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Objective: The recommended HbA(1c) diagnostic categories remain controversial and their utility in doubt in pediatrics. We hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes may be evident in the American Diabetes Association recommended at-risk/prediabetes category (HbA(1c) 5.7 to <6.5%).Research Design and Methods: We compared in vivo hepatic and peripheral insulin sensitivity by [6,6-(2)H(2)] glucose and a 3-h hyperinsulinemic-euglycemic clamp and β-cell function by a 2-h hyperglycemic clamp (∼225 mg/dL) in overweight/obese (BMI ≥85th percentile) adolescents with prediabetes (HbA(1c) 5.7 to <6.5%) (n = 160) to those with normal HbA(1c) (<5.7%) (n = 44). β-Cell function was expressed relative to insulin sensitivity (i.e., the disposition index = insulin sensitivity × first-phase insulin).Results: In the prediabetes versus normal HbA(1c) category, fasting glucose, insulin, and oral glucose tolerance test (OGTT) area under the curve for glucose and insulin were significantly higher; hepatic and peripheral insulin sensitivity were lower; and β-cell function relative to insulin sensitivity was lower (366 ± 48 vs. 524 ± 25 mg/kg/min; P = 0.005). A total of 27% of youth in the normal HbA(1c) category and 41% in the prediabetes HbA(1c) category had dysglycemia (impaired fasting glucose and/or impaired glucose tolerance) by a 2-h OGTT.Conclusions: Overweight/obese adolescents with HbA(1c) in the at-risk/prediabetes category demonstrate impaired β-cell function relative to insulin sensitivity, a metabolic marker for heightened risk of type 2 diabetes. Thus, HbA(1c) may be a suitable screening tool in large-scale epidemiological observational and/or interventional studies examining the progression or reversal of type 2 diabetes risk. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationships between plasma 25-hydroxyvitamin D [25(OH)D] and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity, disposition index (DI), in black and white youth.Research Design and Methods: Plasma 25(OH)D concentrations were analyzed in banked specimens in healthy youth aged 8 to 18 years who had existing data on hyperinsulinemic-euglycemic and hyperglycemic clamp to assess insulin sensitivity and secretion, and measurements of body composition, and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).Results: A total of 183 research volunteers (mean ± SD; age, 12.6 ± 2.2 years; 98 white, 98 male, 92 obese) were studied. Analysis of HbA(1c), fasting glucose and insulin, insulin sensitivity, and DI across quartiles of plasma 25(OH)D revealed no differences among whites. In blacks, the observed significance of higher insulin sensitivity and DI in the highest quartile of 25(OH)D disappeared after adjusting for any of the adiposity measures (BMI or fat mass or VAT or SAT). The difference in insulin sensitivity (9.4 ± 1.2 vs. 5.6 ± 0.5 mg/kg/min per μU/mL; P = 0.006) between 25(OH)D nondeficient (≥20 ng/mL) versus deficient (<20 ng/mL) black youth also was negated when adjusted for adiposity.Conclusions: In healthy youth, plasma 25(OH)D concentrations bear no independent relationship to parameters of glucose homeostasis and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity. It remains to be determined whether in youth with dysglycemia the relationships are different and whether vitamin D optimization enhances insulin sensitivity and β-cell function. [ABSTRACT FROM AUTHOR]

Objective: We compared acylcarnitine (AcylCN) species, common amino acid and fat oxidation (FOX) byproducts, and plasma amino acids in normal weight (NW; n = 39), obese (OB; n = 64), and type 2 diabetic (n = 17) adolescents.Research Design and Methods: Fasting plasma was analyzed by tandem mass spectrometry, body composition by dual energy X-ray absorptiometry and computed tomography, and total-body lipolysis and substrate oxidation by [(2)H(5)]glycerol and indirect calorimetry, respectively. In vivo insulin sensitivity (IS) was assessed with a 3-h hyperinsulinemic-euglycemic clamp.Results: Long-chain AcylCNs (C18:2-CN to C14:0-CN) were similar among the three groups. Medium- to short-chain AcylCNs (except C8 and C10) were significantly lower in type 2 diabetes compared with NW, and when compared with OB, C2-, C6-, and C10-CN were lower. Amino acid concentrations were lower in type 2 diabetes compared with NW. Fasting lipolysis and FOX were higher in OB and type 2 diabetes compared with NW, and the negative association of FOX to C10:1 disappeared after controlling for adiposity, Tanner stage, and sex. IS was lower in OB and type 2 diabetes with positive associations between IS and arginine, histidine, and serine after adjusting for adiposity, Tanner stage, and sex.Conclusions: These metabolomics results, together with the increased rates of in vivo FOX, are not supportive of defective fatty acid or amino acid metabolism in obesity and type 2 diabetes in youth. Such observations are consistent with early adaptive metabolic plasticity in youth, which over time-with continued obesity and aging-may become dysfunctional, as observed in adults. [ABSTRACT FROM AUTHOR]

