RESUMEN

OBJECTIVE: To evaluate the relationship of free 25 hydroxy vitamin D [free 25(OH)D] or bioavailable vitamin D (BioD) concentrations to insulin sensitivity and cardiovascular disease risk markers in normal weight and overweight youth. STUDY DESIGN: Cross-sectional study of 79 adolescents 15.4 ± 0.2 years, 18 normal weight, 30 overweight, and 31 overweight with prediabetes who underwent peripheral arterial tonometry, dual-energy x-ray absorptiometry, and hyperinsulinemic-euglycemic clamp in subset (n = 71) for determination of reactive hyperemia index (RHI), body composition, and insulin sensitivity. 25(OH)D and vitamin D binding protein were measured; free 25(OH)D and BioD were calculated. RESULTS: Across tertiles of free 25(OH)D concentrations (4.0 ± 0.2, 7.5 ± 0.3, and 17.0 ± 2.1 pg/mL, P < .001), the group in the lowest tertile had significantly higher percent body fat (37.8 ± 1.1, 35.2 ± 1.5 and 25.3 ± 2.1%, P < .001), lower insulin sensitivity (4.4 ± 0.4, 6.7 ± 1.2, and 8.2 ± 0.9 mg/kg fat-free mass/minute per µu/mL, P = .03), lower RHI (1.42 ± 0.06, 1.54 ± 0.06, and 1.77 ± 0.09, P = .002), higher high-sensitivity C-reactive protein (3.4 ± 0.6, 1.7 ± 0.3, and 1.6 ± 0.4 mg/L, P = .015) compared with the second and third tertiles, respectively. Free 25(OH)D levels were inversely related to percent body fat and high-sensitivity C-reactive protein, and positively related to RHI and insulin sensitivity. The relationships of free 25(OH)D to RHI and to insulin sensitivity were no longer significant after adjusting for %body fat. Similar relationships were observed for BioD. CONCLUSIONS: Youth with low free 25(OH)D or BioD concentrations have lower insulin sensitivity and worse endothelial function and inflammatory biomarkers compared with those with more sufficient 25(OH)D. However, the effects of vitamin D on these biomarkers may not be independent of the effect of adiposity.

Asunto(s)

Adiposidad , Endotelio Vascular/metabolismo , Resistencia a la Insulina , Sobrepeso/sangre , Vitamina D/análogos & derivados , Adolescente , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Hiperemia/sangre , Masculino , Estado Prediabético/sangre , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Proteína de Unión a Vitamina D/sangre

RESUMEN

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

Asunto(s)

Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Intolerancia a la Glucosa/metabolismo , Glucosa/metabolismo , Peso Corporal Ideal/fisiología , Resistencia a la Insulina , Obesidad Infantil/metabolismo , Adiposidad/fisiología , Adolescente , Glucemia/metabolismo , Niño , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/epidemiología , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Obesidad Infantil/complicaciones , Obesidad Infantil/epidemiología , Adulto Joven

RESUMEN

OBJECTIVE: Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired ß-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in ß-cell function. RESEARCH DESIGN AND METHODS: OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (△C30/△G30), and ß-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups. RESULTS: At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity. CONCLUSIONS: In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced ß-cell function and foretells increased glycemic failure rates with accelerated deterioration in ß-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes.

Asunto(s)

Glucemia/metabolismo , Prueba de Tolerancia a la Glucosa , Células Secretoras de Insulina/metabolismo , Adolescente , Péptido C/sangre , Niño , Diabetes Mellitus Tipo 2/sangre , Ayuno , Femenino , Humanos , Insulina/sangre , Resistencia a la Insulina , Estudios Longitudinales , Masculino , Obesidad/sangre

