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OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. [ABSTRACT FROM AUTHOR]

Objective: 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.Research Design and Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship between health care coverage and HbA1c in young adults with youth-onset type 2 diabetes who transitioned to community diabetes care after receiving care during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.Research Design and Methods: Participants completed questionnaires annually. HbA1c was measured in a central laboratory. Data from 2 years before and after transitioning to community care (2013-2016) were examined and compared between states with and without expanded Medicaid.Results: In 2016 (n = 427; mean age 24 years), 2 years after transitioning to community care, 93% of participants in states with Medicaid expansion had health care coverage compared with 68% (P < 0.0001) in states without Medicaid expansion. Mean HbA1c was 9.8% in participants with government coverage, 9.3% with commercial coverage, and 10.1% in those with no coverage (P = 0.0774). Additionally, 32%, 42%, and 66% of those with government coverage, commercially covered, and no coverage, respectively, were not attending outpatient diabetes visits (P < 0.0001). Of those with government coverage, 83% reported they had adequate coverage for insulin syringes/needles/pens, and 89% for glucose-monitoring supplies, with more limited coverage in those with commercial plans. Participants with commercial coverage had higher education attainment (P < 0.0001); 52% had HbA1c ≥9.0% compared with 64% of those who were government covered and 58% with no coverage (P = 0.0646).Conclusions: More young adults with type 2 diabetes from the TODAY cohort had health care coverage in states with expanded Medicaid but glycemic control remained poor, regardless of coverage. New therapies and approaches are needed for this vulnerable population. [ABSTRACT FROM AUTHOR]

Objective: 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.Research Design and Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective: To describe the longitudinal effects of sex, race-ethnicity, and metabolic factors on the risk of developing diabetic kidney disease (DKD) in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort.Research Design and Methods: Urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) by serum creatinine and cystatin C were assessed annually for up to 15 years after study entry. Markers of DKD included micro- and macroalbuminuria (UACR ≥30 mg/g and ≥300 mg/g, respectively), hyperfiltration (eGFR ≥135 mL/min/1.73 m2), and rapid eGFR annual decline (>3 mL/min/1.73 m2 and/or ≥3.3%). The relationships between risk factors and DKD were evaluated longitudinally using time-to-event models.Results: Data were available on 677 participants, average age at baseline 14 years, with a mean ± SD follow-up of 10.2 ± 4.5 years. Each 1% increment in HbA1c conferred higher risk of microalbuminuria (hazard ratio 1.24 [95% CI 1.18, 1.30]), macroalbuminuria (1.22, [1.11, 1.34]), hyperfiltration (1.11, [1.05, 1.17]), and rapid eGFR decline (1.12, [1.04, 1.20]). Higher systolic blood pressure and baseline serum uric acid, and lower indices of β-cell function (C-peptide index and oral disposition index [oDI]), increased the risk of microalbuminuria, while higher triglycerides increased risk of micro- and macroalbuminuria. Lower oDI levels, female sex, and Hispanic ethnicity were associated with higher risk of hyperfiltration.Conclusions: Elevated HbA1c was a shared risk factor among all phenotypes of DKD in this longitudinal cohort of adolescents and young adults with youth-onset type 2 diabetes. Other risk factors included elevated blood pressure, triglycerides, serum uric acid, and β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Objective: 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.Research Design and Methods: 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.Results: 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, P = 0.002; 14.0% vs. 5.1% via monofilament exam, P = 0.01). Rates did not differ by race/ethnicity. Higher HbA1c 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective: 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.Research Design and Methods: Retinal photographs (n = 517) were obtained in 2010-2011 and again in 2017-2018 (n = 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.Results: 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 HbA1c, higher blood pressure, increased triglycerides, decreased C-peptide, and higher prevalence of other comorbidities. Multivariate analysis demonstrated that HbA1c was the dominant factor impacting DR progression.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective: 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.Research Design and Methods: 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.Results: 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/m2, 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. HbA1c ≥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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood.Methods: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated.Results: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up.Conclusions: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.). [ABSTRACT FROM AUTHOR]