Objective: Overweight in youth is associated with the risk of developing type 2 diabetes. We hypothesized that β-cell function relative to insulin sensitivity decreases with increasing 2-h glucose levels based on an oral glucose tolerance test (OGTT) in overweight youth. RESEARCH DESIGN AND METHODS A total of 147 overweight (BMI ≥85th percentile for age and sex) youth, aged 8 to <20 years, undertook three tests: 1) a 3-h hyperinsulinemic-euglycemic clamp; 2) a 2-h hyperglycemic clamp; and 3) a 2-h OGTT. Participants were categorically assigned to five groups according to their OGTT 2-h plasma glucose level, ranging from <120 to ≥200 mg/dL. β-Cell function relative to insulin sensitivity, assessed by clamp disposition index (DI) and oral disposition index (DI(O)), were compared among groups.Results: Insulin sensitivity, first-phase insulin, and DI declined significantly as 2-h glucose concentrations increased. The highest DI was found in youth with 2-h plasma glucose concentrations <120 mg/dL, with a significant decline of ~40% in those with glucose concentrations between 120 and <140 mg/dL, and an ~75% decline, the lowest DI, in youth with glucose concentrations ≥200 mg/dL. Data were similar with regard to the OGTT DI(O).Conclusions: These data in overweight youth demonstrate that impairment in insulin secretion relative to insulin sensitivity is apparent even with normal glucose tolerance. Below the current cutoff of 140 mg/dL for impaired glucose tolerance, there is a >30% decline in β-cell function relative to insulin sensitivity. Against this back drop of metabolically heightened risk for type 2 diabetes, preventive measures should target the β-cell alongside insulin sensitization. [ABSTRACT FROM AUTHOR]

Objective: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are considered pre-diabetes states. There are limited data in pediatrics in regard to their pathophysiology. We investigated differences in insulin sensitivity and secretion among youth with IFG, IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes.Research Design and Methods: A total of 24 obese adolescents with NGT, 13 with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ([6,6-(2)H(2)]glucose), insulin-stimulated glucose disposal (R(d), euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp), body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomography), and substrate oxidation (indirect calorimetry).Results: Adolescents with NGT, pre-diabetes, and type 2 diabetes had similar body composition and abdominal fat distribution. R(d) was lower (P = 0.009) in adolescents with type 2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulin was lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2 diabetes (P < 0.001), and β-cell function relative to insulin sensitivity (glucose disposition index [GDI]) was also lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), with a further decrease (80%) in those with type 2 diabetes (P < 0.001). GDI was the major determinant of fasting and 2-h glucose levels.Conclusions: Obese adolescents who show signs of glucose dysregulation, including abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulin secretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, they are at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity or secretion may enhance the risk for this progression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility and effectiveness of an enhanced cognitive-behavioral therapy (CBT), Primary and Secondary Control Enhancement Training (PASCET-PI-2), for physical (obesity) and emotional (depression) disturbances in adolescents with polycystic ovary syndrome (PCOS).Method: In an open trial, 12 adolescents with PCOS, obesity, and depression underwent eight weekly sessions and three family-based sessions of CBT enhanced by lifestyle goals (nutrition and exercise), physical illness narrative (meaning of having PCOS), and family psychoeducation (family functioning).Results: Weight showed a significant decrease across the eight sessions from an average of 104 kg (SD = 26) to an average of 93 kg (SD = 18), t(11) = 6.6, p <.05. Depressive symptoms on the Children's Depression Inventory significantly decreased from a mean of 17 (SD = 3) to a mean of 9.6 (SD = 2), t(11) = 16.8, p <.01.Conclusion: A manual-based CBT approach to treat depression in adolescents with PCOS and obesity appears to be promising. [ABSTRACT FROM AUTHOR]

Objective: Impaired glucose tolerance (IGT) represents a pre-diabetic state. Controversy continues in regards to its pathophysiology. The aim of this study was to investigate the differences in insulin sensitivity (IS) and secretion in obese adolescents with IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes.Research Design and Methods: A total of 12 obese adolescents with NGT, 19 with IGT, and 17 with type 2 diabetes underwent evaluation of insulin sensitivity (3-h hyperinsulinemic [80 micro/m(2)/min]-euglycemic clamp), first-phase insulin and second-phase insulin secretion (2-h hyperglycemic clamp), body composition, and abdominal adiposity. Glucose disposition index (GDI) was calculated as the product of first-phase insulin x insulin sensitivity.Results: Insulin-stimulated glucose disposal was significantly lower in subjects with type 2 diabetes compared with subjects with NGT and IGT, with no difference between the latter two. However, compared with youth with NGT, youth with IGT have significantly lower first-phase insulin and C-peptide levels and GDI (P = 0.012), whereas youth with type 2 diabetes have an additional defect in second-phase insulin. Fasting and 2-h glucose correlated with GDI (r = -0.68, P < 0.001 and r = -0.73, P < 0.001, respectively) and first-phase insulin but not with insulin sensitivity.Conclusions: Compared with youth with NGT, obese adolescents with IGT have evidence of a beta-cell defect manifested in impaired first-phase insulin secretion, with a more profound defect in type 2 diabetes involving both first- and second-phase insulin. GDI shows a significantly declining pattern: it is highest in NGT, intermediate in IGT, and lowest in type 2 diabetes. Such data suggest that measures to prevent progression or conversion from pre-diabetes to type 2 diabetes should target improvement in beta-cell function. [ABSTRACT FROM AUTHOR]

