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BACKGROUND: Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits. OBJECTIVE: We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks' gestation. STUDY DESIGN: This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks' gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept. RESULTS: Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41-1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33-0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24-0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62-1.06), or a serious adverse event composite of death before discharge. CONCLUSION: Among nonvigorous infants born at 35 to 42 weeks' gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.
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Doenças do Recém-Nascido , Clampeamento do Cordão Umbilical , Cordão Umbilical , Feminino , Humanos , Recém-Nascido , Gravidez , Transfusão de Sangue , Constrição , Estudos Cross-Over , Hemoglobinas , Hipóxia-Isquemia Encefálica/etiologia , Recém-Nascido Prematuro , Placenta , Cordão Umbilical/cirurgia , Clampeamento do Cordão Umbilical/métodos , Doenças do Prematuro/cirurgia , Doenças do Prematuro/terapia , Doenças do Recém-Nascido/cirurgia , Doenças do Recém-Nascido/terapiaRESUMO
BACKGROUND: We conducted exploratory analyses to identify distinct trajectories of estimated glomerular filtration rate (eGFR) and their relationship with hyperfiltration, subsequent rapid eGFR decline, and albuminuria in participants with youth-onset type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Annual serum creatinine, cystatin C, urine albumin, and creatinine measurements were obtained from 377 participants followed for ≥ 10 years. Albuminuria and eGFR were calculated. Hyperfiltration peak is the greatest eGFR inflection point during follow-up. Latent class modeling was applied to identify distinct eGFR trajectories. RESULTS: At baseline, participants' mean age was 14 years, type 2 diabetes duration was 6 months, mean HbA1c was 6%, and mean eGFR was 120 ml/min/1.73 m2. Five eGFR trajectories associated with different rates of albuminuria were identified, including a "progressive increasing eGFR" group (10%), three "stable eGFR" groups with varying starting mean eGFR, and an "eGFR steady decline" group (1%). Participants who exhibited the greatest peak eGFR also had the highest levels of elevated albuminuria at year 10. This group membership was characterized by a greater proportion of female and Hispanic participants. CONCLUSIONS: Distinct eGFR trajectories that associate with albuminuria risk were identified, with the eGFR trajectory characterized by increasing eGFR over time associating with the highest level of albuminuria. These descriptive data support the current recommendations to estimate GFR annually in young persons with type 2 diabetes and provide insight into eGFR-related factors which may contribute to predictive risk strategies for kidney disease therapies in youth with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00081328, date registered 2002. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Feminino , Adolescente , Diabetes Mellitus Tipo 2/complicações , Estudos de Coortes , Taxa de Filtração Glomerular , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Albuminúria/etiologia , Albuminúria/complicações , Seguimentos , Fatores de Risco , Progressão da DoençaRESUMO
OBJECTIVE: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and ß-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and ß-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and ß-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. ß-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS: In TODAY, ß-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Obesidade Infantil , Adolescente , Criança , Terapia Combinada , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Quimioterapia Combinada , Feminino , Glucoquinase/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Estilo de Vida , Estudos Longitudinais , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Mutação , Obesidade Infantil/complicações , Obesidade Infantil/tratamento farmacológico , Obesidade Infantil/metabolismo , Obesidade Infantil/fisiopatologia , Comportamento de Redução do Risco , Rosiglitazona/administração & dosagem , Rosiglitazona/efeitos adversosRESUMO
OBJECTIVE: To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin + rosiglitazone or metformin + lifestyle in the TODAY study. METHODS: Change in HbA1c after add-on insulin therapy and the factors predictive of glycemic response were evaluated. At 1-year postinsulin initiation, 253 youth had a mean of 3.9 ± 1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change <0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. RESULTS: Within 1-year postinsulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c <0.5%, and 20.6% had an increase ≥0.5%. At randomization into TODAY and at time of insulin initiation, the three glycemia groups were similar in age, sex, race-ethnicity, pubertal stage, BMI z-score, diabetes duration, and insulin secretion indices. Consistent HbA1c improvement was associated with higher insulin sensitivity (1/fasting insulin) at randomization and at time of failure, higher adiponectin at randomization, and was not associated with indices of ß-cell function. CONCLUSIONS: Response to add-on insulin was highly variable among youth in TODAY. Greater insulin sensitivity and higher adiponectin concentrations at randomization were associated with improved glycemic control after initiation of insulin. Due to limited information on adherence to insulin injections, the roles of adherence to the prescribed insulin regimen or psychosocial factors are unknown.