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment than in youth randomized to metformin alone or metformin plus intensive lifestyle intervention. At the end of the study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report postintervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and β-cell function outcomes.Research Design and Methods: A total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA1c ≥8% over a 6-month period, inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY, or sustained HbA1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted, and insulin sensitivity, insulinogenic index, and oral disposition index were calculated.Results: During the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and β-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care but did not differ by treatment group assignment.Conclusions: The added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications. [ABSTRACT FROM AUTHOR]

Objective: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, metformin plus rosiglitazone (M + R) maintained glycemic control better than metformin alone (M) or metformin plus lifestyle (M + L) in youth with type 2 diabetes (T2D). We hypothesized that changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) would explain the differential treatment effects on glycemia.Research Design and Methods: In 626 youth ages 11-17 years with T2D duration <2 years, VAT and SAT were estimated by DXA at baseline and at 6 and 24 months. Changes from baseline were analyzed in linear mixed models.Results: Baseline mean age was 13.9 years, 66.4% were female, 72.2% were Hispanic/non-Hispanic black, and 20.3% were non-Hispanic white (NHW). Mean BMI was 33.7 kg/m2. VAT increased more in M + R (13.1%) than M + L (3.9%, P = 0.0006) or M (6.5%, P = 0.0146). SAT also increased more in M + R (13.3%) than in M + L (5.4%, P < 0.0001) or M (6.4%, P = 0.0005), indicating no significant fat redistribution in M + R. In NHWs, VAT increased more in M + R than M (P = 0.0192) and M + L (P = 0.0482) but did not explain the race-ethnicity differences in treatment effects on glycemic control among treatment groups. VAT and SAT increases correlated with higher HbA1c, lower insulin sensitivity, and lower oral disposition index (all P < 0.05), but associations did not differ by treatment group.Conclusions: In contrast to the existing reports in adults with T2D, in TODAY, M + R resulted in the most VAT accumulation compared with M + L or M. Differential effects on depot-specific indirect measures of adiposity are unrelated to treatment effects in sustaining glycemic control. Additional studies are needed to understand the clinical markers of metabolic risk profile in youth with T2D on rosiglitazone. [ABSTRACT FROM AUTHOR]

Objective: Elevated serum uric acid (SUA) is increasingly recognized as a risk factor for kidney disease in adults with diabetes, but data in youth are limited. We hypothesized that elevated SUA predicts development of elevated urinary albumin excretion (UAE) and hypertension over time in teens with type 2 diabetes (T2D).Research Design and Methods: Serum creatinine, cystatin C, SUA, and the urine albumin-to-creatinine ratio (UACR) were assessed in 539 obese youth, ages 12-17 years, with T2D duration <2 years at baseline in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Estimated glomerular filtration rate (eGFR) was calculated using creatinine and cystatin C. Hypertension was defined as systolic or diastolic blood pressure ≥130/80 mmHg and elevated UAE as UACR ≥30 mg/g. Cox proportional hazards models evaluated the relationship between SUA and outcome variables longitudinally over an average follow-up of 5.7 years, adjusting for age, sex, race/ethnicity, BMI, HbA1c, eGFR, ACE inhibitor/angiotensin receptor blocker use, and TODAY treatment group assignment.Results: At baseline, hyperuricemia (≥6.8 mg/dL) was present in 25.6% of participants, hypertension in 18.7%, and elevated UAE in 6.1%. During follow-up of up to 7 years, hypertension developed in 37.4% and UAE in 18.0%. Higher baseline SUA increased the risk of incident hypertension (hazard ratio [HR] 1.19, 95% CI 1.03-1.38, per 1 mg/dL increase in SUA) and elevated UAE (HR 1.24, 95% CI 1.03-1.48) in adjusted models.Conclusions: Hyperuricemia was common in youth with T2D. Higher baseline SUA independently increased the risk for onset of hypertension and elevated UAE. Research is needed to determine whether SUA-lowering therapies can impede development of diabetic kidney disease and hypertension in T2D youth. [ABSTRACT FROM AUTHOR]