RESUMEN

OBJECTIVES: Data regarding atherogenic dyslipidemia and the inflammation profile in youth with type 2 diabetes is limited and the effect of insulin therapy on these variables has not previously been studied in youth. We determined the impact of insulin therapy on lipid and inflammatory markers in youth with poorly controlled type 2 diabetes. STUDY DESIGN: In the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) multicenter trial, 285 participants failed to sustain glycemic control on randomized treatment (primary outcome, glycated hemoglobin A1c [HbA1c] at ≥8% for 6 months); 363 maintained glycemic control (never reached primary outcome). Statins were used for a low-density lipoprotein cholesterol of ≥130 mg/dL. Upon reaching the primary outcome, insulin was started. Changes in lipids and inflammatory markers (slopes over time) were examined. RESULTS: Progression of dyslipidemia was related to glycemic control. In those with the primary outcome, insulin therapy impacted HbA1c modestly, and dampened the increase in total cholesterol, low-density lipoprotein cholesterol, and total apolipoprotein B, although statin use increased from 8.6% to 22% year after the primary outcome. The increase in triglycerides and plasma nonesterified fatty acids stabilized after insulin was started, independent of HbA1c. There was an increase in high-sensitivity C-reactive protein that continued after insulin initiation, related to HbA1c and percent overweight. CONCLUSIONS: Worsening dyslipidemia and inflammation over time raise concern regarding premature development of atherosclerosis in youth with type 2 diabetes. Insulin therapy has a limited benefit in the absence of glycemic control. Strategies to achieve better glycemic control are needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00081328.

Asunto(s)

Diabetes Mellitus Tipo 2/sangre , Dislipidemias/sangre , Insulina/uso terapéutico , Lípidos/sangre , Adolescente , Glucemia/análisis , Niño , LDL-Colesterol/sangre , Progresión de la Enfermedad , Femenino , Hemoglobina Glucada/análisis , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación , Masculino

RESUMEN

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.

Asunto(s)

Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/sangre , Resistencia a la Insulina/fisiología , Encuestas Nutricionales , Adolescente , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Estudios de Seguimiento , Tasa de Filtración Glomerular , Hemoglobina Glucada/metabolismo , Humanos , Morbilidad/tendencias , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Factores de Tiempo , Estados Unidos

RESUMEN

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.

Asunto(s)

Biomarcadores/sangre , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Adolescente , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico por imagen , Enfermedades Cardiovasculares/fisiopatología , Niño , Terapia Combinada , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Dietoterapia , Quimioterapia Combinada , Ecocardiografía , Terapia por Ejercicio , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Factores de Riesgo , Rosiglitazona , Tiazolidinedionas/uso terapéutico , Resultado del Tratamiento , Función Ventricular Izquierda

RESUMEN

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

Asunto(s)

Tejido Adiposo/metabolismo , Intolerancia a la Glucosa/metabolismo , Resistencia a la Insulina , Células Secretoras de Insulina/fisiología , Lipólisis , Obesidad/metabolismo , Adolescente , Femenino , Glucosa/metabolismo , Humanos , Masculino

Asunto(s)