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Biomarcadores Farmacológicos/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Adiponectina/análise , Adiponectina/sangue , Adolescente , Biomarcadores Farmacológicos/análise , Glicemia/efeitos dos fármacos , Criança , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Resistência à Insulina/fisiologia , Masculino , Prognóstico , Falha de Tratamento , Resultado do TratamentoRESUMO
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.
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Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Adolescente , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/fisiopatologia , Criança , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Dietoterapia , Quimioterapia Combinada , Ecocardiografia , Terapia por Exercício , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Fatores de Risco , Rosiglitazona , Tiazolidinedionas/uso terapêutico , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
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.
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Diabetes Mellitus Tipo 2/sangue , Dislipidemias/sangue , Insulina/uso terapêutico , Lipídeos/sangue , Adolescente , Glicemia/análise , Criança , LDL-Colesterol/sangue , Progressão da Doença , Feminino , Hemoglobinas Glicadas/análise , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação , MasculinoRESUMO
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.
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Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Resistência à Insulina/fisiologia , Inquéritos Nutricionais , Adolescente , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Progressão da Doença , Seguimentos , Taxa de Filtração Glomerular , Hemoglobinas Glicadas/metabolismo , Humanos , Morbidade/tendências , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados UnidosRESUMO
BACKGROUND: Little is known about the feasibility and impact of lifestyle intervention, determined by change in diet and cardiovascular fitness (CRF), on glycemic control in youth who are overweight with type 2 diabetes. This was examined in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial cohort from across 15 US centers. SUBJECTS: TODAY enrolled 699 youth aged 10 to 17 years with type 2 diabetes <2 years and body mass index ≥85th percentile at baseline. METHODS: Dietary data were collected by an interviewer-administered food frequency questionnaire; CRF was assessed using a submaximal cycle ergometer test. Change from baseline in these variables was analyzed using generalized linear mixed models for both continuous and categorical measures. Models were adjusted for age, baseline HbA1c, treatment group, and medication adherence. Data were collected at baseline, 6, and 24 months. Trial registration ClinicalTrials.gov NCT00081328. RESULTS: At 6 months, ~25% of females and ~33% of males improved CRF. In males, this was related to a decreased HbA1c (P = .001) and a lower percent experiencing glycemic failure (HbA1c ≥8%; P = .007). Females who decreased their saturated fat intake and/or increased their fiber intake had lower HbA1c at month 24 (P = .01 and P = .007, respectively). Males who increased their sweetened beverage intake at 6-month follow-up were at a 1.6-fold higher risk of experiencing glycemic failure (P = .04). CONCLUSIONS: Few youth improved fitness and/or diet over time, although those who did showed a beneficial impact on glycemic outcomes. Although lifestyle behaviors are difficult to change in youth with type 2 diabetes, interventions are needed that are feasible (in scope, complexity, and demands), sustainable, and clinically meaningful.
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Diabetes Mellitus Tipo 2/psicologia , Comportamento de Redução do Risco , Adolescente , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Dieta , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Aptidão FísicaRESUMO
OBJECTIVE: To examine the relationships between stressful life events and physiological measures, adherence to prescribed oral medication regimens, depressive symptoms, and impaired quality of life (QoL) in adolescents with recent-onset type 2 diabetes (T2D). STUDY DESIGN: Data were collected from 497 ethnically diverse participants (66% female) in the final year of the Treatment Options for Type 2 Diabetes in Adolescents and Youth multicenter clinical trial. Exposure to 32 possible events over the previous year and rating of subsequent distress were collected by self-report and summarized as a major stressors score. This score was analyzed for relationship to glycemic control (hemoglobin A1c and treatment failure), body mass index, diagnosis of hypertension or triglyceride dyslipidemia, adherence to a prescribed oral medication regimen, presence of depressive symptoms, and impaired QoL. RESULTS: The total number of major stressful life events in the adolescents with T2D was calculated, with 33% reporting none, 67% reporting ≥ 1, 47% reporting ≥ 2, 33% reporting ≥ 3, and 20% reporting ≥ 4. There were no associations between the major stressors score and physiological measures or diagnosis of comorbidities. The odds of medication nonadherence increased significantly from those reporting ≥ 1 major stressor (OR, 1.58; P = .0265) to those reporting ≥ 4 major stressors (OR, 2.70; P = .0009). Significant odds of elevated depressive symptoms and impaired QoL were also found with increased reporting of major stressors. CONCLUSION: Exposure to major stressful life events is associated with lower adherence to prescribed oral medication regimens and impaired psychosocial functioning in adolescents with T2D.