Objective: To determine whether self-monitoring of blood glucose (SMBG) is associated with lower HbA1c in youth with type 2 diabetes taking oral medications only or after starting insulin for persistently elevated HbA1c.Research Design and Methods: Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study participants (n = 699) taking oral medications were asked to perform SMBG twice daily. After reaching primary outcome (PO) (HbA1c ≥8% [64 mmol/mol]) over 6 months or an inability to wean from temporary insulin because of metabolic decompensation), insulin glargine was started. HbA1c and percent of SMBG (SMBG%) (percent days when the meter was used one or more times) before and after PO were analyzed.Results: SMBG declined over time and was inversely related to HbA1c (P < 0.0001). Of 298 youth who reached PO and started insulin, 282 had SMBG data. At PO, mean ± SD age was 15.8 ± 2.3 years, BMI 35.5 ± 7.9 kg/m2, and HbA1c 9.6 ± 2.0% (81 ± 21.9 mmol/mol); 65.3% were female. Median SMBG% was 40% at PO, which increased to 49% after 6 months and fell to 41% after 1 year on insulin. At PO, 22% of youth checked ≥80% of days, which increased to 25% and fell to 19% after 6 and 12 months using insulin, respectively. At PO, compared with those who checked <80%, youth who checked ≥80% were younger and with a lower BMI, HbA1c, and blood pressure. SMBG ≥80% was associated with ≥1% reduction in HbA1c at 6 and 12 months after insulin initiation.Conclusions: Low SMBG adherence was common and associated with higher HbA1c. Optimal SMBG frequency in youth using or not using insulin, and whether less frequent SMBG is a marker for overall worse self-care, require further study. [ABSTRACT FROM AUTHOR]

Objective: Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired β-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in β-cell function.Research Design and Methods: OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (△C30/△G30), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups.Results: At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity.Conclusions: In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced β-cell function and foretells increased glycemic failure rates with accelerated deterioration in β-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To assess the association of proxies of behavioral adherence to the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) lifestyle program with changes in glycemic control and obesity in a multi‐ethnic sample of youth with type 2 diabetes. Methods: The TODAY clinical trial included an intensive lifestyle intervention to promote weight reduction. Adherence was assessed with measures of attendance at intervention sessions and rates of self‐monitoring of diet and physical activity by participants and their caregivers. The relation between participant characteristics and consistency of proxies of adherence were examined across 3 phases of intervention. Results: A total of 234 TODAY youth were randomized to the lifestyle program. Overall rate of session attendance was approximately 60% of planned sessions. Participants with an adequate dose of session attendance (≥75% attended) did not differ from those who attended <75% of sessions in glycemic control, but did have significantly greater reductions in percent overweight compared with those who attended fewer than 75% of sessions. Rates of self‐monitoring were low and additional analysis was not possible. Conclusions: Rates of session attendance were moderate in a lifestyle program for youth with type 2 diabetes, but levels of self‐monitoring, considered a key lifestyle change behavior, were low. Glycemic control was not significantly associated with session attendance but reductions in percent overweight were. Given the salience of program attendance and self‐monitoring to lifestyle weight management established in other populations, future research is needed to understand, develop, and promote strategies and interventions targeting weight loss to achieve improved glycemic control in youth diagnosed with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To identify factors that predict medication adherence and to examine relationships among adherence, glycemic control, and indices of insulin action in TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth).Research Design and Methods: A total of 699 youth 10-17 years old with recent-onset type 2 diabetes and ≥80% adherence to metformin therapy for ≥8 weeks during a run-in period were randomized to receive one of three treatments. Participants took two study pills twice daily. Adherence was calculated by pill count from blister packs returned at visits. High adherence was defined as taking ≥80% of medication; low adherence was defined as taking <80% of medication. Depressive symptoms, insulin sensitivity (1/fasting insulin), insulinogenic index, and oral disposition index (oDI) were measured. Survival analysis examined the relationship between medication adherence and loss of glycemic control. Generalized linear mixed models analyzed trends in adherence over time.Results: In this low socioeconomic cohort, high and low adherence did not differ by sex, age, family income, parental education, or treatment group. Adherence declined over time (72% high adherence at 2 months, 56% adherence at 48 months, P < 0.0001). A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%, P = 0.0415). No adherence threshold predicted the loss of glycemic control. Longitudinally, participants with high adherence had significantly greater insulin sensitivity and oDI than those with low adherence.Conclusions: In the cohort, the presence of baseline clinically significant depressive symptoms was associated with subsequent lower adherence. Medication adherence was positively associated with insulin sensitivity and oDI, but, because of disease progression, adherence did not predict long-term treatment success. [ABSTRACT FROM AUTHOR]

