Prognostic factors in resolution of nonalcoholic fatty liver disease post bariatric surgery in adolescents.

BACKGROUND: The long-term effect of bariatric surgery on adolescent non-alcoholic fatty liver disease is not clear. OBJECTIVES: To evaluate longitudinal change in serum alanine aminotransferase (ALT) levels and to determine the factors independently associated with this change over 2 years after bariatric surgery in adolescents with severe obesity. SETTING: An observational prospective cohort from the Teen-LABS Consortium. METHODS: We examined the relationship of longitudinal change in serum ALT (% change and normalization) to change in body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), high- (HDL) and low-density lipoprotein cholesterol, A1C and fasting glucose, accounting for age, sex, race-ethnicity, blood pressure, and baseline BMI in 219 adolescents during the first 2 years post-surgery. RESULTS: Mean BMI declined from a baseline of 52.6 to 37.2 kg/m2 at 2 years (P < .01). Alanine aminotransferase decreased significantly from baseline (36.5 [95% CI: 31.4, 41.7]) to 6 months (30.5 [95% CI: 25.4, 35.6]), and remained stable at 12 and 24 months, all P < .01 versus baseline. After adjustment, improvement in BMI, fasting glucose, HOMA-IR, triglycerides, TG/HDL ratio, and HDL were independently associated with reduced ALT at 6 months. These remained significantly associated with a decline in ALT after adjusting for BMI change. The %participants with elevated ALT decreased from 71% at baseline to 42% and 36% at 1 and 2 years post-surgery. CONCLUSIONS: Bariatric surgery resulted in significant and sustained improvement in ALT levels over 2 years. Although associated with weight loss, this decline was also associated with improved metabolic indices, independent of weight loss.

Hyperglycemia: A determinant of cardiac autonomic dysfunction in youth with obesity across the spectrum of glycemic regulation.

OBJECTIVES: To characterize the determinants of heart rate variability (HRV) in youth with obesity across the glycemia spectrum. METHODS: A total of 94 adolescents, 15 ± 2.1 years (21 with normal weight, 23 with overweight-normal glucose tolerance, 26 with prediabetes and 24 with type 2 diabetes [T2D]) underwent an assessment of body composition (dual-energy x-ray absorptiometry), 2-h oral glucose tolerance test with the calculation of indices of glycemia and insulin sensitivity (IS), inflammatory markers (high-sensitivity C-reactive protein [hs-CRP] and tumour necrosis factor-α [TNF-α]), and HRV by peripheral arterial tonometry. RESULTS: The HRV frequency-domain index (low-frequency to high-frequency ratio [LF/HF]), an estimate of the ratio between sympathetic and parasympathetic activity, increased across the glycemic spectrum, and was highest in T2D compared with the other three groups (p = 0.004). LF/HF correlated with %body fat (r = 0.22, p = 0.04); fasting (r = 0.39, p < 0.001), 2-h (r = 0.31, p = 0.004), and area under the curve glucose (r = 0.32, p = 0.003); hs-CRP (r = 0.33, p = 0.002) and TNF-α (r = 0.38, p = 0.006). In a linear regression model, fasting glucose (ß = 0.39, p = 0.003) and hs-CRP (ß = 0.21, p = 0.09) contributed to the variance in Ln LF/HF independent of IS, %body fat, age, sex, race-ethnicity and Tanner stage (R2 = 0.23, p = 0.013). CONCLUSIONS: Youth with impaired glucose regulation have evidence of cardiac autonomic dysfunction with decreased HRV, and sympathetic overdrive (increased LF/HF). This dysfunction is mainly related to glycemia and systemic inflammation.

Candidate biomarkers as predictors of future kidney disease and cardiovascular dysfunction in adolescents with type 2 diabetes.

AIMS: Evaluate changes in circulating biomarkers as predictors of kidney disease, and cardiac/vascular dysfunction in participants from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Candidate biomarkers were assessed annually in 507 participants over a mean follow-up of 6.9 ± 2.4 years. Moderate albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g and hyperfiltration as eGFR ≥ 135 mL/min/1.73 m2 at two consecutive visits. Echocardiography (n = 256) and pulse wave velocity (n = 193) were evaluated twice, 5 years apart. Adjusted Cox proportional hazard models and logistic regression models were used to examine associations between biomarkers and outcomes. RESULTS: At baseline, 35.7% were male, with a mean age 13.9 years, diabetes duration 7.8 months, and HbA1c 6.0%. Higher concentrations of E-selectin and proinsulin were associated with incident moderate albuminuria and hyperfiltration. Higher concentrations of FGF-23 were associated with lower risk of hyperfiltration and negatively correlated with eGFR. No candidate biomarkers predicted a decline in cardiac or vascular function. CONCLUSIONS: Circulating biomarkers of endothelial dysfunction and markers of ß-cell dysfunction and insulin sensitivity could be used in a more personalized risk assessment of kidney disease in youth-onset type 2 diabetes. However, biomarkers studied have limited value in predicting cardiac dysfunction or vascular stiffness.