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Diabetes Mellitus Tipo 2 , Acontecimentos que Mudam a Vida , Adesão à Medicação/psicologia , Adesão à Medicação/estatística & dados numéricos , Adolescente , Criança , Depressão/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/psicologia , Feminino , Humanos , Masculino , Qualidade de Vida , Adulto JovemRESUMO
AIMS: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome (HbA1c ≥ 8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with decline in beta cell function. METHODS: Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. RESULTS: Using a backward selection approach, four baseline miRNA log2 fold changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p < 0.05). Increased levels of miRNA-155 (OR:1.2, 95%CI:1.1-1.4) and miRNA-130b (OR:1.3, 95%CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.6, 95%CI: 0.4-0.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R = 0.22, p < 0.01 and R = 0.19, p < 0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60- months (R = 0.26, p < 0.01, R = 0.26, p < 0.01, R = 0.18, p < 0.01, respectively). CONCLUSIONS: The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.
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OBJECTIVES: Neonatal trials have traditionally used binary composite short-term (such as death or bronchopulmonary dysplasia) or longer-term (such as death or severe neurodevelopmental impairment) outcomes. We applied the Desirability Of Outcome Ranking (DOOR) method to rank the overall patient outcome by best (no morbidities) to worst (death). STUDY DESIGN: Using a completed large multicenter trial (Milking In Non-Vigorous Infants [MINVI]) of umbilical cord milking (UCM) vs. early cord clamping (ECC), we applied the DOOR methodology to neonatal outcomes. Six outcomes were chosen and ranked: no interventions or NICU admission (most desirable); received initial cardiorespiratory support at birth; neonatal intensive care unit (NICU) admission for predefined criteria; mild hypoxic-ischemic encephalopathy (HIE); moderate to severe HIE; and death (least desirable). RESULTS: 1524 non-vigorous newborns born between 35 and 42 weeks' gestation had data for analysis. The DOOR distribution was different between the UCM and ECC arms, with a significantly greater probability (55.8 % [95 % CI 53.1-58.5 %; p < 0.0001]) of a randomly selected neonate having a more desirable outcome if they were in the UCM arm. DOOR probabilities of averting individual adverse outcomes such as NICU admission for predefined criteria (52.8 %; 95%CI 50.5-55.1 %) and cardiorespiratory support (54.0 %; 95%CI 51.6-56.4 %) were significantly higher among those in the UCM group. CONCLUSION: DOOR provides an overall assessment of the benefits and harms with greater insight than typical binary composite measures to clinicians and parents when evaluating an intervention. Future neonatal trials should consider the a priori use of the DOOR methodology to evaluate trial outcomes.
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Recém-Nascido Prematuro , Cordão Umbilical , Humanos , Recém-Nascido , Lactente , Idade Gestacional , ConstriçãoRESUMO
Importance: Youth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk. Objective: To identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D. Design, Setting, and Participants: This post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023. Exposure: Plasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1). Main Outcomes and Measures: Main outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index). Results: This analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P < .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (ß [SE], 0.015 [0.003]; P < .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (ß [SE], -0.02 [0.006]; P < .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (ß [SE], 431 [156]; P = .007). Conclusions and Relevance: This study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00081328.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Adulto , Feminino , Adolescente , Humanos , Hormônio do Crescimento , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Fator de Crescimento Insulin-Like I , Diabetes Mellitus Tipo 2/tratamento farmacológico , Controle Glicêmico , Adiponectina , Peptídeo C , Hemoglobinas Glicadas , Metformina/uso terapêuticoRESUMO
OBJECTIVE: We aimed to identify metabolites associated with loss of glycemic control in youth-onset type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured 480 metabolites in fasting plasma samples from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study. Participants (N = 393; age 10-17 years) were randomly assigned to metformin, metformin plus rosiglitazone, or metformin plus lifestyle intervention. Additional metabolomic measurements after 36 months were obtained in 304 participants. Cox models were used to assess baseline metabolites, interaction of metabolites and treatment group, and change in metabolites (0-36 months), with loss of glycemic control adjusted for age, sex, race, treatment group, and BMI. Metabolite prediction models of glycemic failure were generated using elastic net regression and compared with clinical risk factors. RESULTS: Loss of glycemic control (HbA1c ≥8% or insulin therapy) occurred in 179 of 393 participants (mean 12.4 months). Baseline levels of 33 metabolites were associated with loss of glycemic control (q < 0.05). Associations of hexose and xanthurenic acid with treatment failure differed by treatment randomization; youths with higher baseline levels of these two compounds had a lower risk of treatment failure with metformin alone. For three metabolites, changes from 0 to 36 months were associated with loss of glycemic control (q < 0.05). Changes in d-gluconic acid and 1,5-AG/1-deoxyglucose, but not baseline levels of measured metabolites, predicted treatment failure better than changes in HbA1c or measures of ß-cell function. CONCLUSIONS: Metabolomics provides insight into circulating small molecules associated with loss of glycemic control and may highlight metabolic pathways contributing to treatment failure in youth-onset diabetes.