Objective: We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.Research Design and Methods: The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother's prenatal care and delivery and the infant's health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed.Results: Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly.Conclusions: Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity. [ABSTRACT FROM AUTHOR]

Objective: To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy.Research Design and Methods: 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.Results: 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).Conclusions: 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. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes increases cardiovascular risk. We examined lipid profiles and inflammatory markers in 699 youth with recent-onset type 2 diabetes in the TODAY clinical trial and compared changes across treatment groups: metformin alone (M), metformin plus rosiglitazone (M+R), and metformin plus intensive lifestyle program (M+L).Research Design and Methods: Multiethnic youth with type 2 diabetes received M, M+R, or M+L. Statin drugs were begun for LDL cholesterol (LDL) ≥ 130 mg/dL or triglycerides ≥ 300 mg/dL. Lipids, apolipoprotein B (apoB), LDL particle size, high-sensitivity c-reactive protein (hsCRP), homocysteine, plasminogen activator inhibitor-1 (PAI-1), and HbA1c were measured over 36 months or until loss of glycemic control.Results: LDL, apoB, triglycerides, and non-HDL cholesterol (HDL) rose over 12 months and then stabilized over the next 24 months. Participants with LDL ≥ 130 mg/dL or using LDL-lowering therapy increased from 4.5 to 10.7% over 36 months, while 55.9% remained at LDL goal (<100 mg/dL) over that time. Treatment group did not impact LDL, apoB, or non-HDL. Small dense LDL (particle size, ≤ 0.263 relative flotation rate) was most common in M. Triglycerides were lower in M+L than M, and M+L attenuated the negative effect of hyperglycemia on triglycerides and HDL in females. hsCRP, PAI-1, and homocysteine increased over time. However, hsCRP was lower in M+R compared with M or M+L.Conclusions: Dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and worsened over time. Diabetes treatment, despite some treatment group differences in lipid and inflammatory marker change over time, is generally inadequate to control this worsening risk. [ABSTRACT FROM AUTHOR]

Objective: Data related to the safety and tolerability of treatments for pediatric type 2 diabetes are limited. The TODAY clinical trial assessed severe adverse events (SAEs) and targeted nonsevere adverse events (AEs) before and after treatment failure, which was the primary outcome (PO).Research Design and Methods: Obese 10- to 17-year-olds (N = 699) with type 2 diabetes for <2 years and hemoglobin A1c (A1C) ≤ 8% on metformin monotherapy were randomized to one of three treatments: metformin, metformin plus rosiglitazone (M + R), or metformin plus lifestyle program (M + L). Participants were followed for 2-6.5 years.Results: Gastrointestinal (GI) disturbance was the most common AE (41%) and was lower in the M + R group (P = 0.018). Other common AEs included anemia (20% before PO, 14% after PO), abnormal liver transaminases (16, 15%), excessive weight gain (7, 9%), and psychological events (10, 18%); the AEs were similar across treatments. Permanent medication reductions/discontinuations occurred most often because of abnormal liver transaminases and were lowest in the M + R group (P = 0.005). Treatment-emergent SAEs were uncommon and similar across treatments. Most (98%) were unrelated or unlikely related to the study intervention. There were no deaths and only 18 targeted SAEs (diabetic ketoacidosis, n = 12; severe hypoglycemia, n = 5; lactic acidosis, n = 1). There were 62 pregnancies occurring in 45 participants, and 6 infants had congenital anomalies.Conclusions: The TODAY study represents extensive experience managing type 2 diabetes in youth and found that the three treatment approaches were generally safe and well tolerated. Adding rosiglitazone to metformin may reduce GI side effects and hepatotoxicity. [ABSTRACT FROM AUTHOR]