Relationship between Arterial Stiffness and Subsequent Cardiac Structure and Function in Young Adults with Youth-Onset Type 2 Diabetes: Results from the TODAY Study.

BACKGROUND: Higher arterial stiffness may contribute to future alterations in left ventricular systolic and diastolic function. We tested this hypothesis in individuals with youth-onset type 2 diabetes from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Arterial stiffness (pulse wave velocity [carotid-femoral, femoral-foot, and carotid-radial], augmentation index, brachial distensibility) was measured in 388 participants with type 2 diabetes (mean age, 21 years; diabetes duration, 7.7 ± 1.5 years). To reflect overall (composite) vascular stiffness, the five arterial stiffness measures were aggregated. An echocardiogram was performed in the same cohort 2 years later. Linear regression models assessed whether composite arterial stiffness was associated with left ventricular mass index or systolic and diastolic function, independent of age, sex, race/ethnicity, current cigarette smoking, and long-term exposure (time-weighted mean values over 9.1 years) of hemoglobin A1c, blood pressure, and body mass index. Interactions among arterial stiffness and time-weighted mean hemoglobin A1c, blood pressure, and body mass were also examined. RESULTS: After adjustment, arterial stiffness remained significantly associated with left ventricular mass index and diastolic function measured by mitral valve E/Em, despite attenuation by time-weighted mean body mass index. A significant interaction revealed a greater adverse effect of composite arterial stiffness on mitral valve E/Em among participants with higher levels of blood pressure over time. Arterial stiffness was unrelated to left ventricular systolic function. CONCLUSIONS: The association of higher arterial stiffness with future left ventricular diastolic dysfunction suggests the path to future heart failure may begin early in life in this setting of youth-onset type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328.

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

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

Diagnostic Evaluation, Comorbidity Screening, and Treatment of Polycystic Ovary Syndrome in Adolescents in 3 Specialty Clinics.

STUDY OBJECTIVE: A polycystic ovary syndrome (PCOS) diagnosis in adolescence can have significant long-term health implications. The criteria for its diagnosis in adolescents have been subject to much debate. In this study we aimed to characterize the variability in diagnosis and management among different pediatric specialties. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: This was a retrospective review of electronic medical records of female patients (11-21 years old) who presented to 3 specialties (adolescent medicine [ADO], pediatric endocrinology [ENDO], and gynecology [GYN]), with a postvisit diagnosis of PCOS, menstrual disorders, or hirsutism, at a large tertiary care center, from November 1, 2011 to October 31, 2012. Demographic, clinical, laboratory, and treatment data were abstracted. MAIN OUTCOME MEASURES: Testing for diagnosis of PCOS and its comorbidities, and treatment strategies in the 3 pediatric specialties. RESULTS: One hundred forty-one patients (50 ADO, 48 ENDO, and 43 GYN) were eligible. Testing for hyperandrogenemia (17-hydroxy-progesterone, dehydroepiandrosterone, estradiol), thyroxine, and use of pelvic ultrasound differed among specialties. Providers failed to document weight concerns in 28.3% (29 of 101) of overweight or obese patients. Patients seen by ENDO were most likely, and GYN least likely, to be identified as having elevated weight, and to be tested for glucose abnormalities, dyslipidemia, and liver disease. ENDO providers prescribed metformin more often and hormonal therapy less often than ADO and GYN. CONCLUSION: There is considerable variability across pediatric specialties in the evaluation of PCOS, with significant underassessment of comorbidities. Use of unified guidelines, including for the evaluation of comorbidities, would improve evidence-based management of adolescent PCOS.

Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study.