Objective: To evaluate clinically useful measures of beta-cell function derived from the oral glucose tolerance test (OGTT) or mixed-meal (ie, Boost) tolerance test to assess insulin secretion in comparison with the gold standard, the hyperglycemic clamp (Hyper-C) test.Study Design: We hypothesized that OGTT/Boost-derived measures are useful estimates of beta-cell function and correlate well with insulin secretion measured by the Hyper-C test. This study was designed to assess the correlation between the ratio of the early incremental insulin/glucose responses at 15 and 30 minutes (DeltaI(15)/DeltaG(15) and DeltaI(30)/DeltaG(30)) of the OGTT and the Boost test with insulin secretion measured during the Hyper-C test (225 mg/dL). The same indices were evaluated using C-peptide. A total of 26 children (14 males, 12 females; mean age, 9.9 +/- 0.2 years; mean body mass index = 22.1 +/- 1.2 kg/m(2)) underwent a 2-hour Hyper-C test (225 mg/dL) and 3-hour OGTT and Boost tests with measurements of glucose, insulin, and C-peptide.Results: Correlations between Hyper-C- and OGTT-derived measures of insulin secretion were stronger for the 15-minute index than for the 30-minute index of insulin secretion and stronger for C-peptide levels than for insulin levels (r = .7, P < .001 for first-phase C-peptide vs both OGTT and Boost, DeltaC(15)/DeltaG(15)).Conclusions: In children with normal glucose tolerance, C-peptide rather than insulin level measured after 15 minutes of the OGTT or Boost test provides a reliable estimate of beta-cell function that correlates well with Hyper-C-derived insulin secretion. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate 1) whether adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in African-American and Caucasian youth and 2) whether adiponectin is associated with racial differences in insulin sensitivity.Research Design and Methods: Total body fat was measured by dual-energy X-ray absorptiometry and abdominal adipose tissue with computed tomography. Insulin sensitivity was measured by a 3-h hyperinsulinemic-euglycemic clamp.Results: Adiponectin was inversely associated (P < 0.01) with visceral adipose tissue, fasting insulin, and proinsulin and was positively related (P < 0.01) to insulin sensitivity after controlling for Tanner stage and sex independent of race. Stepwise multiple regression revealed that adiponectin was a strong independent predictor of insulin sensitivity, explaining 27% of the variance in insulin sensitivity. When subjects were categorized into tertiles of visceral adipose tissue and further low (< or = 50th) and high (>50th) adiponectin groups, insulin sensitivity was significantly different across the visceral adipose tissue groups (main effect, P < 0.01) in both races. However, within each visceral adipose tissue group, subjects with high adiponectin had higher insulin sensitivity (main effect, P < 0.05) than subjects with low adiponectin, independent of race. Racial differences in insulin sensitivity remained significant (P < 0.01) after controlling for leptin and visceral adipose tissue but not (P > 0.05) after additional adjustment for adiponectin.Conclusions: Adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in both African-American and Caucasian youth. Low adiponectin in African-American youth may be a biological marker that predisposes them to a greater risk of insulin resistance. [ABSTRACT FROM AUTHOR]

Objective: Adiponectin is an adipose tissue protein that enhances insulin sensitivity and has antiatherogenic properties. The present study investigated the relationship of adiponectin levels in adolescents to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X.Research Design and Methods: Twenty-three normal-weight and 26 obese adolescents had fasting adiponectin, lipid profile, and proinsulin measurements performed. Hepatic and peripheral insulin sensitivity were assessed with constant-rate [6,6-(2)H(2)]glucose infusion and a 3-h hyperinsulinemic-euglycemic clamp, respectively. Body composition was evaluated by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) and subcutaneous adipose tissue were measured by computed tomography scan at the L(4)-L(5) level.Results: Obese adolescents had approximately 50% lower adiponectin than normal-weight adolescents. Moreover, obese adolescents with high (111.8 +/- 9.3 cm(2)) versus low (55.4 +/- 2.1 cm(2)) VAT had lower adiponectin levels (6.2 +/- 0.9 vs. 9.0 +/- 1.0 microg/ml, P = 0.05). Plasma adiponectin correlated positively with peripheral and hepatic insulin sensitivity (r = 0.67, P < 0.001 and r = 0.54, P < 0.001, respectively) and HDL (r = 0.52, P < 0.001) and negatively with fasting proinsulin and the proinsulin-to-insulin ratio (r = -0.64, P < 0.001 and r = -0.43, P = 0.003, respectively). In a multiple regression analysis, adiponectin, independently and together with BMI, explained 73% (R(2) = 0.73, P < 0.001) of the variance in insulin sensitivity. Adiponectin, but not adiposity, was the significant independent determinant of the proinsulin-to-insulin ratio (R(2) = 0.18, P = 0.008) and of HDL (R(2) = 0.45, P < 0.001).Conclusions: In summary, hypoadiponectinemia in youth is a strong and independent correlate of insulin resistance, beta-cell dysfunction, visceral adiposity, and syndrome X. The antidiabetogenic and antiatherogenic properties of adiponectin are evident early in life and compromised in youth-onset obesity. [ABSTRACT FROM AUTHOR]