Objective: Among adolescents with type 2 diabetes, there is limited information regarding incidence and progression of hypertension and microalbuminuria. Hypertension and microalbuminuria assessments made during the TODAY clinical trial were analyzed for effect of treatment, glycemic control, sex, and race/ethnicity.Research Design and Methods: A cohort of 699 adolescents, 10-17 years of age, <2 years duration of type 2 diabetes, BMI ≥ 85%, HbA1c ≤ 8% on metformin therapy, controlled blood pressure (BP), and calculated creatinine clearance >70 mL/min, were randomized to metformin, metformin plus rosiglitazone, or metformin plus intensive lifestyle intervention. Primary study outcome was loss of glycemic control for 6 months or sustained metabolic decompensation requiring insulin. Hypertension and microalbuminuria were managed aggressively with standardized therapy to maintain BP <130/80 or <95th percentile for age, sex, and height and microalbuminuria <30 μg/mg.Results: In this cohort, 319 (45.6%) reached primary study outcome, and 11.6% were hypertensive at baseline and 33.8% by end of study (average follow-up 3.9 years). Male sex and higher BMI significantly increased the risk for hypertension. Microalbuminuria was found in 6.3% at baseline and rose to 16.6% by end of study. Diagnosis of microalbuminuria was not significantly different between treatment arms, sex, or race/ethnicity, but higher levels of HbA1c were significantly related to risk of developing microalbuminuria.Conclusions: Prevalence of hypertension and microalbuminuria increased over time among adolescents with type 2 diabetes regardless of diabetes treatment. The greatest risk for hypertension was male sex and higher BMI. The risk for microalbuminuria was more closely related to glycemic control. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.Research Design and Methods: Children (10-17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations.Results: Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects.Conclusions: Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Objective: The current study examines the prevalence of binge eating and its association with adiposity and psychosocial functioning in a large, diverse sample of youth with type 2 diabetes.Research Design and Methods: In the TODAY study, 678 (mean age 14.0 years; 64.9% girls) of the 704 youth randomized to the study completed a self-report measure of eating disorder symptoms and were categorized as nonovereaters, overeaters, subclinical binge eaters, or clinical binge eaters.Results: Youth with clinical (6%) and subclinical (20%) levels of binge eating had significantly higher levels and rates of extreme obesity, global eating disorder and depressive symptoms, and impaired quality of life.Conclusions: These findings highlight the importance of evaluating youth with type 2 diabetes for the presence of binge eating. Future research is needed to determine the cumulative effects of disordered eating, obesity, and psychosocial distress on adherence to lifestyle change recommendations and longitudinal response to treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To characterize, during a 2-year period, the proportion of youth with type 2 diabetes (T2D) enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study that reported ever at least trying smoking cigarettes and/or drinking alcohol.Study Design: Longitudinal data were examined for participants with T2D ages 10-18 years at baseline. Youth psychosocial, parent/family, environmental, and biological correlates of trying health risk behaviors were tested via cross-sectional multivariate models at each time point. Longitudinal models were explored for selected factors.Results: Data were obtained from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study's ethnically diverse participants at baseline (N=644), 6-month (N=616), and 24-month (N=543) assessments. The percentage of youth ever trying only smoking remained stable at 4%; only drinking alcohol increased from 17% to 26%, and both smoking and drinking increased from 10% to 18% during the 2-year period. Factors related to trying health risk behaviors were older age, male sex, non-Hispanic white race-ethnicity, lower grades, more depressive symptoms, and stressful life events. Depressive symptoms, stressful life events, and body mass index Z-score (the latter with smoking only) were related to engagement in health risk behaviors over time.Conclusions: Youth with T2D who are already at risk for health complications and who reported engaging in activities that further increase the likelihood of life-threatening morbidities were characterized. Although most correlates of trying these risk behaviors are nonmodifiable, intervention efforts may need to focus on potentially modifiable factors, such as depressive symptoms and lower grades. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated that glycemic failure rates in the three treatments combined-metformin plus rosiglitazone, metformin alone, and metformin plus lifestyle-were higher in non-Hispanic blacks (NHB; 52.8%) versus non-Hispanic whites (NHW; 36.6%) and Hispanics (H; 45.0%). Moreover, metformin alone was less effective in NHB versus NHW versus H youth. This study describes treatment-associated changes in adiponectin, insulin sensitivity, and β-cell function over time among the three racial/ethnic groups to understand potential mechanism(s) responsible for this racial/ethnic disparity.Research Design and Methods: TODAY participants underwent periodic oral glucose tolerance tests to determine insulin sensitivity, C-peptide index, and oral disposition index (oDI), with measurements of total and high-molecular-weight adiponectin (HMWA).Results: At baseline NHB had significantly lower HMWA than NHW and H and exhibited a significantly smaller increase (17.3% vs. 33.7% vs. 29.9%, respectively) during the first 6 months overall. Increases in HMWA were associated with reductions in glycemic failure in the three racial/ethnic groups combined (hazard ratio 0.61, P < 0.0001) and in each race/ethnicity separately. Over time, HMWA was significantly lower in those who failed versus did not fail treatment, irrespective of race/ethnicity. There were no differences in treatment-associated temporal changes in insulin sensitivity, C-peptide index, and oDI among the three racial/ethnic groups.Conclusions: HMWA is a reliable biomarker of treatment response in youth with type 2 diabetes. The diminutive treatment-associated increase in HMWA in NHB (∼50% lower) compared with NHW and H may explain the observed racial/ethnic disparity with higher therapeutic failure rates in NHB in TODAY. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationships of cardiac structure and function with body composition and cardiorespiratory fitness (CRF) among adolescents with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study.Study Design: Cross-sectional evaluation of 233 participants (median age 18.3 [min-max 12.4-24.2] years, 63% females, median hemoglobin A1c 6.8%) who had echocardiography measurements of left ventricular (LV) mass, ejection fraction, left atrial dimensions, LV diastolic function (early transmitral flow velocity to early mitral annular velocity ratio from tissue Doppler imaging), and right ventricular function (tricuspid annular plane systolic excursion [TAPSE]) and body composition (dual-energy x-ray absorptiometry) and CRF (cycle ergometry determination of physical work capacity at heart rate of 170 beats per minute).Results: LV mass correlated positively with CRF (r = 0.5, P < .0001), lean body mass (LBM) (r = 0.7, P < .0001), and fat mass (FM) (r = 0.2, P = .00047); LV ejection fraction did not. Early transmitral flow velocity to early mitral annular velocity was positively related to FM (r = 0.14, P = .03) and % body fat (r = 0.18, P = .007), and left atrial internal diameter correlated with FM (r = 0.4, P < .0001), LBM (r = 0.3, P < .001), and CRF (r = 0.2, P = .0033). TAPSE weakly correlated with CRF (r = 0.2, P = .0014) and LBM (r = 0.13, P < .05) but not with FM. In multivariable regression analyses, LBM (β = 2.13, P < .0001) and CRF (β = 0.023, P = .008) were related to LV mass independent of race, sex, age, hemoglobin A1c, hypertension, smoking, and diabetes medications. CRF (β = 0.0002, P = .0187) and hemoglobin A1c (β = -0.022, P = .0142) were associated with TAPSE.Conclusions: In youth with type 2 diabetes, LV size is related to physical fitness. LV ejection fraction is within normal limits. LV diastolic function is inversely related to FM. Greater fitness may counteract adverse effects of poor glycemic control on right ventricular function.Trial Registration: ClinicalTrials.gov:NCT00081328. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Examine barriers for taking glucose-lowering oral medications, associated baseline characteristics, strategies used, and the adherence impact in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.Methods: We studied youth prescribed oral diabetes medications over two years (N = 611, 583, and 525 at 6, 12, and 24 months). Clinicians documented barriers (e.g. forgetting, routines, other concerns) in the subsample that reported missed doses (N = 423 [69.2%], 422 [72.4%], and 414 [78.9%] at 6, 12, and 24 months, respectively). Adherence strategies were also assessed (e.g. family, schedule, reminder device) using standard questions. Logistic regression was used to analyze associations with medication adherence.Results: Those missing doses were not different from the total sample (61.5% female, 13.9 ± 2.0 years, >80% racial/ethnic minorities). No baseline demographic or clinical predictors of barriers to medication adherence were identified. Among those for whom barriers were assessed, "forgetting" with no reason named (39.3%) and disruptions to mealtime, sleep, and schedule (21.9%) accounted for the largest proportion of responses. Family support was the primary adherence strategy identified by most youth (≥50%), followed by pairing the medication regimen with daily routines (>40%); the latter strategy was associated with significantly higher adherence rates (p = 0.009).Conclusions: Family supported medication adherence was common in this mid-adolescent cohort, but self-management strategies were also in evidence. Findings are similar to those reported among youth with other serious chronic diseases. Prospective studies of multi-component family support and self-management interventions for improving medication adherence are warranted.Trial Registration: ClinicalTrials.gov NCT00081328. [ABSTRACT FROM AUTHOR]