Tejido Adiposo , Pericardio

RESUMEN

OBJECTIVE: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated that glycemic failure rates in the three treatments combined-metformin plus rosiglitazone, metformin alone, and metformin plus lifestyle-were higher in non-Hispanic blacks (NHB; 52.8%) versus non-Hispanic whites (NHW; 36.6%) and Hispanics (H; 45.0%). Moreover, metformin alone was less effective in NHB versus NHW versus H youth. This study describes treatment-associated changes in adiponectin, insulin sensitivity, and ß-cell function over time among the three racial/ethnic groups to understand potential mechanism(s) responsible for this racial/ethnic disparity. RESEARCH DESIGN AND METHODS: TODAY participants underwent periodic oral glucose tolerance tests to determine insulin sensitivity, C-peptide index, and oral disposition index (oDI), with measurements of total and high-molecular-weight adiponectin (HMWA). RESULTS: At baseline NHB had significantly lower HMWA than NHW and H and exhibited a significantly smaller increase (17.3% vs. 33.7% vs. 29.9%, respectively) during the first 6 months overall. Increases in HMWA were associated with reductions in glycemic failure in the three racial/ethnic groups combined (hazard ratio 0.61, P < 0.0001) and in each race/ethnicity separately. Over time, HMWA was significantly lower in those who failed versus did not fail treatment, irrespective of race/ethnicity. There were no differences in treatment-associated temporal changes in insulin sensitivity, C-peptide index, and oDI among the three racial/ethnic groups. CONCLUSIONS: HMWA is a reliable biomarker of treatment response in youth with type 2 diabetes. The diminutive treatment-associated increase in HMWA in NHB (∼50% lower) compared with NHW and H may explain the observed racial/ethnic disparity with higher therapeutic failure rates in NHB in TODAY.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/etnología , Etnicidad/estadística & datos numéricos , Disparidades en el Estado de Salud , Hipoglucemiantes/administración & dosificación , Adiponectina/sangre , Adolescente , Población Negra/estadística & datos numéricos , Glucemia/efectos de los fármacos , Péptido C/análisis , Niño , Diabetes Mellitus Tipo 2/fisiopatología , Combinación de Medicamentos , Femenino , Prueba de Tolerancia a la Glucosa , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Resistencia a la Insulina/fisiología , Estilo de Vida , Masculino , Metformina/administración & dosificación , Tiazoles/administración & dosificación , Insuficiencia del Tratamiento , Población Blanca/estadística & datos numéricos

RESUMEN

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.

Asunto(s)

Adiposidad/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Endotelio/fisiopatología , Resistencia a la Insulina/fisiología , Sobrepeso/fisiopatología , Tejido Adiposo , Adolescente , Biomarcadores/metabolismo , Niño , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Sobrepeso/complicaciones , Adulto Joven

RESUMEN

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.

Asunto(s)

Composición Corporal , Capacidad Cardiovascular , Diabetes Mellitus Tipo 2/fisiopatología , Ventrículos Cardíacos/anatomía & histología , Función Ventricular Izquierda , Adolescente , Niño , Estudios Transversales , Diástole , Femenino , Humanos , Masculino , Sístole , Adulto Joven

RESUMEN

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.

Asunto(s)

Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Prueba de Tolerancia a la Glucosa , Obesidad Infantil/sangre , Adiposidad , Adolescente , Composición Corporal , Índice de Masa Corporal , Péptido C/sangre , Estudios Transversales , Femenino , Polipéptido Inhibidor Gástrico/sangre , Glucagón/sangre , Péptido 1 Similar al Glucagón/sangre , Hemoglobina Glucada/metabolismo , Humanos , Incretinas/sangre , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Factores de Riesgo

RESUMEN

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.

Asunto(s)

Diabetes Mellitus Tipo 2/metabolismo , Incretinas/metabolismo , Células Secretoras de Insulina/metabolismo , Obesidad/metabolismo , Adolescente , Femenino , Intolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Masculino , Estado Prediabético/metabolismo