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OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.
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Importance: Compared with early cord clamping (ECC), umbilical cord milking (UCM) reduces delivery room cardiorespiratory support, hypoxic-ischemic encephalopathy, and therapeutic hypothermia in nonvigorous near-term and full-term infants. However, UCM postdischarge outcomes are not known. Objective: To determine the 2-year outcomes of children randomized to UCM or ECC at birth in the Milking in Nonvigorous Infants (MINVI) trial. Design, Setting, and Participants: A secondary analysis to evaluate longer-term outcomes of a cluster-randomized crossover trial was conducted from January 9, 2021, to September 25, 2023. The primary trial took place in 10 medical centers in the US, Canada, and Poland from January 5, 2019, to June 1, 2021, and hypothesized that UCM would reduce admission to the neonatal intensive care unit compared with ECC; follow-up concluded September 26, 2023. The population included near-term and full-term infants aged 35 to 42 weeks' gestation at birth who were nonvigorous; families provided consent to complete developmental screening questionnaires through age 2 years. Intervention: UCM and ECC. Main Outcomes and Measures: Ages and Stages Questionnaire, 3rd Edition (ASQ-3) and Modified Checklist for Autism in Toddlers, Revised/Follow-Up (M-CHAT-R/F) questionnaires at ages 22 to 26 months. Intention-to-treat analysis and per-protocol analyses were used. Results: Among 1730 newborns from the primary trial, long-term outcomes were evaluated in 971 children (81%) who had ASQ-3 scores available at 2 years or died before age 2 years and 927 children (77%) who had M-CHAT-R/F scores or died before age 2 years. Maternal and neonatal characteristics by treatment group were similar, with median birth gestational age of 39 (IQR, 38-40) weeks in both groups; 224 infants (45%) in the UCM group and 201 (43%) in the ECC group were female. The median ASQ-3 total scores were similar (UCM: 255 [IQR, 225-280] vs ECC: 255 [IQR, 230-280]; P = .87), with no significant differences in the ASQ-3 subdomains. Medium- to high-risk M-CHAT-R/F scores were also similar (UCM, 9% [45 of 486] vs ECC, 8% [37 of 441]; P = .86). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial among late near-term and full-term infants who were nonvigorous at birth, ASQ-3 scores at age 2 years were not significantly different between the UCM and ECC groups. Combined with previously reported important short-term benefits, this follow-up study suggests UCM is a feasible, no-cost intervention without longer-term neurodevelopmental risks of cord milking in nonvigorous near-term and term newborns. Trial Registration: ClinicalTrials.gov Identifier: NCT03631940.
