RESUMO
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.
Assuntos
Albuminúria , Diabetes Mellitus Tipo 2 , Taxa de Filtração Glomerular , Peptídeos Semelhantes ao Glucagon , Fragmentos Fc das Imunoglobulinas , Proteinúria , Proteínas Recombinantes de Fusão , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Adolescente , Criança , Proteinúria/fisiopatologia , Masculino , Feminino , Albuminúria/fisiopatologia , Proteínas Recombinantes de Fusão/uso terapêutico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Hipoglicemiantes/uso terapêutico , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/tratamento farmacológicoRESUMO
OBJECTIVE: To investigate whether prediction equations including a limited but selected number of anthropometrics that consider differences in subcutaneous abdominal adipose tissue may improve prediction of the visceral adipose tissue (VAT) in youth. STUDY DESIGN: Anthropometrics and abdominal adipose tissue by MRI were available in 7-18 years old youth with overweight or obesity: 181 White Europeans and 186 White and Black Americans. Multivariable regressions were performed to develop and validate the VAT anthropometric predictive equations in a cross-sectional study. RESULTS: A model with both waist circumference (WaistC) and hip circumference (HipC) (VAT = [1.594 × WaistC] - [0.681 × HipC] + [1.74 × Age] - 48.95) more strongly predicted VAT in girls of White European ethnicity (R2 = 50.8%; standard error of the estimate [SEE] = 13.47 cm2), White American ethnicity (R2 = 41.9%; SEE, 15.63 cm2), and Black American ethnicity (R2 = 25.1%; SEE, 16.34 cm2) (P < .001), than WaistC or BMI. In boys, WaistC was the strongest predictor of VAT; HipC did not significantly improve VAT prediction. CONCLUSIONS: A model including both WaistC and HipC that considers differences in subcutaneous abdominal adipose tissue more accurately predicts VAT in girls and is superior to commonly measured anthropometrics used individually. In boys, other anthropometric measures did not significantly contribute to the prediction of VAT beyond WaistC alone. This demonstrates that selected anthropometric predictive equations for VAT can be an accessible, cost-effective alternative to imaging methods that can be used in both clinics and research.
Assuntos
Gordura Intra-Abdominal , Obesidade , Masculino , Feminino , Humanos , Adolescente , Pessoa de Meia-Idade , Criança , Gordura Intra-Abdominal/diagnóstico por imagem , Estudos Transversais , Antropometria/métodos , Sobrepeso , Índice de Massa Corporal , Tecido AdiposoRESUMO
OBJECTIVE: To use combined glycemic (HbA1c) and BMI z-score (BMIZ) trajectories spanning the coronavirus disease 2019 (COVID-19) pandemic to identify high-risk subgroups of adolescents with diabetes. RESEARCH DESIGN AND METHODS: Retrospective cohort of adolescents 10-19 years old with type 1 and type 2 diabetes with one or more visits at a large pediatric hospital from January 2018 through February 2020 (prepandemic) and April 2020 through August 2021 (pandemic). Group-based trajectory models were used to identify latent classes of combined BMIZ and HbA1c trajectories. Multinomial logistic regression was used to evaluate predictors of class membership, including Area Deprivation Index (ADI) (socioeconomic status proxy). RESULTS: The cohort included 1,322 youth with type 1 diabetes (93% White and 7% Black) and 59 with type 2 diabetes (53% Black and 47% White). For type 1 diabetes, six trajectory classes emerged. Black youth were more likely to be in the class with worsening glycemic control and concurrent BMIZ decrease at pandemic onset (relative risk ratio [RRR] vs. White: 3.0 [95% CI 1.3-6.8]) or in the class with progressively worsening glycemic control and obesity (RRR 3.0 [95% CI 1.3-6.8]), while those from the most deprived neighborhoods (RRR ADI tertile 3 vs. 1: 1.9 [95% CI 1.2-2.9]) were more likely to be in the class with stable obesity and glycemic control. For type 2 diabetes, three distinct trajectories emerged, two of which experienced worsening glycemic control with concurrent BMIZ decline at pandemic onset. CONCLUSIONS: Race and neighborhood deprivation were independently associated with distinct glycemic and BMIZ trajectory classes in youth with diabetes, highlighting persistent and widening disparities associated with the COVID-19 pandemic.