African-American (AA) children are hyperinsulinemic and insulin resistant compared with American White (AW) children. This study investigated 1) whether AA/AW differences in insulinemia are associated with differences in insulin clearance; 2) whether dietary patterns, mainly carbohydrate and fat intake, play a role; and 3) whether the quantitative relationship between insulin sensitivity and secretion is similar between AA and AW children. Forty-four prepubertal children (22 AA and 22 AW) with comparable body composition and visceral adiposity were studied. All underwent a 3-h hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp to calculate insulin sensitivity and insulin clearance and a 2-h hyperglycemic clamp (12.5 mmol/l) to assess first- and second-phase insulin responses. Twenty-four-hour food recalls were analyzed for macronutrient intake. Insulin clearance (19.5 +/- 0.7 vs. 22.9 +/- 1.1 ml x min(-1) x kg(-1) fat-free mass [FFM]; P = 0.011) and insulin sensitivity were lower in AA versus AW children (14.8 +/- 1.0 vs. 18.9 +/- 1.4 micro mol x min(-1) x kg(-1) FFM; P = 0.021). Both insulin clearance and insulin sensitivity correlated inversely with dietary fat/carbohydrate ratio, which was higher in AA than in white children. Fasting C-peptide and insulin were higher in AA children with no difference in proinsulin levels. First- and second-phase insulin concentrations and glucose disposition index (insulin sensitivity x first-phase insulin) were higher in AA than in white children (12.8 +/- 2.1 vs. 7.2 +/- 0.6 micro mol. min(-1) x kg(-1) FFM; P = 0.019). In conclusion, the hyperinsulinemia observed in AA children is due to both lower insulin clearance and higher insulin secretion compared with their white peers. The quantitative relationship between insulin secretion and sensitivity is upregulated in AA children. This suggests that increased insulin secretion in AA children is not merely a compensatory response to lower insulin sensitivity. Dietary factors may have a role. Additional studies are needed to determine whether metabolic/nutritional factors, possibly mediated through free fatty acids, may play a role in the hyperinsulinism observed in AA children. [ABSTRACT FROM AUTHOR]

Adiponectin is an adipocytokine with antidiabetogenic properties. The present study investigated: (i) the effect of race on adiponectin levels and (ii) the relationship of adiponectin levels in children to insulin sensitivity and secretion. Fasting adiponectin levels were determined in 22 healthy prepubertal black compared with 22 white children of similar body composition. We previously reported these black children to have lower insulin sensitivity and higher first-phase insulin secretion than their white peers. Fasting adiponectin levels were lower in black children (9.9 +/- 1.0 microg/mL vs. 15.7 +/- 1.1 microg/mL, p < 0.001). Adiponectin correlated positively with insulin sensitivity (r = 0.29, p = 0.06) and negatively with first-phase insulin levels (r = -0.47, p = 0.001). In a multiple regression analysis, 48% of the variance in first-phase insulin secretion was explained by the independent effects of race (p = 0.017), adiponectin (p = 0.03), and percentage of body fat (p < 0.001). Adiponectin did not contribute significantly to the variance in insulin sensitivity. In summary, black children have approximately 35% lower adiponectin levels than their white peers. Lower adiponectin does not seem to explain the racial differences in insulin sensitivity. The relationship of hyperinsulinemia and hypoadiponectinemia needs to be further explored. [ABSTRACT FROM AUTHOR]

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., (© 2024 by the American Diabetes Association.)

Efficient and accurate methods to estimate insulin sensitivity ( S I ) and β-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 S I 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 ( S I ) and β-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.

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.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and β-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes., Methods: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and β-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time., Results: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of β-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on β-cell function., Conclusions: Reducing demand on the β-cell by improving IS through weight loss does not reverse β-cell dysfunction. L + M was the only treatment that enhanced β-cell function., (© 2022 The Obesity Society.)

Objective: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols., Research Design and Methods: Glucagon was measured in three randomized, parallel, clinical studies: 1 ) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2 ) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3 ) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs)., Results: No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months ( P < 0.05 for all, except AGR at 12 months [ P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss., Conclusions: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions., (© 2021 by the American Diabetes Association.)

Objective: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study., Research Design and Methods: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA 1c increase ≥0.5% from baseline)., Results: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 ( P = 0.008) and in 36% of youth versus 20% of adults at month 21 ( P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening ( P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening ( P < 0.05). In youth, higher baseline HbA 1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening ( P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening ( P < 0.05)., Conclusions: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults., (© 2021 by the American Diabetes Association.)

Objective: To determine whether β-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release., Research Design and Methods: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L, and arginine-stimulated glucagon (acute glucagon response [AGR]) and C-peptide (ACPRmax) responses at glucose >25 mmol/L., Results: Mean ± SD fasting glucagon (7.63 ± 3.47 vs. 8.55 ± 4.47 pmol/L; P = 0.063) and steady-state glucagon (2.24 ± 1.46 vs. 2.49 ± 1.96 pmol/L, P = 0.234) were not different in youth and adults, respectively, while AGR was lower in youth (14.1 ± 5.2 vs. 16.8 ± 8.8 pmol/L, P = 0.001). Significant age-group differences in insulin sensitivity, fasting C-peptide, steady-state C-peptide, and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults ( r = 0.133, P = 0.012) and negatively correlated in youth ( r = -0.143, P = 0.251). In both age-groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r = 0.209, P = 0.091; adults r = 0.335, P < 0.001) and lower insulin sensitivity (youth r = -0.228, P = 0.066; adults r = -0.324, P < 0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth., Conclusions: Youth with IGT or recently diagnosed type 2 diabetes (drug naive) have hyperresponsive β-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared with those in adults. Thus, α-cell dysfunction does not appear to explain the difference in β-cell function and insulin sensitivity in youth versus adults., (© 2021 by the American Diabetes Association.)