Aim: To understand the relationship of obesity and 27 circulating inflammatory biomarkers to the prevalence of non-proliferative diabetic retinopathy (NPDR) in youth with type 2 diabetes.Methods: Youth with type 2 diabetes who participated in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study were followed for 2-6.5 years. Digital fundus photographs were obtained in the last year of the study. Blood samples during the study were processed for inflammatory biomarkers, and these were correlated with obesity tertiles and presence of retinopathy.Results: Higher BMI was associated with an increase in circulating levels of metabolic biomarkers including high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor 1 (PAI-1), fibrinogen, LDL-cholesterol (LDL-C) and Apolipoprotein B (ApoB), tumor necrosis factor receptors 1 and 2 (TNFR-1 and -2), interleukin 6 (IL-6), E-selectin, and homocysteine, as well as a decrease in the metabolic risk markers HDL-cholesterol (HDLC), and insulin-like growth factor binding protein 1 (IGFBP-1). Although NPDR risk decreased with increasing obesity, it was not associated with any of the measured biomarkers.Conclusions: Circulating levels of measured biomarkers did not elucidate the "obesity paradox" of decreased NPDR in the most obese participants in the TODAY study.Trial Registration: clinicaltrials.govNCT00081328. [ABSTRACT FROM AUTHOR]