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Clampeamento do Cordão Umbilical , Humanos , Feminino , Recém-Nascido , Masculino , Lactente , Clampeamento do Cordão Umbilical/métodos , Estudos Cross-Over , Cordão Umbilical , Hipóxia-Isquemia Encefálica/terapia , Pré-EscolarRESUMO
CONTEXT: Prenatal exposures, including undernutrition, overnutrition, and parental diabetes, are recognized risk factors for future cardiometabolic disease. There are currently no data on effects of parental diabetes on disease progression or complications in youth-onset type 2 diabetes (T2D). OBJECTIVE: We analyzed effects of parental diabetes history on glycemic outcomes, ß-cell function, and complications in a US cohort of youth-onset T2D. METHODS: Participants (N = 699) aged 10 to 17 years with T2D were enrolled at 15 US centers and followed for up to 12 years as part of the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) and TODAY2 follow-up studies. Information about diabetes diagnosis in biological mothers was available for 621 participants (never = 301; before or during pregnancy = 218; after pregnancy = 102) and in biological fathers for 519 (no diabetes = 352; paternal diabetes = 167). RESULTS: Maternal, but not paternal, diabetes was associated with loss of glycemic control over time, defined as glycated hemoglobin A1c greater than or equal to 8% for more than 6 months (P = .001). Similarly, maternal, but not paternal, diabetes was associated with increased risk of glomerular hyperfiltration (P = .01) and low heart rate variability (P = .006) after 12 years of follow-up. Effects were largely independent of age, sex, race/ethnicity, and household income. Maternal diabetes during vs after pregnancy had similar effects on outcomes. CONCLUSION: Maternal diabetes, regardless of whether diagnosed during vs after pregnancy, is associated with worse glycemic control, glomerular hyperfiltration, and reduced heart rate variability in youth with T2D in TODAY. The strong associations of diabetes outcomes with maternal diabetes suggest a possible role for in utero programming.
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Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Masculino , Gravidez , Feminino , Humanos , Adolescente , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Gestacional/epidemiologia , Fatores de Risco , Hemoglobinas Glicadas , SeguimentosRESUMO
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.
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Diabetes Mellitus Tipo 2 , Nefropatias , Humanos , Masculino , Adolescente , Feminino , Diabetes Mellitus Tipo 2/complicações , Albuminúria/urina , Análise de Onda de Pulso , Taxa de Filtração Glomerular , Biomarcadores/urina , Fatores de RiscoRESUMO
OBJECTIVE: We examined predictors of early and late loss of glycemic control in individuals with youth-onset type 2 diabetes, as well as predictors of short-term deterioration in youth from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Demographic, physical, and biochemical measures at baseline and 48 months, and change over time, were examined in 584 participants separated into those with loss of glycemic control (sustained HbA1câ ≥â 8%) before 48 months or at 48 months or later, and those who remained in control until the end of the study (median 6.8 years). Univariate and multivariate models, and receiver operating characteristic curve analyses were performed. RESULTS: Approximately 45% of youth remained in control at 48 months; of these, 30% subsequently lost glycemic control prior to the end of follow-up. Predictors of early loss of glycemic control included baseline HbA1c, C-peptide index, oral disposition index, proinsulin, and proinsulin to insulin ratio. Predictors of late loss included baseline measures of insulin secretion and change in HbA1c and insulin processing at 48 months. A baseline HbA1c cutoff ofâ ≥â 6.2% was optimally predictive of loss of glycemic control at any time, while an absolute rise in HbA1câ >â 0.5% related to loss of glycemic control within 3 to 6 months. CONCLUSION: This analysis demonstrates that youth with type 2 diabetes at risk for loss of glycemic control, including impending rapid deterioration, can be identified using available clinical measures, allowing for closer monitoring of at-risk youth, and facilitating the design of research on better therapeutic options.
