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 m
2
. 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.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
To assess pregnancy outcomes in young women with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
Pregnancy information ...(outcome and any maternal or fetal complications) was obtained from the female participants by self-report. Additionally, medical records for the pregnancy and the child's neonatal course were obtained with data abstracted into standardized forms.
Over a maximum of 15 years, 260 pregnancies were reported by 141 women (aged 21.5 ± 3.2 years, BMI 35.6 ± 7.2 kg/m
, and diabetes duration 8.1 ± 3.2 years). Contraception use prior to pregnancy was reported by 13.5% of the women. Complications were reported by 65% of the women during their pregnancy. Pregnancy loss was observed in 25.3% and preterm birth in 32.6% of pregnancies. HbA
≥8% was observed in 31.9% of the pregnancies, and 35% of the pregnancies were complicated by chronic hypertension. Nephropathy prior to pregnancy was observed in 25% of the women. In the offspring, 7.8% were classified as small for gestational age, 26.8% large for gestational age, and 17.9% in the macrosomic range.
Based on observations from the TODAY cohort, young women with pregestational, youth-onset type 2 diabetes had very high rates of maternal complications stemming from significant socioeconomic disadvantage. The substantial maternal and infant complications seen in these young moms could potentially be avoided with improved contraception rates and reproductive planning.
This analysis compared microvascular and cardiac outcomes from women in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, originally diagnosed with youth-onset Type 2 ...diabetes between the ages of 10-17 yrs, who experienced a pregnancy lasting 20 wks during the course of the study vs. those without. Pregnancy information was obtained prospectively by self-report followed by medical record review. Neuropathy and nephropathy were assessed annually. Retinopathy, echocardiography, and arterial stiffness were assessed twice during the study. Women with a history of pregnancy prior to the initial assessment were excluded. Of the 4women in TODAY, 116 reported a pregnancy lasting ≥ 20 weeks, with 67 having a single pregnancy and 49 with multiple pregnancies. The mean age at first pregnancy was 21.6 yrs. and mean diabetes duration 8 yrs. At study entry, women who reported a pregnancy during the trial were older (14 yrs. vs. 13.6 yrs., p=0.05) with lower household income (51.5% vs. 37.8% below $25,000, p=0.002) . Primary study outcome, defined as HbA1c >8% or inability to wean from insulin, was similar between the two groups. In Cox regression models adjusted for participant characteristics from study entry including age, race/ethnicity, household income, diabetes duration, HbA1c (>6%) , and BMI, women with a pregnancy had an increased risk of hyperfiltration, 2.76 (1.38-5.49) , p=0.0vs. those without a pregnancy. No differences were observed in rates of retinopathy, neuropathy, or macro- and microalbuminuria in women with vs. without a history of pregnancy. In fully adjusted models, history of pregnancy did not impact echocardiographic measures or arterial stiffness obtained prior to the reported pregnancy versus the measures after the pregnancy. These results suggest that pregnancy increases the risk of hyperfiltration in women with youth-onset T2D, but not other micro or macrovascular complications.
Disclosure
J.B.Tryggestad: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. S.Chernausek: None. K.Drews: None. E.N.Escaname: None. M.Geffner: Advisory Panel; Novo Nordisk, Pfizer Inc., Research Support; Novo Nordisk. E.M.Isganaitis: Research Support; AstraZeneca, Dexcom, Inc., Insulet Corporation.
Funding
U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254
•Microvascular complications in type 2 diabetes during pregnancy are inconsistent.•Women with youth onset T2D have higher rates of hyperfiltration after pregnancy.•Risk for micro- or macrovascular ...complications was not increased after pregnancy.•Complications are high in youth with T2D, but pregnancy did not increase the risk.
To examine the impact of pregnancy on microvascular and cardiovascular measures in women with youth-onset T2D.