Objective: The aim of this study was to examine the relationship between changes in liver fat and changes in insulin sensitivity and β-cell function 2 years after gastric banding surgery., Methods: Data included 23 adults with the surgery who had prediabetes or type 2 diabetes for less than 1 year and BMI 30 to 40 kg/m 2 at baseline. Body adiposity measures including liver fat content (LFC), insulin sensitivity (M/I), and β-cell responses (acute, steady-state, and arginine-stimulated maximum C-peptide) were assessed at baseline and 2 years after surgery. Regression models were used to assess associations adjusted for age and sex., Results: Two years after surgery, all measures of body adiposity, LFC, fasting and 2-hour glucose, and hemoglobin A1c significantly decreased; M/I significantly increased; and β-cell responses adjusted for M/I did not change significantly. Among adiposity measures, reduction in LFC had the strongest association with M/I increase (r = -0.61, P = 0.003). Among β-cell measures, change in LFC was associated with change in acute C-peptide response to arginine at maximal glycemic potentiation adjusted for M/I (r = 0.66, P = 0.007). Significant reductions in glycemic measures and increase in M/I were observed in individuals with LFC loss >2.5%., Conclusions: Reduction in LFC after gastric banding surgery appears to be an important factor associated with long-term improvements in insulin sensitivity and glycemic profiles in adults with obesity and prediabetes or early type 2 diabetes., (© 2021 The Obesity Society.)

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.

Objective: We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSThis was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and βCF at baseline and the change in glucose response curves 12 months after randomization were assessed.RESULTSAt randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults ( P < 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults ( P < 0.05), yet compared with adults, youth had higher βCF in BPh and MPh ( P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect.CONCLUSIONSDespite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve., (© 2021 by the American Diabetes Association.)

Background: The RISE Pediatric Medication Study compared strategies for preserving β-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability., Objective: Evaluate OGTT measures of glucose and β-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 β-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 β-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 β-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Glycemic control deteriorates more rapidly in youth vs adults. We compared model-derived measures of β-cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a β-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/m 2 , 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/m 2 , P = .002). Within IGT, glucose sensitivity (Y-IGT 140 ± 153 vs A-IGT 112 ± 70 pmol/min/m 2 /mM, P = .004) and rate sensitivity (median[interquartile range]:Y-IGT 2271[1611, 3222] vs A-IGT 1164[685, 1565] pmol/m 2 /mM, P < .001) were higher in youth, but not different by age group within diabetes., Conclusions: Model-derived measures of β-cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and β-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 β-cells that are healthier or whether this is a defect that contributes to more rapid loss of function., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: It is not known if dysglycemia and sleep-disordered breathing are linked in adolescents, as in adults., Objective: To perform a pilot study evaluating measures of sleep-disordered breathing across the spectrum of glucose tolerance in obese adolescents. We hypothesized that dysglycemia would be associated with sleep-disordered breathing., Participants/methods: This was a prospective, cross-sectional clinical pilot study that included 57 adolescents [body mass index (BMI) 38.9 ± 8.4 kg/m 2 ] aged 12-18 years (14.5 ± 1.6) with normal glucose tolerance (NGT), or dysglycemia [impaired glucose tolerance (IGT) or type 2 diabetes (T2D)]., Measures: Anthropometrics, overnight polysomnogram, and oral glucose tolerance tests were performed. Participant characteristics and outcome measures were compared by glucose tolerance status. Correlational analyses were conducted to assess the associations between variables of interest., Results: Participants with dysglycemia ( n  = 21) were not different from those with NGT ( n  = 36) for BMI, waist circumference, body fat, or sleep characteristics. Nocturnal oxygen desaturation was associated with higher BMI ( r  = -0.334, p  = 0.012). The apnea-hypopnea index (AHI) was not associated with physical and metabolic parameters. Although participants with dysglycemia tended to have higher AHIs (median 3.2, 2.2, and 1.6 events/h for T2D, IGT, and NGT, respectively), there was not a linear relationship between measures of glycemia and AHI., Conclusion: Further study with a larger proportion of youth with prediabetes and T2D is necessary to determine whether evaluation for sleep-disordered breathing is uniformly warranted.

Context: Little is known about reproductive function in girls with youth-onset type 2 diabetes., Objectives: To characterize girls with irregular menses and effects of glycemic treatments on menses and sex steroids in the Treatment Options for Type 2 Diabetes in Youth (TODAY) study., Design: Differences in demographic, metabolic, and hormonal characteristics between regular- vs irregular-menses groups were tested; treatment group (metformin with or without rosiglitazone, metformin plus lifestyle) effect on menses and sex steroids over time in the study was assessed. This is a secondary analysis of TODAY data., Setting: Multicenter study in an academic setting., Patients: TODAY girls not receiving hormonal contraception and those at least 1-year postmenarche were included. Irregular menses was defined as three or fewer periods in the prior 6 months., Results: Of eligible participants with serum measurement of sex steroids (n = 190; mean age, 14 years), 21% had irregular menses. Those with irregular vs regular menses had higher body mass index (BMI) (P = 0.001), aspartate aminotransferase (AST) (P = 0.001), free androgen index (P = 0.0003), and total testosterone (P = 0.01) and lower sex hormone-binding globulin (SHBG) (P = 0.004) and estradiol (P = 0.01). Differences remained after adjustment for BMI. There was no treatment group effect on menses or sex steroids at 12 or 24 months, and no association of sex steroids was seen with measures of insulin sensitivity or secretion., Conclusions: Menstrual dysfunction is common in girls with recently diagnosed type 2 diabetes and associated with alterations in sex steroids, SHBG, and AST but not with alteration in insulin sensitivity or β-cell function and did not improve with 2 years of antihyperglycemic treatment.

