin secretion rates (ISRs), glucose sensitivity, and rate sensitivity. Insulin sensitivity was quantified as the glucose infusion rate/insulin (M/I) from a hyperglycemic clamp. RESULTS: Youth had lower insulin sensitivity despite similar body mass index. Analyses were adjusted for insulin sensitivity. Youth had higher basal ISRs (Y-IGT 200 ± 161 vs A-IGT 152 ± 74, P < .001; Y-D 245 ± 2.5 vs A-D 168 ± 115 pmol/min/m2 , P = .007) and total ISRs (Y-IGT 124 ± 86 vs A-IGT 98 ± 39, P < .001; Y-D 116 ± 110 vs A-D 97 ± 62 nmol/m2 , P = .002). Within IGT, glucose sensitivity (Y-IGT 140 ± 153 vs A-IGT 112 ± 70 pmol/min/m2 /mM, P = .004) and rate sensitivity (median[interquartile range]:Y-IGT 2271[1611, 3222] vs A-IGT 1164[685, 1565] pmol/m2 /mM, P < .001) were higher in youth, but not different by age group within diabetes. CONCLUSIONS: Model-derived measures of ß-cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and ß-cell secretion more responsive to glucose in youth relative to adults even after adjusting for differences in insulin sensitivity. It is unknown whether these findings in youth reflect ß-cells that are healthier or whether this is a defect that contributes to more rapid loss of function.

Review of methods for measuring ß-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium.

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of ß-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of ß-cell function and changes in ß-cell function in response to interventions. In the present paper, we review approaches for measurement of ß-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of ß-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure ß-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in ß-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.

Maternal excess gestational weight gain and infant waist circumference: a 2-y observational study.

BACKGROUND: The purpose of this study was to examine the effects of gestational weight gain (GWG) and infant feeding practices on infant growth parameters in infants from 6 to 24 mo of age. METHODS: Forty mother-infant pairs were recruited after delivery and followed up to 24 mo postpartum. GWG was calculated as prepregnancy weight subtracted from weight at delivery. Infant weight velocity was calculated as the change in weight between consecutive visits divided by the intervening time. Infant feeding practices were measured by interview and infant growth and waist circumference by standard anthropometry. RESULTS: Infants born to mothers with excess GWG were heavier at birth (3,521 ± 91 vs. 3,196 ± 97 g, P = 0.02) and had an average 2.16 ± 1.1 cm (P = 0.03) larger waist circumference throughout the 24 mo compared with infants born to mothers with appropriate GWG. Waist circumference increased by 0.12 and 2.0 cm for every 1 unit increase in GWG and infant birth weight. CONCLUSION: Infants born to women who exceeded the Institute of Medicine (IOM)-recommended guidelines for GWG were heavier at birth and had a significantly higher waist circumference up to 2 y of age. Strategies to control maternal excess GWG and thus the outcome on infant birth weight and waist circumference should be pursued.

Race or vitamin D: A determinant of intima media thickness in obese adolescents?

OBJECTIVE: Carotid intima media thickness (IMT), a predictor of cardiovascular events, is reported to be higher in African-American (AA) vs White (AW) individuals. We investigated whether racial differences in IMT in obese adolescents could be explained by differences in 25 hydroxy-vitamin D [25(OH)D]. RESEARCH DESIGN AND METHODS: A total of 63 obese adolescents had 25(OH)D levels, determination of IMT, body composition, insulin sensitivity (IS) by hyperinsulinemic-euglycemic clamp, lipids and blood pressure (BP). RESULTS: IMT was higher and 25(OH)D lower in AA vs AW. IMT correlated with 25(OH)D level (r = -0.38, P = .002) but not with IS. In multiple regression analysis, race, HbA1c, BP and age, and not 25(OH)D, BMI or IS, were the significant determinants of IMT (R2 = 0.44, P < .001). Without race in the model, 25(OH)D (ß = -0.36, P = .009) contributed to the variance in IMT (R2 = 0.32, P = .007). CONCLUSION: Obese AA adolescents vs AW, have higher IMT, explained by race, BP, and HbA1c. Although 25(OH)D levels contribute to the variance in IMT, the observed racial difference in IMT could be mediated through other unknown race-related factors besides 25(OH)D.