OBJECTIVES: To examine cardiac biomarkers over time in youth-onset type 2 diabetes, and relate serum concentrations to cardiovascular disease risk factors, and left ventricular structure and function. STUDY DESIGN: TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) was a multicenter randomized trial of 3 treatments including 521 participants with type 2 diabetes, aged 10-17 years, and with 2-6 years of follow-up. Participants were 36% male, obese, and ethnically diverse. Annual serum concentrations of brain natriuretic peptide, troponin, tumor necrosis factor (TNF)-α, receptors 1 and 2 were related to blood pressure, body mass index, hemoglobin A1c, and left ventricular ejection fraction, diastolic function, relative wall thickness, and mass. RESULTS: Elevated concentrations of brain natriuretic peptide (≥100 pg/mL), TNF-α (≥5.6 pg/mL) and troponin (≥0.01 ng/mL), were present in 17.8%, 18.3%, and 34.2% of the cohort, respectively, at baseline, and in 15.4%, 17.1%, and 31.1% at the end of the study, with wide variability over time, without persistence in individuals or clear relationship to glycemia or cardiovascular structure/function. TNF receptors concentrations were increased at baseline and not significantly different from end-of-study concentrations. Adverse echocardiographic measures were more likely in the highest TNF receptor tertile (all P < .05): higher left ventricular mass (39.3 ± 9.0 g/m2.7), left atrial internal dimension (3.7 ± 0.4 cm) and E/Em ratio, a measure of diastolic dysfunction (6.2 ± 1.9). After adjustment for body mass index, these relationships were no longer significant. CONCLUSIONS: Elevated serum concentrations of cardiac biomarkers were common in youth with type 2 diabetes, but their clinical significance is unclear and will require further long-term study. TRIAL REGISTRATION: ClinicalTrials.govNCT00081328.

Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial.

BACKGROUND: Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. STUDY DESIGN: Observational prospective cohort study. SETTING & PARTICIPANTS: 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. PREDICTORS: Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. OUTCOMES: Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30µg/mg at 3 consecutive annual visits. RESULTS: Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. LIMITATIONS: Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. CONCLUSIONS: Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

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

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

Endothelial Function in Youth: A Biomarker Modulated by Adiposity-Related Insulin Resistance.

OBJECTIVE: To investigate the physical and metabolic determinants of endothelial dysfunction, an early marker of subclinical atherosclerosis, in normal weight and overweight adolescents with and without type 2 diabetes mellitus. STUDY DESIGN: A cross-sectional study of 81 adolescents: 21 normal weight, 25 overweight with normal glucose tolerance, 19 overweight with impaired glucose regulation, and 16 with type 2 diabetes mellitus underwent evaluation of reactive hyperemia index (RHI) and augmentation index (AIx) at heart rate 75 bpm by peripheral arterial tonometry; oral glucose tolerance test, lipid profile, and hyperinsulinemic-euglycemic clamp to measure insulin sensitivity; and dual energy X-ray absorptiometry scan and abdominal magnetic resonance imaging for percentage of body fat and abdominal fat partitioning. RESULTS: Participants across tertiles of RHI (1.2 ± 0.02, 1.5 ± 0.02, and 2.0 ± 0.05, P < .001) had similar age, sex, race, lipid profile, and blood pressure. Body mass index z-score, percentage body fat, abdominal fat, and hemoglobin A1c decreased, and insulin sensitivity increased from the first to third tertile. RHI was inversely related to percentage body fat (r = -0.29, P = .008), total (r = -0.37, P = .004), subcutaneous (r = -0.39, P = .003), and visceral (r = -0.26, P = .04) abdominal fat. AIx at heart rate 75 bpm was higher (worse) in the lower RHI tertiles (P = .04), was positively related to percentage body fat (r = 0.26, P = .021), and inversely related to age, insulin sensitivity, and inflammatory markers (tumor necrosis factor-α and plasminogen activator inhibition-1). CONCLUSIONS: Childhood obesity, particularly abdominal adiposity, is associated with endothelial dysfunction manifested by worse reactive hyperemia and higher AIx. Insulin resistance appears to mediate this relationship.

Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes.