RESUMEN

OBJECTIVE: To compare indices of insulin secretion, insulin sensitivity (IS), and oral disposition index (oDI) during the liquid mixed-meal test in obese youth with clinically diagnosed type 2 diabetes mellitus (T2DM) and negative autoantibodies (Ab(-)) versus those with T2DM and positive autoantibodies (Ab(+)) to examine whether differences in ß-cell function can be detected between the 2 groups. STUDY DESIGN: Twenty-seven youth with Ab(-) and 15 youth with Ab(+) clinically diagnosed T2DM underwent a mixed-meal test (Boost; 55% carbohydrate, 25% protein, and 20% fat). Fasting and mixed-meal-derived insulin and C-peptide indices of IS, secretion (30-minute insulinogenic [ΔI(30)/ΔG(30)] and C-peptide [ΔC(30)/ΔG(30)]), and oDI were calculated. RESULTS: Indices of insulin secretion were ~40%-50% lower in patients with Ab(+) T2DM compared with those with Ab(-) T2DM. After controlling for body mass index, ΔI(30)/ΔG(30), ΔC(30)/ΔG(30), C-peptide area under the curve (AUC)/glucose AUC, and insulin AUC/glucose AUC were significantly (P < .05) lower in the Ab(+) group compared with the Ab(-) group. Sensitivity indices were significantly higher in the Ab(+) group. The oDI, 1/fasting insulin × ΔI(30)/ΔG(30) (0.04 ± 0.02 vs 0.12 ± 0.02 mg/dL(-1); P = .005), and 1/fasting C-peptide × ΔC(30)/ΔG(30) (0.02 ± 0.009 vs 0.05 ± 0.006 mg/dL(-1); P = .018) were lower in the Ab(+) group. Receiver operating characteristic curve analyses revealed that fasting C-peptide <3.2 ng/mL had 87% sensitivity and 74% specificity and ΔC(30)/ΔG(30) <0.075 ng/mL per mg/dL had 93% sensitivity and 80% specificity for identifying youth with Ab(+) T2DM. CONCLUSION: During a liquid mixed-meal test, indices of ß-cell function were lower and IS was higher in patients with Ab(+) T2DM versus those with Ab(-) T2DM, with high sensitivity and specificity for fasting and stimulated C-peptide as markers of Ab(+) status. Indices of insulin secretion during this standardized mixed-meal test could be used to assess ß-cell function in therapeutic trials of ß-cell restoration in youth with T2DM.

Asunto(s)

Glucemia/análisis , Péptido C/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Obesidad/metabolismo , Adolescente , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Resistencia a la Insulina , Secreción de Insulina , Masculino , Comidas

RESUMEN

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

Asunto(s)

Diabetes Mellitus/metabolismo , Técnica de Clampeo de la Glucosa , Obesidad/metabolismo , Estado Prediabético/metabolismo , Adolescente , Femenino , Humanos , Masculino

RESUMEN

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.

Asunto(s)

Prueba de Tolerancia a la Glucosa/métodos , Resistencia a la Insulina/fisiología , Células Secretoras de Insulina/metabolismo , Insulina/sangre , Insulina/metabolismo , Sobrepeso/metabolismo , Péptido C/sangre , Niño , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Secreción de Insulina , Masculino , Reproducibilidad de los Resultados

RESUMEN

OBJECTIVES: To examine the prevalence of the metabolic syndrome using different pediatric definitions reported in the literature and its relationship to abdominal adipose tissue (AT), in vivo insulin resistance, and inflammatory biomarkers in children and adolescents, as well as the utility of fasting insulin and adiponectin as predictors of the metabolic syndrome. STUDY DESIGN: Cross-sectional measurements were obtained from 122 African Americans and 129 Caucasians age 8 to 19 years. Insulin sensitivity (IS) was measured by a 3-h hyperinsulinemic-euglycemic clamp. Blood pressure, fasting lipids, adiponectin, interleukin (IL)-6, adhesion molecules (intercellular adhesion molecule [ICAM]-1, vascular cell adhesion molecule [VCAM]-1, and E-selectin), and abdominal AT were measured. RESULTS: Regardless of the metabolic syndrome criteria used, the prevalence of the metabolic syndrome was higher in overweight (24% approximately 51%) compared with non-overweight youths (1% approximately 3%) in both African Americans and Caucasians (P <.01). Youths with the metabolic syndrome had higher visceral AT and fasting insulin and lower IS and adiponetin independent of race (P < .01). In Caucasians, youths with the metabolic syndrome had higher levels of inflammatory biomarkers (IL-6, ICAM-1, and E-selectin). The area under the receiver operating curve (AUC) for insulin was 0.86 approximately 0.89 in African Americans and 0.86 approximately 0.89 in Caucasians, depending on the metabolic syndrome criteria used. For adiponetin, the AUC was 0.73 approximately 0.78 in African Americans and 0.81 approximately 0.86 in Caucasians. CONCLUSIONS: The prevalence of metabolic syndrome varies depending on the definition used in the literature. Thus, there is a need for a unified definition of this syndrome in children and adolescents to streamline the research in this area. Independent of race, visceral obesity, insulin resistance, hyperinsulinemia, and hypoadiponectinemia are the common characteristics of youths with the metabolic syndrome. In Caucasians but not in African Americans, the metabolic syndrome is associated with increased inflammatory markers; however, the translation of such findings remains to be determined based on long-term longitudinal outcome studies in different racial groups.