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.

Gestational Weight Gain and Offspring Longitudinal Growth in Early Life.

BACKGROUND: Excessive gestational weight gain (GWG) increases the risk of childhood obesity, but little is known about its association with infant growth patterns. AIM: The aim of this study was to examine the association between GWG and infant growth patterns. METHODS: Pregnant women (n = 743) self-reported GWG at delivery, which we classified as inadequate, adequate or excessive based on the current guidelines. Offspring weight-for-age z-score (WAZ), length-for-age z-score (LAZ (with height-for-age (HAZ) in place of length at 36 months)) and body mass index z-score (BMIZ) were calculated at birth, 8, 18 and 36 months using the 2006 World Health Organization growth standards. Linear mixed models estimated the change in z-score from birth to 36 months by GWG. RESULTS: The mean (SD) WAZ was -0.22 (1.20) at birth. Overall, WAZ and BMIZ increased from birth to, approximately, 24 months and decreased from 24 to 36 months, while LAZ/HAZ decreased from birth through 36 months. Excessive GWG was associated with higher offspring WAZ and BMIZ at birth, 8 and 36 months, and higher HAZ at 36 months, compared with adequate GWG. Compared with the same referent, inadequate GWG was associated with smaller WAZ and BMIZ at birth and 8 months. CONCLUSION: Excessive GWG may predispose infants to obesogenic growth patterns, while inadequate GWG may not have a lasting impact on infant growth.

Morning blood pressure is associated with sleep quality in obese adolescents.

OBJECTIVE: To examine relationships among blood pressure (BP), adiposity, and sleep quality with the use of overnight polysomnography in obese adolescents. STUDY DESIGN: Overnight polysomnogram and morning BP measurements were performed in obese (body mass index [BMI] >95th percentile) nondiabetic adolescents (eligible age range 12-18 years, n = 49). Subjects were stratified into 2 groups, one with normal BP, and one with elevated BP, and demographic and clinical characteristics were compared between the groups. Multiple linear regression analysis was used to assess the effects of sleep quality on BP. RESULTS: Participants (n = 27) had a normal morning BP, and 22 (44.9%) had elevated morning BP. There were no differences in age (P = .53), sex (P = .44), race (P = .58), or BMI (P = .56) between the 2 BP groups. The group with elevated BP spent shorter percentages of time in rapid eye movement (REM; P = .006) and slow-wave sleep (SWS; P = .024). Multiple linear regression analysis showed that a lower percentage of both REM and SWS was associated with increased morning BP after we adjusted for pubertal stage, sex, race, and BMI. CONCLUSION: Lack of deeper stages of sleep, REM sleep, and SWS is associated with greater morning BP in obese adolescents, independent of BMI. Poor sleep quality should be considered in the work-up of obese youth with hypertension. Intervention studies are needed to evaluate whether improving the quality of sleep will decrease BP elevation.

Dulaglutide and Glomerular Hyperfiltration, Proteinuria, and Albuminuria in Youth With Type 2 Diabetes: Post Hoc Analysis of the AWARD-PEDS Study.

OBJECTIVE: To examine changes in glomerular hyperfiltration and other measures of kidney function in youth with type 2 diabetes treated with dulaglutide or placebo. RESEARCH DESIGN AND METHODS: Post hoc analysis was performed on kidney laboratory data from 154 youths (age 10-18 years) with type 2 diabetes enrolled in a completed placebo-controlled glycemic control trial of dulaglutide. RESULTS: Mean estimated glomerular filtration rate (eGFR) decreased from baseline to 26 weeks in participants treated with dulaglutide versus placebo (-5.8 vs. -0.1 mL/min/1.73 m2; P = 0.016). Decreases in eGFR were observed primarily in participants with baseline glomerular hyperfiltration. At 26 weeks, the prevalence of both glomerular hyperfiltration and proteinuria increased with placebo but decreased with dulaglutide (P = 0.014 and 0.004 vs. placebo, respectively). CONCLUSIONS: Dulaglutide was associated with attenuated glomerular hyperfiltration and proteinuria in youth with type 2 diabetes. The impact of these changes on the risk of diabetic kidney disease is unclear.

