Circulating MicroRNAs as Predictors of Beta Cell Function in Youth-Onset Type 2 Diabetes: The TODAY study.

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.

Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes.

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.

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial.

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.

Application of desirability of outcome ranking to the milking in non-vigorous infants trial.

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.

Trajectories of eGFR and risk of albuminuria in youth with type 2 diabetes: results from the TODAY cohort study.

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.

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

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

Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial.

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.

Maternal Diabetes in Youth-Onset Type 2 Diabetes Is Associated With Progressive Dysglycemia and Risk of Complications.

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.

Cardiometabolic Risk Factors and Incident Cardiovascular Disease Events in Women vs Men With Type 1 Diabetes.

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.

Weight loss and ß-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial.

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

Deterioration of Glycemic Control in Youth-Onset Type 2 Diabetes: What Are the Early and Late Predictors?

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 HbA1c ≥ 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 of ≥ 6.2% was optimally predictive of loss of glycemic control at any time, while an absolute rise in HbA1c > 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.

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

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

Longitudinal changes in vascular stiffness and heart rate variability among young adults with youth-onset type 2 diabetes: results from the follow-up observational treatment options for type 2 diabetes in adolescents and youth (TODAY) study.

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.

Differential loss of ß-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study.

AIMS: To compare OGTT-derived estimates of ß-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE. METHODS: Youth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and ß-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm. RESULTS: After treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, ß-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, ß-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline ß-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms. CONCLUSIONS: After treatment withdrawal youth demonstrated progressive decline in ß-cell function after stopping treatment with either G/M or MET. In contrast, ß-cell function in adults remained stable despite an increase in HbA1c over time. ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.

OGTT Glucose Response Curves, Insulin Sensitivity, and ß-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve ß-Cell Function.

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.

Consumption of Beverages Containing Low-Calorie Sweeteners, Diet, and Cardiometabolic Health in Youth With Type 2 Diabetes.

BACKGROUND: Low-calorie sweetened beverages (LCSBs) are commonly used as a lower-calorie alternative to sugar-sweetened beverages (SSBs) by individuals with type 2 diabetes. However, little is known about how intake of LCSBs is related to dietary intake and cardiometabolic health, particularly among youth. OBJECTIVE: To test the hypothesis that having higher baseline LCSB intake and increasing LCSB intake over 2 years of follow-up are associated with poorer dietary intake and higher cardiometabolic risk factors among youth enrolled in the Treatment Option for Type 2 Diabetes in Adolescents and Youth (TODAY) study. DESIGN: Secondary, exploratory, analysis of baseline and longitudinal data from the TODAY study, which was a randomized, multisite trial conducted from 2004 to 2012, to compare effects of 3 interventions (metformin alone, metformin + rosiglitazone, and metformin + intensive lifestyle intervention) on glycemic control in youth with type 2 diabetes. PARTICIPANTS/SETTING: The study included 476 children and adolescents (10-17 years, mean body mass index 34.9 ± 7.8 kg/m2), who were participants in the multicenter (n = 15) TODAY study. MAIN OUTCOME MEASURES: Diet was assessed using a food frequency questionnaire. Differences in energy intake, macronutrients, food group intakes, and cardiometabolic biomarkers were evaluated in 3 groups of LCSB consumers at baseline (low [1-4 servings/wk], medium [5-11 servings/wk], and high [≥12 servings/wk]), each compared with nonconsumers, and between 4 groups of change in LCSB intake (nonconsumption at start of study and nonconsumption after 2 years, increase in consumption after 2 years, decrease in consumption after 2 years, and high consumption at start of study and high consumption after 2 years). STATISTICAL ANALYSES PERFORMED: Multivariable linear regression was performed at baseline and longitudinally over 2 years of follow-up. RESULTS: Energy (kilocalories), fiber, carbohydrate, total fat, saturated fat, and protein intake (grams) were higher among high LCSB consumers compared with nonconsumers at baseline. No associations were observed between LCSB consumption and cardiometabolic risk factors at baseline. Change in LCSB intake between baseline and follow-up was not associated with change in energy intake or cardiometabolic risk factors. Participants who decreased LCSB consumption reported greater increases in sugar intake (18.4 ± 4.8 g) compared with those who increased LCSB consumption (5.7 ± 4.9 g) or remained high LCSB consumers (5.9 ± 7.4 g), but this trend was not statistically significant after a correction for multiple testing. CONCLUSIONS: LCSB consumption was associated with higher energy intake in youth with type 2 diabetes, with the highest energy intakes reported in high LCSB consumers. Those who reduced LCSB consumption tended to report greater increases in sugar intake during follow-up, but further studies are needed to better understand this trend.

Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure.

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.

Adherence to multiple medications in the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) cohort: effect of additional medications on adherence to primary diabetes medication.

Background Non-adherence to diabetes medication leads to poor outcomes and increased healthcare costs. Multiple factors affecting adherence in adults with type 2 diabetes (T2D) have been identified, but pediatric data is sparse. We aimed to determine whether initiation of additional oral medications or insulin affects adherence to primary study medication (PSM) in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods Six hundred and ninety-nine youth (aged 10-17 years) with recent-onset T2D were randomized in the TODAY study. Participants were categorized as adherent (≥80% taken by pill count) or non-adherent (<80%), and adherence was compared between those on additional medications or not. Subgroup analyses to assess influence of race/ethnicity, gender, medication type, or depression were performed. Results At 36 months, 46.3% of participants were taking additional oral medications and 31.9% were on insulin. There was no difference in study medication adherence with additional oral medications (55.1%, 67.1%, and 56.7% at month 36 in those prescribed 0, 1, or 2+ additional medications; p = 0.16). Girls on oral contraceptives (OC) had higher adherence (65.2% vs. 55.8% at month 36; p = 0.0054). Participants on insulin had lower adherence (39.7% vs. 59.3% at 36 months; p < 0.0001). There was decreased adherence in participants with baseline depression (p = 0.008). Conclusions Additional oral medications did not influence adherence to diabetes medications in TODAY. Addition of insulin led to reduced adherence. In subgroup analyses, OC use was associated with higher adherence in girls, while baseline depression was associated with lower adherence overall. Further studies examining potentially modifiable risk factors of adherence in pediatric T2D are needed.

Heart Rate Variability and Cardiac Autonomic Dysfunction: Prevalence, Risk Factors, and Relationship to Arterial Stiffness in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study.

OBJECTIVE: To determine whether prior type 2 diabetes (T2D) treatment or glycemic control over time are independently associated with heart rate variability (HRV) and whether the presence of cardiac autonomic dysfunction is associated with arterial stiffness in young adults with youth-onset T2D enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS: Heartbeats over 10 min were measured to derive the normal R-Rs (NN intervals). Outcomes included the standard deviation of the NN intervals (SDNN), the root mean square differences of successive NN intervals (RMSSD), percent of NN beats that differ by more than 50 ms (PNN50), and the low-frequency (LF) power domain, high-frequency (HF) power domain, and their ratio (LF:HF). Autonomic dysfunction was defined as ≥3 of 5 abnormal HRV indices compared with obese controls from a separate study. RESULTS: A total of 397 TODAY participants were evaluated 7 years after randomization. TODAY participants had reduced HRV (SDNN 58.1 ± 29.6 ms vs. controls 67.1 ± 25.4 ms; P < 0.0001) with parasympathetic loss (RMSSD 53.2 ± 36.7 ms vs. controls 67.9 ± 35.2 ms; P < 0.0001) with sympathetic overdrive (LF:HF ratio 1.4 ± 1.7 vs. controls 1.0 ± 1.1; P < 0.0001). Cardiac autonomic dysfunction was present in 8% of TODAY participants, and these participants had greater pulse wave velocity compared with those without dysfunction (P = 0.0001). HRV did not differ by randomized treatment, but higher hemoglobin A1c (HbA1c) over time was independently associated with lower SDNN and RMSSD and higher LF:HF ratio after adjustment for age, race-ethnicity, sex, and BMI. CONCLUSIONS: Young adults with youth-onset T2D show evidence of cardiac autonomic dysfunction with both parasympathetic and sympathetic impairments that are associated with higher HbA1c.

Predictors of response to insulin therapy in youth with poorly-controlled type 2 diabetes in the TODAY trial.

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.