Asunto(s)

Grasa Abdominal/patología , Adiponectina/biosíntesis , Regulación de la Expresión Génica , Síndrome Metabólico/complicaciones , Síndrome Metabólico/diagnóstico , Pediatría/métodos , Grasa Abdominal/metabolismo , Adolescente , Adulto , Biomarcadores , Niño , Diagnóstico Diferencial , Femenino , Humanos , Inflamación , Resistencia a la Insulina , Masculino , Obesidad/complicaciones , Pediatría/normas

RESUMEN

OBJECTIVES: To examine whether waist circumference (WC) predicts blood pressure (BP) and lipid components of the metabolic syndrome independent of body mass index (BMI) percentile in youths. STUDY DESIGN: The study group comprised 70 African-American youths and 97 Caucasian youths. Outcome measures included BP, lipid profile, and abdominal adipose tissue (AT). RESULTS: Both BMI percentile and WC were significantly (P < .05) associated with daytime and nighttime systolic and diastolic BP, triglycerides (TG), high-density lipoprotein (HDL), and TG/HDL ratio independent of race. In African-Americans and Caucasians, WC remained a significant (P < .05) correlate of daytime (r = .50 and .59, respectively) and nighttime (r = .49 and .62, respectively) systolic BP, and in Caucasians, TG, HDL, TG/HDL, and very-low-density lipoprotein after controlling for BMI percentile. After accounting for age, sex, and race, the addition of WC to BMI percentile increased the variance (R(2)) in systolic BP by 15% (P < .05). The inclusion of WC with BMI percentile explained an additional 3% and 7% of the variance in TG and HDL, respectively (P < .05). CONCLUSIONS: The prediction of childhood obesity-related health risks is significantly improved by the inclusion of WC in addition to BMI percentile. This observation supports the notion that WC should be included in the evaluation of childhood obesity along with BMI percentile to identify those at increased health risks due to excess abdominal fat.

Asunto(s)

Presión Sanguínea , Pesos y Medidas Corporales , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Grasa Abdominal , Adolescente , Niño , Femenino , Humanos , Lipoproteínas HDL/sangre , Masculino , Triglicéridos/sangre

RESUMEN

OBJECTIVES: We examined how well waist circumference (WC) reflects total and abdominal fat and whether WC predicts insulin resistance independent of body mass index (BMI) percentile in youths. STUDY DESIGN: Body composition was measured by dual-energy x-ray absorptiometry and abdominal adiposity by computed tomography. Insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp. RESULTS: Both BMI percentile and WC were significantly associated (P < .01) with total and abdominal fat and insulin sensitivity. WC remained a significant (P < .01) correlate of total and abdominal fat and insulin sensitivity after controlling for BMI percentile. By contrast, BMI percentile did not remain a significant correlate of visceral fat and markers of insulin resistance after controlling for WC. Without exception, WC explained a greater variance in abdominal fat and metabolic profiles than did BMI percentile. CONCLUSIONS: Our findings suggest that the prediction of health risks associated with obesity in youths is improved by the additional inclusion of WC measure to the BMI percentile. Such observations would reinforce the importance of including WC in the assessment of childhood obesity to identify those at increased metabolic risk due to excess abdominal fat.

Asunto(s)

Población Negra , Resistencia a la Insulina/fisiología , Relación Cintura-Cadera , Población Blanca , Absorciometría de Fotón , Tejido Adiposo/diagnóstico por imagen , Adolescente , Glucemia/análisis , Índice de Masa Corporal , Niño , Femenino , Humanos , Insulina/sangre , Masculino , Obesidad/sangre , Obesidad/fisiopatología , Pennsylvania , Proinsulina/sangre , Radiografía Abdominal , Análisis de Regresión , Tomografía Computarizada por Rayos X