Progressive deterioration of ß-cell function in obese youth with type 2 diabetes.

OBJECTIVE: In adults, type 2 diabetes (T2DM) is characterized with progressive deterioration in insulin secretion. Data are scanty in youth. We investigated prospectively the change in ß-cell function and in insulin sensitivity in youth with T2DM. RESEARCH DESIGN AND METHODS: Six adolescents with T2DM [hemoglobin A1c (HbA1c) 6.6 ± 1.0%] underwent evaluation of hepatic glucose production (HGP; [6,6-²H2] glucose), insulin-stimulated glucose disposal (Rd; hyperinsulinemic-euglycemic clamp), first- and second-phase insulin/C-peptide secretion (hyperglycemic clamp), body composition dual energy X-ray absorptiometry (DEXA), and abdominal adiposity (computed tomography) within 3 yr of the diagnosis of diabetes and after 12-16 months of follow-up. RESULTS: Weight, body mass index (37.1 ± 6.9), HbA1c (6.3 ± 0.7%), HGP (2.8 ± 1.2 mg/kg/min), and Rd (4.9 ± 3.4 mg/kg/min) did not change significantly from baseline. However, first-phase insulin and C-peptide declined (152.6 ± 261.2 vs. 75.9 ± 108.5 µU/mL, p = 0.028; 8.0 ± 6.3 vs. 5.9 ± 4.4 ng/mL, p = 0.048, respectively) with no significant change in second-phase insulin/C-peptide. The rate of decline in ß-cell function was ∼20% per year. CONCLUSIONS: After a median duration of 20 months of diabetes, youth with T2DM manifest a rapid decline in ß-cell function with no significant changes in peripheral or hepatic insulin sensitivity. Interventions to retard this deterioration in ß-cell function should be investigated.

Depressive symptoms and metabolic markers of risk for type 2 diabetes in obese adolescents.

OBJECTIVE: Although higher rates of depression are found among individuals with type 2 diabetes, it remains unknown if the presence of depressive symptoms is associated with heightened metabolic risk for the development of type 2 diabetes among youth. The objective of this study was to evaluate whether depressive symptoms in obese adolescents are associated with impaired ß-cell function relative to insulin sensitivity [oral disposition index (oDI)] and/or dysglycemia or prediabetes, predictors of type 2 diabetes development. RESEARCH DESIGN AND METHODS: Fasting and oral glucose tolerance test (OGTT)-derived indices of glucose tolerance, insulin sensitivity, secretion, and oDI were evaluated in obese youth (n = 56, age 15.0 ± 1.6 yr, 68% female). The Children's Depression Inventory was utilized to determine depressive symptomatology. RESULTS: Despite no association between depressive symptoms and measures of adiposity, youth with higher depressive symptoms had (i) significantly higher fasting and stimulated glucose levels (13% higher glucose area under the OGTT curve), (ii) ∼50% lower oDI, and (iii) a 50% frequency of prediabetes. CONCLUSIONS: These data point to an important relationship between depressive symptoms and a heightened metabolic risk for type 2 diabetes in obese adolescents, including prediabetes and impairment in ß-cell function relative to insulin sensitivity. While the directionality of these relationships is unknown, it should be determined if treating one disorder improves the other or vice versa.

Surrogate lipid markers for small dense low-density lipoprotein particles in overweight youth.

OBJECTIVES: To determine if the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL) and non-HDL cholesterol concentration could identify youth with small dense low-density lipoprotein (LDL). STUDY DESIGN: One hundred forty-one (75 black and 66 white) overweight adolescents (9 to <18 years) had a fasting measurement of plasma lipids and LDL particle concentrations and size. Receiver operating characteristic curves were used to indicate the ability of different TG/HDL ratios and non-HDL cholesterol concentrations to identify overweight youth with atherogenic LDL concentration and size. RESULTS: Youth with a TG/HDL ratio of ≥3 vs <3 had higher concentrations of small dense LDL (1279.5 ± 60.1 vs 841.8 ± 24.2 nmol/L, P < .001) and smaller LDL particle size (20.3 ± 0.1 vs 21.2 ± 0.1 nm, P < .001). In receiver operating characteristic analyses a TG/HDL cut-point of 3 best predicted LDL concentration in white youth, and 2.5 in black youth. Non-HDL cholesterol cut-point of 120 mg/dL and 145 mg/dL predicted LDL particle concentration in white and in black youth, respectively. TG/HDL ratio with body mass index or waist circumference explained 71% and 79% of the variance, respectively, in total small LDL. CONCLUSIONS: TG/HDL ratio and non-HDL cholesterol can identify overweight youth with atherogenic LDL particles. These easily obtained clinical lipid markers, in combination with body mass index and waist circumference, could be cost effective, in observational or interventional studies, for screening and follow-up of youth at heightened risk for atherogenic LDL.