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Diabetes Mellitus Tipo 2 , Controle Glicêmico , Falha de Tratamento , Adolescente , Idade de Início , Glicemia/análise , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , ProinsulinaRESUMO
Importance: The lower risk of cardiovascular disease (CVD) among women compared with men in the general population may be diminished among those with diabetes. Objective: To evaluate cardiometabolic risk factors and their management in association with CVD events in women vs men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Design, Setting, and Participants: This cohort study used data obtained during the combined DCCT (randomized clinical trial, conducted 1983-1993) and EDIC (observational study, conducted 1994 to present) studies through April 30, 2018 (mean [SD] follow-up, 28.8 [5.8] years), at 27 clinical centers in the US and Canada. Data analyses were performed between July 2021 and April 2022. Exposure: During the DCCT phase, patients were randomized to intensive vs conventional diabetes therapy. Main Outcomes and Measures: Cardiometabolic risk factors and CVD events were assessed via detailed medical history and focused physical examinations. Blood and urine samples were assayed centrally. CVD events were adjudicated by a review committee. Linear mixed models and Cox proportional hazards models evaluated sex differences in cardiometabolic risk factors and CVD risk over follow-up. Results: A total of 1441 participants with type 1 diabetes (mean [SD] age at DCCT baseline, 26.8 [7.1] years; 761 [52.8%] men; 1390 [96.5%] non-Hispanic White) were included. Over the duration of the study, compared with men, women had significantly lower body mass index (BMI, calculated as weight in kilograms divided by height in meters squared; ß = -0.43 [SE, 0.16]; P = .006), waist circumference (ß = -10.56 cm [SE, 0.52 cm]; P < .001), blood pressure (systolic: ß = -5.77 mm Hg [SE, 0.35 mm Hg]; P < .001; diastolic: ß = -3.23 mm Hg [SE, 0.26 mm Hg]; P < .001), and triglyceride levels (ß = -10.10 mg/dL [SE, 1.98 mg/dL]; P < .001); higher HDL cholesterol levels (ß = 9.36 mg/dL [SE, 0.57 mg/dL]; P < .001); and similar LDL cholesterol levels (ß = -0.76 mg/dL [SE, 1.22 mg/dL]; P = .53). Women, compared with men, achieved recommended targets more frequently for blood pressure (ie, <130/80 mm Hg: 90.0% vs 77.4%; P < .001) and triglycerides (ie, <150 mg/dL: 97.3% vs 90.5%; P < .001). However, sex-specific HDL cholesterol targets (ie, ≥50 mg/dL for women, ≥40 mg/dL for men) were achieved less often (74.3% vs 86.6%; P < .001) and cardioprotective medications were used less frequently in women than men (ie, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker: 29.6% [95% CI, 25.7%-33.9%] vs 40.0% [95% CI, 36.1%-44.0%]; P = .001; lipid-lowering medication: 25.3% [95% CI, 22.1%-28.7%] vs 39.6% [95% CI, 36.1%-43.2%]; P < .001). Women also had significantly higher pulse rates (mean [SD], 75.2 [6.8] beats per minute vs 71.8 [6.9] beats per minute; P < .001) and hemoglobin A1c levels (mean [SD], 8.3% [1.0%] vs 8.1% [1.0%]; P = .01) and achieved targets for tighter glycemic control less often than men (ie, hemoglobin A1c <7%: 11.2% [95% CI, 9.3%-13.3%] vs 14.0% [95% CI, 12.0%-16.3%]; P = .03). Conclusions and Relevance: These findings suggest that despite a more favorable cardiometabolic risk factor profile, women with type 1 diabetes did not have a significantly lower CVD event burden than men, suggesting a greater clinical impact of cardiometabolic risk factors in women vs men with diabetes. These findings call for conscientious optimization of the control of CVD risk factors in women with type 1 diabetes.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 1 , Adulto , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , HDL-Colesterol , Estudos de Coortes , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Fatores de Risco , Adulto JovemRESUMO
AIMS: (1) To describe changes in arterial stiffness and heart rate variability (HRV) over a 5-year interval, (2) examine changes by sex and race-ethnicity, and (3) evaluate the risk factors associated with the longitudinal changes in arterial stiffness and HRV. METHODS: Participants with youth-onset type 2 diabetes enrolled in the observational follow-up phase of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial had arterial stiffness [(pulse wave velocity, augmentation index, brachial distensibility] and six indices of HRV measured 5 years apart. Multivariable linear regression models assessed risk factors associated with changes in the outcomes over time. RESULTS: At initial vascular assessment, the 304 participants were a mean age of 21 years, 34% male, and had a mean diabetes duration of 8 years. In more than half the cohort pulse wave velocity, augmentation index and HRV increased over 5 years (p<0.01). Brachial distensibility did not change. There were no differences in the 5-year change by race/ethnicity except for a single HRV measure, where non-Hispanic Blacks had greater worsening of parasympathetic function compared to non-Hispanic Whites, p = 0.008. Blood pressure was related to greater worsening in augmentation index and pulse wave velocity. Higher hemoglobin A1c over time was related to worsening pulse wave velocity and HRV. CONCLUSIONS: Arterial stiffness and HRV worsened over 5 years. Blood pressure and glycemic control may be potential targets to influence adverse changes in arterial stiffness and HRV in young adults with youth-onset type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328.