Abstract
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, β-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.
To examine the effect of different patterns of durable glycemic control on the development of comorbidities among youth with type 2 diabetes (T2D) and to assess the impact of fasting glucose (FG) ...variability on the clinical course of T2D.
From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 457 participants (mean age, 14 years) with mean diabetes duration <2 years at entry and a minimum study follow-up of 10 years were included in these analyses. HbA1c, FG concentrations, and β-cell function estimates from oral glucose tolerance tests were measured longitudinally. Prevalence of comorbidities by glycemic control status after 10 years in the TODAY study was assessed.
Higher baseline HbA1c concentration, lower β-cell function, and maternal history of diabetes were strongly associated with loss of glycemic control in youth with T2D. Higher cumulative HbA1c concentration over 4 years and greater FG variability over a year within 3 years of diagnosis were related to higher prevalence of dyslipidemia, nephropathy, and retinopathy progression over the subsequent 10 years. A coefficient of variability in FG ≥8.3% predicted future loss of glycemic control and development of comorbidities.
Higher baseline HbA1c concentration and FG variability during year 1 accurately predicted youth with T2D who will experience metabolic decompensation and comorbidities. These values may be useful tools for clinicians when considering early intensification of therapy.
Data related to diabetic neuropathy in youth with type 2 diabetes are limited. We examined the relationship of glycemic control, sex, race/ethnicity, BMI, and other type 2 diabetes-associated factors ...with the development of diabetic peripheral neuropathy (DPN) in youth with type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.
The Michigan Neuropathy Screening Instrument (MNSI) and a 10-g monofilament exam were performed annually. DPN was defined as a score (>2) on the MNSI-exam or combined MNSI-exam and MNSI-survey scores (exam >2 and/or survey ≥4), or monofilament exam (<8 of 10 correct responses) at two or more consecutive visits. Multivariable time-to-event models assessed the association of risk factors evaluated longitudinally with DPN events.
A total of 674 participants (35% male), with a mean age of 14 years and diabetes duration <2 years at study entry, were evaluated annually over an average of 10.2 years. Male subjects had a significantly higher cumulative incidence of DPN than female subjects (38.5% vs. 27.2% via MNSI-exam,
= 0.002; 14.0% vs. 5.1% via monofilament exam,
= 0.01). Rates did not differ by race/ethnicity. Higher HbA
and BMI were associated with higher DPN, by both MNSI and the monofilament test. In multivariable models, male sex, older age, and higher BMI were associated with MNSI-exam DPN risk.
DPN was evident early in the course of youth-onset type 2 diabetes and increased over time. It was higher in male subjects and related to glycemic control. These findings raise concern for long-term development of neuropathy-related morbidity in youth with type 2 diabetes and the need to achieve improved glycemic control.
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.
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.
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.
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.
To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy.
TODAY was a randomized clinical trial ...of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: (1) those who remained in glycemic control for at least 48 months of follow-up and (2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C-peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points.
In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio PLR 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1).
Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non-diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control.
Little is known about the impact of early attainment of tight glycemic control on long-term β-cell function and glycemic control in youth-onset type 2 diabetes. We examined the effect of the initial ...6 months of glycemic control on β-cell function and glycemic control longitudinally over 9 years and the impact of sex, race/ethnicity, and BMI on these relationships in adolescents with youth-onset type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
Oral glucose tolerance tests were performed longitudinally through year 9 to derive estimates of insulin sensitivity and secretion. Early glycemia was defined by mean HbA1c during the first 6 months postrandomization, categorized into five HbA1c groups (<5.7%, 5.7 to <6.4%, 6.4 to <7.0%, 7.0 to <8.0%, and ≥8.0%). The long-term period was defined as the period between years 2 and 9.
A total of 656 participants (64.8% female, baseline mean age 14 years, diabetes duration <2 years) had longitudinal data available over an average of 6.4 ± 3.2 years of follow-up. HbA1c significantly increased in all early glycemic groups during years 2-9, with a steeper increase (+0.40%/year) among participants with the tightest initial control (mean early HbA1c <5.7%), in parallel to a decline in the C-peptide-derived disposition index. Nevertheless, the lower HbA1c categories continued to have relatively lower HbA1c over time.
Early tight glycemic control in the TODAY study was related to β-cell reserve and translated to better long-term glycemic control. However, tight early glycemic control on the randomized treatment in the TODAY study did not prevent deterioration of β-cell function.
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.
Objective
To examine the stability of severe pediatric obesity relative to moderate obesity and associated changes in cardiometabolic risk from the beginning of 6th to the end of 8th grade.
Methods
...Participants in HEALTHY, a multi‐site, cluster randomized school‐based study designed to mitigate risk for type 2 diabetes, completed standardized assessments of height, weight, glucose, insulin, lipids, and blood pressure at the beginning of 6th grade and the end of 8th grade. Youth were classified as moderately obese (100‐119% of the 95th percentile of BMI for age and gender) or severely obese (≥120% of the 95th percentile of BMI for age and gender). Generalized linear mixed models (GLMM) that controlled for relevant covariables were used to examine the relation between baseline demographic and cardiometabolic risk factors and BMI status, as well as changes in relative weight category and risk factors during middle school.
Results
Severe obesity was more likely to endure over the course of middle school than was moderate obesity, and was associated with significantly higher levels of cardiometabolic risk.
Conclusions
Research with a specific focus on understanding, preventing, and treating severe obesity in children is warranted.
Too many reports of associations between genetic variants and common cancer sites and other complex diseases are false positives. A major reason for this unfortunate situation is the strategy of ...declaring statistical significance based on a P value alone, particularly, any P value below.05. The false positive report probability (FPRP), the probability of no true association between a genetic variant and disease given a statistically significant finding, depends not only on the observed P value but also on both the prior probability that the association between the genetic variant and the disease is real and the statistical power of the test. In this commentary, we show how to assess the FPRP and how to use it to decide whether a finding is deserving of attention or "noteworthy." We show how this approach can lead to improvements in the design, analysis, and interpretation of molecular epidemiology studies. Our proposal can help investigators, editors, and readers of research articles to protect themselves from overinterpreting statistically significant findings that are not likely to signify a true association. An FPRP-based criterion for deciding whether to call a finding noteworthy formalizes the process already used informally by investigators--that is, tempering enthusiasm for remarkable study findings with considerations of plausibility.
To compare OGTT-derived estimates of β-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE.
...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 β-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.
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, β-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, β-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline β-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms.
After treatment withdrawal youth demonstrated progressive decline in β-cell function after stopping treatment with either G/M or MET. In contrast, β-cell function in adults remained stable despite an increase in HbA1c over time.
ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.
PDF