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-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 β-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 β-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., (© 2017 John Wiley & Sons Ltd.)

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 (R 2 = 0.44, P < .001). Without race in the model, 25(OH)D (β = -0.36, P = .009) contributed to the variance in IMT (R 2 = 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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cosponsoring Associations: The European Society of Endocrinology and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society., Objective: To formulate clinical practice guidelines for the assessment, treatment, and prevention of pediatric obesity., Participants: The participants include an Endocrine Society-appointed Task Force of 6 experts, a methodologist, and a medical writer., Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The Task Force commissioned 2 systematic reviews and used the best available evidence from other published systematic reviews and individual studies., Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and co-sponsoring organizations reviewed and commented on preliminary drafts of this guideline., Conclusion: Pediatric obesity remains an ongoing serious international health concern affecting ∼17% of US children and adolescents, threatening their adult health and longevity. Pediatric obesity has its basis in genetic susceptibilities influenced by a permissive environment starting in utero and extending through childhood and adolescence. Endocrine etiologies for obesity are rare and usually are accompanied by attenuated growth patterns. Pediatric comorbidities are common and long-term health complications often result; screening for comorbidities of obesity should be applied in a hierarchal, logical manner for early identification before more serious complications result. Genetic screening for rare syndromes is indicated only in the presence of specific historical or physical features. The psychological toll of pediatric obesity on the individual and family necessitates screening for mental health issues and counseling as indicated. The prevention of pediatric obesity by promoting healthful diet, activity, and environment should be a primary goal, as achieving effective, long-lasting results with lifestyle modification once obesity occurs is difficult. Although some behavioral and pharmacotherapy studies report modest success, additional research into accessible and effective methods for preventing and treating pediatric obesity is needed. The use of weight loss medications during childhood and adolescence should be restricted to clinical trials. Increasing evidence demonstrates the effectiveness of bariatric surgery in the most seriously affected mature teenagers who have failed lifestyle modification, but the use of surgery requires experienced teams with resources for long-term follow-up. Adolescents undergoing lifestyle therapy, medication regimens, or bariatric surgery for obesity will need cohesive planning to help them effectively transition to adult care, with continued necessary monitoring, support, and intervention. Transition programs for obesity are an uncharted area requiring further research for efficacy. Despite a significant increase in research on pediatric obesity since the initial publication of these guidelines 8 years ago, further study is needed of the genetic and biological factors that increase the risk of weight gain and influence the response to therapeutic interventions. Also needed are more studies to better understand the genetic and biological factors that cause an obese individual to manifest one comorbidity vs another or to be free of comorbidities. Furthermore, continued investigation into the most effective methods of preventing and treating obesity and into methods for changing environmental and economic factors that will lead to worldwide cultural changes in diet and activity should be priorities. Particular attention to determining ways to effect systemic changes in food environments and total daily mobility, as well as methods for sustaining healthy body mass index changes, is of importance., (Copyright © 2017 by the Endocrine Society)

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.

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Type 2 Diabetes Mellitus (T2DM) and obesity are linked to specific patterns of subcortical brain atrophy and decreased microstructural integrity of white matter. Fifteen adolescents (12-21-years-old, 80% Caucasian, 15% African American, mean BMI=32)-five with T2DM confirmed by oral glucose tolerance test, five matched obese adolescent controls without diabetes (OBCN), and five matched (race, sex) normal-weight controls (NWCN)-underwent Magnetic Resonance Imaging (MRI) for the collection of gray matter volume and white matter integrity. Analyses of Variance (ANOVAs) of the neuroimaging data revealed significant differences in caudate nucleus volume [F(2,12)=7.79, p<0.05] such that the normal-weight group had significantly greater volume than the obese and T2DM groups (NWCN>OBCN, p=0.020; OBCN>T2DM, p=0.042; and NWCN>T2DM; p=0.003) after controlling for participant Body Mass Index (BMI). Similarly, there was a main effect for the volume of the thalamus [F(2,12)=4.39, p<0.05] with greater volume for both the NWC and the OBC groups in comparison to the T2DM group (NWC>T2DM, p=0.020; OBC>T2DM; p=0.040). Finally, an examination of white matter integrity among the three groups illustrated a pattern of white matter integrity reduction between normal-weight participants and both obese controls and T2DM participants, with T2DM demonstrating the greatest deficit in functional anisotropy (FA) volume, but these results were not significant after further controlling for BMI. Results from the current pilot study illuminate a host of brain morphology differences between youth with T2DM, obese youth, and normal-weight controls; future research with a larger sample size is critical., (Copyright © 2015. Published by Elsevier Ltd.)