OBJECTIVE: To investigate the relationships of cardiac structure and function with body composition and cardiorespiratory fitness (CRF) among adolescents with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study. STUDY DESIGN: Cross-sectional evaluation of 233 participants (median age 18.3 [min-max 12.4-24.2] years, 63% females, median hemoglobin A1c 6.8%) who had echocardiography measurements of left ventricular (LV) mass, ejection fraction, left atrial dimensions, LV diastolic function (early transmitral flow velocity to early mitral annular velocity ratio from tissue Doppler imaging), and right ventricular function (tricuspid annular plane systolic excursion [TAPSE]) and body composition (dual-energy x-ray absorptiometry) and CRF (cycle ergometry determination of physical work capacity at heart rate of 170 beats per minute). RESULTS: LV mass correlated positively with CRF (r = 0.5, P < .0001), lean body mass (LBM) (r = 0.7, P < .0001), and fat mass (FM) (r = 0.2, P = .00047); LV ejection fraction did not. Early transmitral flow velocity to early mitral annular velocity was positively related to FM (r = 0.14, P = .03) and % body fat (r = 0.18, P = .007), and left atrial internal diameter correlated with FM (r = 0.4, P < .0001), LBM (r = 0.3, P < .001), and CRF (r = 0.2, P = .0033). TAPSE weakly correlated with CRF (r = 0.2, P = .0014) and LBM (r = 0.13, P < .05) but not with FM. In multivariable regression analyses, LBM (ß = 2.13, P < .0001) and CRF (ß = 0.023, P = .008) were related to LV mass independent of race, sex, age, hemoglobin A1c, hypertension, smoking, and diabetes medications. CRF (ß = 0.0002, P = .0187) and hemoglobin A1c (ß = -0.022, P = .0142) were associated with TAPSE. CONCLUSIONS: In youth with type 2 diabetes, LV size is related to physical fitness. LV ejection fraction is within normal limits. LV diastolic function is inversely related to FM. Greater fitness may counteract adverse effects of poor glycemic control on right ventricular function. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00081328.

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

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

Depressive Symptoms in Youth With Type 1 or Type 2 Diabetes: Results of the Pediatric Diabetes Consortium Screening Assessment of Depression in Diabetes Study.

OBJECTIVE: To evaluate the frequency of depressive symptoms and the diagnosis and management of depression in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium T1D and T2D registries. RESEARCH DESIGN AND METHODS: The Children's Depression Inventory (CDI) 2 Self-Report (Short) version was completed by 261 T1D and 339 T2D youth aged 10-17 years. RESULTS: Symptoms of depression were identified in 13% of T1D and 22% of T2D (P = 0.007) participants; of these, only 4% of T1D and 9% of T2D youth were treated by a therapist within the prior 12 months. Depressive symptoms were associated with lower family income (P = 0.006) and obesity (P = 0.002) in T1D but not T2D youth. CONCLUSIONS: Depressive symptoms are more frequent than diagnosed depression in youth with T1D or T2D. These results underscore the need for regular depression screening and appropriate referral for youth with diabetes.

Alterations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabetes participating in the TODAY clinical trial.

Data on cardiovascular disease (CVD) risk in adolescents with type 2 diabetes (T2D) are limited. Echocardiography was performed in the last year of the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial (median 4½ yr from diagnosis of T2D, average age 18 yr), including MMode and 2D measurements of left ventricular (LV) and left atrial (LA) dimensions, LV tissue Doppler imaging (TDI), and tricuspid annular plane systolic excursion (TAPSE). Relationships between cardiac structure and function with demographic characteristics and baseline and change-from-baseline in CVD risk factors were examined in 455 participants. Mean LV mass (LVM) was high/normal and 16.2% had adverse LV geometry (8.1% concentric geometry, 4.5% LV hypertrophy, and 3.6% both). Determinants of higher LVM were male gender, black race, baseline and increasing body mass index (BMI), baseline and increasing systolic blood pressure (SBP), use of blood pressure (BP) medications, maintenance of glycemic control, and smoking; heart rate (HR) was inversely related. LV shortening fraction was high/normal and related to increasing BMI and higher baseline SBP. LV relative wall thickness was related to race-ethnicity, change in BMI, baseline glycated hemoglobin (HbA1c), and baseline and change in SBP. Mean LA internal dimension was high/normal and gender, baseline and increasing BMI, increasing SBP, and HR (inverse) were related. LV TDI was positively related to obesity (higher with adverse geometry). TAPSE was normal and related to higher baseline BMI and lower HR. There was no effect of T2D treatment on cardiac target organ injury. Adolescents with T2D have adverse measures of cardiac structure and function positively related to BMI and BP.

Coronary artery calcification in obese youth: what are the phenotypic and metabolic determinants?

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.

ß-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to type 2 diabetes.

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired ß-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled ß-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. ß-Cell function parameters were derived from established mathematical models yielding ß-cell glucose sensitivity (ßCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-ßCGS to the 2-h hyperglycemic clamp-ßCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, ßCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.

Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood.