The relationship between depressive symptoms and glycemic control in youth with type 2 diabetes was assessed at baseline (n = 682), 6, and/or 24 months (n = 576). Neither baseline nor persistence of depressive symptoms was significantly associated with maintenance of glycemic control. Nevertheless, depressive symptoms were common, suggesting the importance of repeated screening. [ABSTRACT FROM AUTHOR]

Aims: Youth-onset type 2 diabetes (T2D) confers a high risk of early adverse cardiovascular morbidity. We describe the cumulative incidence and prevalence of cardiovascular risk factors over time and examine relationships with diabetes progression in young adults with youth-onset T2D from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.Methods: Longitudinal data was used to evaluate the relationships between hypertension, LDL-C dyslipidemia, hypertriglyceridemia, and smoking with risk factors in 677 participants.Results: Baseline mean age was 14 ± 2 years and mean follow-up 10.2 ± 4.5 years. The 14-year cumulative incidence of hypertension, LDL-C dyslipidemia, and hypertriglyceridemia was 59%, 33%, and 37% respectively. Average prevalence of reported smoking was 23%. Male sex, non-Hispanic white race/ethnicity, obesity, poor glycemic control, lower insulin sensitivity, and reduced beta-cell function were significantly associated with an unfavorable risk profile. At end of follow-up, 54% had ≥2 cardiovascular risk factors in addition to T2D.Conclusions: Cardiovascular risk factor incidence and prevalence was high over a decade of follow-up in young adults with youth-onset T2D. Glucose control and management of cardiovascular risk factors is critical in youth with T2D for prevention of cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]