Microvascular and cardiovascular measures were compared in in a cohort of 116 women who experienced a pregnancy of ≥ 20 weeks gestation and 291 women who did not among women in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
Cox regression models adjusted for participant characteristics at baseline including age, race/ethnicity, household income, diabetes duration, HbA1c (>6%), and BMI, demonstrated those who experienced pregnancy had 2.76 (1.38–5.49; p = 0.004) fold increased risk of hyperfiltration (eGFR ≥ 135 ml/min/1.73 m2), compared to those without a pregnancy. No differences were observed in rates of retinopathy (48.9% vs. 41.1%) or neuropathy (23.3% vs. 16.3%) in women who experienced pregnancy vs. women who did not, respectively. In fully adjusted models, pregnancy did not impact changes in echocardiographic or arterial stiffness compared to changes in women who were never pregnant.
These results indicate that pregnancy increases the risk of hyperfiltration in women with youth-onset T2D, but not other micro or macrovascular complications. The rates of vascular complications are very high in youth-onset T2D potentially obscuring micro- and macrovascular changes attributable to pregnancy.
Clinical Trial Information: ClinicalTrials.gov numbers,NCT01364350andNCT02310724.
Obesity and diabetes mellitus are directly implicated in many adverse health consequences in adults as well as in the offspring of obese and diabetic mothers. Hispanic Americans are particularly at ...risk for obesity, diabetes, and end-stage renal disease. Maternal obesity and/or diabetes through prenatal programming may alter the fetal epigenome increasing the risk of metabolic disease in their offspring. The aims of this study were to determine if maternal obesity or diabetes mellitus during pregnancy results in a change in infant methylation of CpG islands adjacent to targeted genes specific for obesity or diabetes disease pathways in a largely Hispanic population.
Methylation levels in the cord blood of 69 newborns were determined using the Illumina Infinium MethylationEPIC BeadChip. Over 850,000 different probe sites were analyzed to determine whether maternal obesity and/or diabetes mellitus directly attributed to differential methylation; epigenome-wide and regional analyses were performed for significant CpG sites.
Following quality control, agranular leukocyte samples from 69 newborns (23 normal term (NT), 14 diabetes (DM), 23 obese (OB), 9 DM/OB) were analyzed for over 850,000 different probe sites. Contrasts between the NT, DM, OB, and DM/OB were considered. After correction for multiple testing, 15 CpGs showed differential methylation from the NT, associated with 10 differentially methylated genes between the diabetic and non-diabetic subgroups, CCDC110, KALRN, PAG1, GNRH1, SLC2A9, CSRP2BP, HIVEP1, RALGDS, DHX37, and SCNN1D. The effects of diabetes were partly mediated by the altered methylation of HOOK2, LCE3C, and TMEM63B. The effects of obesity were partly mediated by the differential methylation of LTF and DUSP22.
The presented data highlights the associated altered methylation patterns potentially mediated by maternal diabetes and/or obesity. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the effects on newborn body composition and future health risk factors for metabolic disease. Additional future consideration should be targeted to the role of Hispanic inheritance. Potential future targeting of transgenerational propagation and developmental programming may reduce population obesity and diabetes risk.
Diabetes exposure during pregnancy affects health outcomes in offspring; however, little is known about in utero exposure to preexisting parental youth-onset type 2 diabetes. Offspring born to ...participants during the Treatment Options for Type 2 Diabetes in Adolescent and Youth (TODAY) study were administered a questionnaire at the end of the study. Of 457 participants, 37% of women and 18% of men reported 228 offspring, 80% from female participants. TODAY mothers had lower household income (<$25,000) compared to TODAY fathers (69.4% vs. 37.9%, p = 0.0002). At 4.5 years of age (range 0–18 years), 16.7% of offspring were overweight according to the parental report of their primary care provider, with no sex difference. Offspring of TODAY mothers reported more daily medication use compared to TODAY fathers (50/183, 27.7% vs. 6/46, 12.2%, p = 0.04), a marker of overall health. TODAY mothers also reported higher rates of recidivism (13/94) than TODAY fathers (0/23). An Individualized Education Plan was reported in 20/94 (21.3%) offspring of TODAY mothers compared to 2/23 (8.7%) of TODAY fathers. This descriptive study, limited by parental self-reports, indicated offspring of participants in TODAY experience significant socioeconomic disadvantages, which, when combined with in utero diabetes exposure, may increase their risk of health and educational disparities.