Polycystic ovary syndrome (PCOS) is a prevalent hyperandrogenic infertility and cardiometabolic disorder that increases a woman's lifetime risk of type 2 diabetes mellitus. It is heritable and intensely familial. Progress toward a cure has been delayed by absence of an etiology. Evidence is mounting, however, for in utero T excess, together with gestational hyperglycemia, contributing to either early differentiation of PCOS or phenotypic amplification of its genotypes. Abnormal endocrine, ovarian, and hyperinsulinemic traits are detectable as early as 2 months of age in daughters of women with PCOS, with adiposity enhancement of hyperinsulinemia during childhood potentially contributing to hyperandrogenism and LH excess by adolescence. These findings encourage increasing clinical focus on early childhood markers for adiposity and hyperinsulinemia accompanying ovarian and adrenal endocrine abnormalities that precede a diagnosable PCOS phenotype. They raise the possibility for lifestyle or therapeutic intervention before and during pregnancy or during childhood and adolescence alleviating the manifestations of a familial genetic predisposition to PCOS.

In vivo insulin sensitivity and secretion in obese youth: what are the differences between normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes?

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.

Ghrelin and peptide YY in youth: are there race-related differences?

OBJECTIVE: Obesity prevalence is higher in African-American (AA) vs. American white (AW) youth. Ghrelin is a "hunger" peptide that is high preprandially and decreases postprandially, and peptide YY (PYY) is a "satiety" hormone increasing after meals. Impaired regulation of ghrelin/PYY may be conducive to obesity. We hypothesized that racial differences in childhood obesity could partly be explained by differences in ghrelin/PYY dynamics. RESEARCH DESIGN AND METHODS: We investigated: 1) ghrelin suppression/PYY elevation in response to an oral glucose tolerance test (OGTT) in AA vs. AW, and 2) the relationship of ghrelin and PYY dynamics to insulin sensitivity. Thirty-three AA and 54 AW prepubertal children underwent an OGTT measuring ghrelin, PYY, glucose, and insulin. Fasting glucose to insulin ratio (G(F)/I(F)) was used to assess the relationship of insulin sensitivity to fasting and post-OGTT ghrelin and PYY levels. RESULTS: OGTT-induced suppression in ghrelin (Delta ghrelin) was lower in AA youth. Delta ghrelin correlated with G(F)/I(F) (r = 0.47, P < 0.001) and Delta insulin at 30 min (r = -0.47, P < 0.001). In multiple regression analysis, race (P = 0.013) and G(F)/I(F) (P = 0.004) contributed independently to the variance in Delta ghrelin (R(2) = 0.28, P < 0.001). Fasting and post-OGTT PYY levels were lower in AAs and were not related to insulin sensitivity. CONCLUSION: The lower suppression of ghrelin in AA, but not the lower PYY levels, correlates with insulinemia and insulin resistance. Less ghrelin suppression and PYY elevation after a meal in black youth could be a potential mechanism of race-related differences in hunger/satiety predisposing to risk of obesity.

Ghrelin suppression in overweight children: a manifestation of insulin resistance?

Ghrelin levels increase before and decrease after meals, potentially playing a role in meal initiation and satiety in an inverse pattern to that of insulin. The role of ghrelin in childhood obesity, a state associated with hyperinsulinism and insulin resistance, is not fully understood. Therefore, the aims of the present study were to investigate the dynamics of ghrelin suppression after an oral glucose tolerance test (OGTT) in normal weight (NW) vs overweight (OW) children and the relationship of ghrelin suppression to insulin sensitivity. Thirty-seven NW (15 males and 22 females; 9.4 +/- 0.2 yr old) and 23 OW (13 males and 10 females; 9.4 +/- 0.3 yr old) prepubertal children underwent a 3-h OGTT with measurements of ghrelin, glucose, and insulin. The fasting glucose to insulin ratio and the whole body insulin sensitivity index were used to assess the relationship of insulin sensitivity to fasting ghrelin and ghrelin response to the OGTT, respectively. Fasting ghrelin levels were significantly lower in OW vs NW youth and were mainly influenced by insulin sensitivity independent of adiposity. OGTT-induced absolute suppression in ghrelin was approximately 50% less in OW vs NW children, resulting in a similar percent suppression from baseline in the two groups despite a significantly higher insulin response in OW. The suppression of ghrelin correlated positively with the whole body insulin sensitivity index (r = 0.43; P = 0.001) and negatively with the change in insulin at 30 min (r = -0.31; P = 0.02). Fasting ghrelin, the change in insulin, and the change in glucose during the OGTT were the significant independent variables contributing to the variance in absolute suppression of ghrelin (r2 = 0.42; P < 0.001). Only the change in glucose contributed significantly to the variance in the percent suppression of ghrelin (r2 = 0.14; P = 0.019). Fasting ghrelin and ghrelin suppression after OGTT are modulated by insulin sensitivity. Alterations in ghrelin suppression in OW children may be yet another manifestation of the insulin resistance of obesity. Whether this is responsible for differences in satiety in OW individuals merits additional investigation.