Relationships among obstructive sleep apnea, anthropometric measures, and neurocognitive functioning in adolescents with severe obesity.

OBJECTIVE: To explore associations between measures of obstructive sleep apnea (OSA) and sleep quality, anthropometrics, and neurocognitive functioning in severely obese adolescents. STUDY DESIGN: This was a cross-sectional pilot study performed at an academic medical center in 37 severely obese (body mass index [BMI] >97th percentile) adolescents. Study evaluations included polysomnography, BMI, waist circumference, and standardized neurocognitive tests to assess memory, executive functioning, psychomotor efficiency, academic achievement, and an approximation of full-scale IQ. Outcome data were evaluated categorically, based on clinical criteria for the diagnosis of OSA, and continuously to quantify associations between sleep parameters, anthropometrics, and neurocognitive test results. RESULTS: Sleep fragmentation and poorer sleep quality were associated with reduced psychomotor efficiency, poorer memory recall, and lower scores on standardized academic tests. Having evidence of OSA was associated with lower math scores, but not with other neurocognitive measures. BMI and waist circumference were negatively associated with oxygen saturation. CONCLUSION: Our pilot study findings suggest that sleep fragmentation and poorer sleep quality have implications for neurocognitive functioning in obese adolescents. The epidemic of childhood obesity has dire implications, not only for increasing cardiometabolic pathology, but also for possibly promoting less readily apparent neurologic alterations associated with poor sleep quality.

Type 2 diabetes in youth: are there racial differences in ß-cell responsiveness relative to insulin sensitivity?

OBJECTIVE: Non-diabetic African American (AA) youth have an upregulated insulin secretion relative to insulin sensitivity (IS) compared with their American White (AW) peers. We investigated if similar racial differences exist in youth with T2DM. RESEARCH DESIGN AND METHODS: Fourteen AAs and 14 AWs T2DM adolescents underwent evaluation of IS and clearance (hyperinsulinemic-euglycemic clamp), first- and second-phase insulin and C-peptide secretion (hyperglycemic clamp); body composition (DEXA); and abdominal adiposity (CT). RESULTS: AA and AW T2DM had similar HbA1c, diabetes duration, BMI, and % body fat, with lower visceral fat in AAs (p = 0.013). While insulin-stimulated glucose disposal was similar in AA and AW (7.5 ± 1.0 vs. 7.3 ± 0.9 mg/kg FFM/min), IS tended to be lower (2.5 ± 0.4 vs. 3.8 ± 0.6 mg/kg FFM/min per µU/mL, p = 0.081). First-phase insulin (175.7 ± 52.9 vs. 66.6 ± 10.8 µU/mL, p = 0.01) and second-phase insulin (236.2 ± 40.7 vs. 105.1 ± 17.9 µU/mL, p = 0.008), and first-phase C-peptide (8.2 ± 1.2 vs. 5.0 ± 0.3 ng/mL, p = 0.02) and second-phase C-peptide (10.8 ± 0.9 vs. 7.6 ± 0.6 ng/mL, p = 0.012) were higher in AA. ß-Cell function relative to IS was higher in AA vs. AW (259.5 ± 35.3 vs. 168.8 ± 25.1 mg/kg FFM/min, p = 0.043). CONCLUSIONS: Racial differences in insulin secretion can be demonstrated with the clamp technique in obese adolescents with T2DM. Similar to non-diabetic youth, AA adolescents with T2DM compared with their AW counterparts have an upregulated ß-cell function relative to IS, the reasons for which remain to be investigated.