Objective: To study the association between gestational weight gain (GWG) and offspring obesity risk at ages chosen to approximate prepuberty (10 years) and postpuberty (16 years)., Design: Prospective pregnancy cohort., Setting: Pittsburgh, PA, USA., Sample: Low-income pregnant women (n = 514) receiving prenatal care at an obstetric residency clinic and their singleton offspring., Methods: Gestational weight gain was classified based on maternal GWG-for-gestational-age Z-score charts and was modelled using flexible spline terms in modified multivariable Poisson regression models., Main Outcome Measures: Obesity at 10 or 16 years, defined as body mass index (BMI) Z-scores ≥95th centile of the 2000 CDC references, based on measured height and weight., Results: The prevalence of offspring obesity was 20% at 10 years and 22% at 16 years. In the overall sample, the risk of offspring obesity at 10 and 16 years increased when GWG exceeded a GWG Z-score of 0 SD (equivalent to 30 kg at 40 weeks); but for gains below a Z-score of 0 SD there was no relationship with child obesity risk. The association between GWG and offspring obesity varied by prepregnancy BMI. Among mothers with a pregravid BMI <25 kg/m(2) , the risk of offspring obesity increased when GWG Z-score exceeded 0 SD, yet among overweight women (BMI ≥25 kg/m(2) ), there was no association between GWG Z-scores and offspring obesity risk., Conclusions: Among lean women, higher GWG may have lasting effects on offspring obesity risk., (© 2015 Royal College of Obstetricians and Gynaecologists.)

The incidence of youth type 2 diabetes (T2D), linked with obesity and declining physical activity in high-risk populations, is increasing. Recent multicenter studies have led to a number of advances in our understanding of the epidemiology, pathophysiology, diagnosis, treatment, and complications of this disease. As in adult T2D, youth T2D is associated with insulin resistance, together with progressive deterioration in β cell function and relative insulin deficiency in the absence of diabetes-related immune markers. In contrast to adult T2D, the decline in β cell function in youth T2D is three- to fourfold faster, and therapeutic failure rates are significantly higher in youth than in adults. Whether the more aggressive nature of youth T2D is driven by genetic heterogeneity or physiology/metabolic maladaptation is yet unknown. Besides metformin, the lack of approved pharmacotherapeutic agents for youth T2D that target the pathophysiological mechanisms is a major barrier to optimal diabetes management. There is a significant need for effective therapeutic options, in addition to increased prevention, to halt the projected fourfold increase in youth T2D by 2050 and the consequences of heightened diabetes-related morbidity and mortality at younger ages., (© 2015 New York Academy of Sciences.)

Objective: We examined the association between gestational weight gain (GWG) and offspring obesity at age 36 months., Methods: Mother-infant dyads (n = 609) were followed from a first study visit (mean [standard deviation]: 18.8 [2.7] weeks gestation) to 36 months postpartum. Total GWG over the entire pregnancy was defined as excessive or non-excessive according to the 2009 Institute of Medicine guidelines. Four mutually exclusive categories of excessive or non-excessive GWG across early (conception to first study visit) and late (first study visit to delivery) pregnancy defined GWG pattern. Body mass index (BMI) z-scores ≥95th percentile of the 2000 Centers for Disease Control (CDC) references defined offspring obesity at 36 months. Multivariable log-binomial models adjusted for pre-pregnancy BMI and breastfeeding were used to estimate the association between GWG and childhood obesity risk., Results: Nearly half of the women had total excessive GWG. Of these, 46% gained excessively during both early and late pregnancy while 22% gained excessively early and non-excessively late, and the remaining 32% gained non-excess weight early and excessively later. Thirteen per cent of all children were obese at 36 months. Excessive total GWG was associated with more than twice the risk of child obesity (adjusted risk ratio [95% confidence interval]: 2.20 [1.35, 3.61]) compared with overall non-excessive GWG. Compared with a pattern of non-excessive GWG in both early and late pregnancy, excessive GWG in both periods was associated with an increased risk of obesity (2.39 [1.13, 5.08])., Conclusions: Excessive GWG is a potentially modifiable factor that may influence obesity development in early childhood., (© 2014 World Obesity.)

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.