Assuntos
COVID-19 , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Criança , Humanos , Adolescente , Adulto Jovem , Adulto , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Estudos Retrospectivos , Pandemias , Hemoglobinas Glicadas , Índice de Massa Corporal , Controle Glicêmico , COVID-19/complicações , Obesidade/complicaçõesRESUMO
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 ß-cell function (ßCF) 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 ßCF 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). ßCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher ßCF 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 ß-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of ß-cell dysfunction in youth with this least favorable glucose response curve.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Resistência à Insulina , Células Secretoras de Insulina , Adolescente , Adulto , Glicemia , Estudos Transversais , Glucose , Teste de Tolerância a Glucose , Humanos , Insulina , Distribuição AleatóriaRESUMO
OBJECTIVE: To examine whether a combined aerobic exercise and resistance exercise is more effective than either aerobic exercise or resistance exercise alone in improving insulin sensitivity and reducing total adiposity and ectopic fat in adolescents. STUDY DESIGN: A total of 118 sedentary adolescents with overweight/obesity (body mass index >85th percentile, 12-17 years) were recruited from October 2013 through April 2017 at Children's Hospital of Pittsburgh. Participants were randomized to 1 of the following 6-month exercise groups (3 d/wk, 180 min/wk): aerobic exercise (n = 38), resistance exercise (n = 40), and combined aerobic exercise and resistance exercise (n = 40). The primary outcome was the change in insulin-stimulated glucose disposal by a 3-hour hyperinsulinemic-euglycemic clamp. The secondary outcomes were changes in liver fat by proton magnetic resonance spectroscopy and intermuscular adipose tissue by computed tomography. RESULTS: Of the 118 participants randomized, 85 participants (72%) completed the study with 90% exercise attendance. Total adiposity reduced similarly in all groups (-2%, P < .05). After adjusting for age and sex, insulin-stimulated glucose disposal increased (P < .05) in all groups, with the increase in the aerobic exercise group being greater than the resistance exercise group (1.7 ± 0.1 vs 0.7 ± 0.1 mg/kg/min, P < .05) but not different from the combined group (1.2 ± 0.1 mg/kg/min). Liver fat was reduced (P < .05) in the aerobic exercise (-0.6%) and combined (-0.6%) groups but not in the resistance exercise group (-0.3%, P > .05). Intermuscular adipose tissue decreased (P < .05) similarly in all groups. CONCLUSION: Combined aerobic exercise and resistance exercise and aerobic exercise alone are similarly beneficial in improving insulin sensitivity and reducing ectopic fat in adolescents with obesity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938950.
Assuntos
Exercício Físico , Resistência à Insulina , Sobrepeso/sangue , Sobrepeso/terapia , Obesidade Infantil/sangue , Obesidade Infantil/terapia , Tecido Adiposo/patologia , Adiposidade , Adolescente , Antropometria , Índice de Massa Corporal , Criança , Dieta , Terapia por Exercício , Fígado Gorduroso/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Comportamento SedentárioRESUMO
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.
Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Peso Corporal Ideal/fisiologia , Resistência à Insulina , Obesidade Infantil/metabolismo , Adiposidade/fisiologia , Adolescente , Glicemia/metabolismo , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Intolerância à Glucose/complicações , Intolerância à Glucose/epidemiologia , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Obesidade Infantil/complicações , Obesidade Infantil/epidemiologia , Adulto JovemRESUMO
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 (â³C30/â³G30), 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.
Assuntos
Glicemia/metabolismo , Teste de Tolerância a Glucose , Células Secretoras de Insulina/metabolismo , Adolescente , Peptídeo C/sangue , Criança , Diabetes Mellitus Tipo 2/sangue , Jejum , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Estudos Longitudinais , Masculino , Obesidade/sangueRESUMO
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.