To report the prevalence of depression, eating disorder symptoms, and impaired health-related quality of life (HRQOL) and examine their longitudinal associations with glycemia and diabetes ...complications in young adults with youth-onset type 2 diabetes.
Participants recruited over a 4-year period were enrolled at 15 clinical diabetes centers in the follow-up observational Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY2) study. From 2014-2020, prevalence of symptoms of depression, eating disorders, and HRQOL by sex, race/ethnicity, and baseline family income were assessed annually. Longitudinal relationships between assessments of glycemia and complications with psychiatric symptoms and HRQOL were evaluated in adjusted models.
Participants (n = 514) were 21.7 ± 2.5 years old with a diabetes duration of 8.6 ± 1.5 years in year 1 of TODAY 2 (2014). Symptoms of depression and impaired HRQOL were common and increased significantly over 6 years (14.0% to 19.2%, P = 0.003; and 13.1% to 16.7%, P = 0.009, respectively). Depression and impaired HRQOL were more common in women and those with lower baseline family income but did not differ by race/ethnicity. Rates of binge eating were stable over time; self-reported purging increased. Over time, symptoms of depression were associated with higher HbA1c, hypertension, and retinopathy progression; impaired HRQOL was associated with higher BMI, systolic blood pressure, hypertension, and retinopathy progression; and symptoms of eating disorders were associated with higher BMI.
Significant psychiatric symptoms and impaired HRQOL are common among emerging adults with youth-onset type 2 diabetes and are positively associated with glycemia, hypertension, and retinopathy progression in this group that is at ongoing risk for medical morbidity.
The worrisome rise in pediatric type 2 diabetes (T2DM) is most prevalent among minority ethnic/racial populations. Typically, T2DM occurs during puberty in high risk obese adolescents with evidence ...of insulin resistance. Screening for T2DM in obese youth can be a daunting task for pediatricians and differentiating between pediatric T1DM and T2DM in obese youth can be challenging for pediatric endocrinologists. There is very limited data regarding the prevalence of T2DM among youth < 10 years of age. Here we present the case of a 5‐year‐old Hispanic male diagnosed with T2DM after referral by his pediatrician for abnormal weight gain, acanthosis nigricans and an elevated HbgA1c. He subsequently became symptomatic for diabetes with confirmed hyperglycemia and HbgA1c of 9.7% (83 mmol/mol) at the time of formal diagnosis. Type 1 diabetes autoantibodies (GAD65, Islet, and ZincT8) and monogenic diabetes genetic tests were negative. Due to elevated liver enzymes and baseline HbgA1c, he received basal insulin as his initial therapy. In this paper, we will discuss this case and present an IRB approved retrospective review of the characteristics of the 20 T2DM patients <10 years of age identified to date in our pediatric diabetes center. This review highlights that while uncommon, the diagnosis of T2DM merits consideration even in prepubertal children. This is especially true when working with a high risk population, such as our Hispanic South Texas youth.
The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study reported a 13.9% prevalence of diabetic retinopathy (DR) in youth with mean ± SD type 2 diabetes duration of 4.9 ± 1.5 ...years. After 7 years of additional follow-up, we report the risk factors for progression of DR in the TODAY cohort.
Retinal photographs (
= 517) were obtained in 2010-2011 and again in 2017-2018 (
= 420) with standard stereoscopic seven-field digital fundus photography. Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. A total of 367 patients with gradable fundus photographs in at least one eye at both assessments were included in analyses of progression of DR, defined as an increase of three or more steps on the ETDRS scale.
With mean ± SD age of 25.4 ± 2.5 years and diabetes duration of 12.0 ± 1.5 years, there was a 49% prevalence of any DR among participants. Prevalence by DR stage was as follows: 39% for very mild or mild nonproliferative DR (NPDR), 6% moderate to severe NPDR, and 3.8% proliferative DR. Compared with nonprogressors, participants who progressed three or more steps had significantly lower BMI, higher HbA
, higher blood pressure, increased triglycerides, decreased C-peptide, and higher prevalence of other comorbidities. Multivariate analysis demonstrated that HbA
was the dominant factor impacting DR progression.
Poor glycemic control of youth-onset type 2 diabetes imparts a high risk for progression of DR, including advanced, sight-threatening disease by young adulthood.
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