Purpose: To compare atherogenic lipoprotein particles and vascular smooth muscle biomarkers in overweight youth with pre-diabetes (PD) vs. normal glucose tolerance (NGT)., Methods: 144 adolescents (60 black, 84 white; 102 female; PD=45, NGT=99) aged 10-19 years underwent a fasting blood draw and 2-h OGTT. Lipoprotein particle size and subclass concentration and vascular smooth muscle biomarkers (ICAM-1, VCAM-1 and E-selectin) were compared between youth with PD and NGT., Results: Compared with NGT, PD adolescents had smaller LDL (mean±SE: 20.5±0.1 vs. 21.0±0.1 nm; P=0.002) and HDL (8.62±0.05 vs. 8.85±0.04 nm; P=0.013) size and elevated medium small (159.2±10.3 vs. 123.8±6.4 nmol/L; P=0.037) and very small (626.3±45.4 vs. 458.5±26.4 nmol/L; P=0.032) LDL particle concentrations, after adjustment for race and BMI. Further adjusting for fasting insulin or visceral adiposity obviated these differences between the groups except for LDL size. ICAM-1 and E-selectin did not differ in youth with PD but correlated with LDL and HDL size, and small LDL particle concentrations., Conclusions: Overweight adolescents with PD have an atherogenic lipoprotein profile of small LDL and HDL size and increased concentrations of small LDL, moderated by insulin resistance and visceral adiposity, but independently driven by dysglycemia for LDL size. Associations between smooth muscle biomarkers and lipoproteins could be an early signal heralding the atherogenic process. It remains to be determined if correction of dysglycemia and associated lipoprotein abnormalities in obese youth could prove effective in halting this process., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Obesity in adolescence has been associated with increased risk for coronary heart disease in adulthood. This study evaluated subclinical atherosclerosis in obese youth and the underlying risk factors., Research Design and Methods: Ninety obese adolescents (37 normal glucose tolerant, 27 prediabetes, and 26 type 2 diabetes) underwent evaluation of coronary artery calcifications (CACs) by electron beam computed tomography, aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT), lipids, leptin, inflammatory markers, and body composition (DEXA). A total of 68 underwent evaluation of insulin sensitivity (IS) (hyperinsulinemic-euglycemic clamp) and abdominal adiposity (computed tomography)., Results: A total of 50% had CACs (CAC+: Agatston CAC score ≥1). CAC+ youth had higher BMI, fat mass, and abdominal fat, with no difference in sex, race, IS per fat-free mass (ISFFM), glucose tolerance, PWV, or IMT compared with the CAC- group. PWV was inversely related to IS. In multiple regression analyses with age, race, sex, HbA1c, BMI (or waist circumference), ISFFM, diastolic blood pressure, non-HDL cholesterol, and leptin as independent variables, BMI (or waist) (R(2) = 0.41; P = 0.001) was the significant determinant of CAC; leptin (R(2) = 0.37; P = 0.034) for PWV; and HbA1c, race, and age (R(2) = 0.34; P = 0.02) for IMT., Conclusions: Early in the course of obesity, there is evidence of CAC independent of glycemia. The different biomarkers of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia, age, and race for IMT, and leptin and IS for arterial stiffness. These findings highlight the increased cardiovascular disease risk in obese youth and the need for early interventions to reverse obesity and atherosclerosis., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS)., Participants: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer developed the guideline., Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence., Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence., Conclusions: We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study.

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 β-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 β-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., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced β-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide-modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, β-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in β-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to β-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of β-cell insulin secretion, consistent with our theory.

Objective: To 1) determine if plasma 25-hydroxyvitamin D (25[OH]D) concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes and 2) assess the relationships between 25(OH)D and in vivo insulin sensitivity and β-cell function in this cohort., Research Design and Methods: Plasma 25(OH)D concentrations were examined in banked specimens in 9- to 20-year-old obese youth (n = 175; male 42.3%, black 46.3%) (NGT, n = 105; impaired glucose tolerance [IGT], n = 43; type 2 diabetes, n = 27) who had in vivo insulin sensitivity and secretion measured by hyperinsulinemic-euglycemic and hyperglycemic clamp techniques and had an assessment of total body composition and abdominal adiposity., Results: The mean age and BMI of the subjects were 14.3 ± 2.1 years and 35.7 ± 5.6 kg/m(2), respectively. BMI, plasma 25(OH)D, and the proportion of vitamin D-deficient and -insufficient children did not differ across the three groups. Furthermore, there was no association between 25(OH)D and in vivo insulin sensitivity or β-cell function relative to insulin sensitivity (disposition index) in all groups combined or in each group separately., Conclusions: Our data in obese youth show 1) no differences in plasma 25(OH)D concentrations across the glucose tolerance groups and 2) no relationship between 25(OH)D and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity in any of the groups. It remains uncertain if enhancement of the vitamin D status could improve pathophysiological mechanisms of prediabetes and type 2 diabetes in obese youth.

Objective: Overweight/obese (OW/OB) African American (AA) adolescents have a more diabetogenic insulin secretion/sensitivity pattern compared with their American white (AW) peers. The present study investigated β-cell lipotoxicity to test whether increased free fatty acid (FFA) levels result in greater β-cell dysfunction in AA vs AW OW/OB adolescents., Research Design and Methods: Glucose-stimulated insulin secretion was modeled, from glucose and C-peptide concentrations during a 2-hour hyperglycemic (225 mg/dL) clamp in 22 AA and 24 AW OW/OB adolescents, on 2 occasions after a 12-hour overnight infusion of either normal saline or intralipid (IL) in a random sequence. β-Cell function relative to insulin sensitivity, the disposition index (DI), was examined during normal saline and IL conditions. Substrate oxidation was evaluated with indirect calorimetry and body composition and abdominal adiposity with dual-energy X-ray absorptiometry and magnetic resonance imaging at L4-L5, respectively., Results: Age, sex, body mass index, total and sc adiposity were similar between racial groups, but visceral adiposity was significantly lower in AAs. During IL infusion, FFAs and fat oxidation increased and insulin sensitivity decreased similarly in AAs and AWs. β-Cell glucose sensitivity of first- and second-phase insulin secretion did not change significantly during IL infusion in either group, but DI in each phase decreased significantly and similarly in AAs and AWs., Conclusions: Overweight/obese AA and AW adolescents respond to an overnight fat infusion with significant declines in insulin sensitivity, DI, and β-cell function relative to insulin sensitivity, suggestive of β-cell lipotoxicity. However, contrary to our hypothesis, there does not seem to be a race differential in β-cell lipotoxicity. Longer durations of FFA elevation may unravel such race-related contrasts.