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

BACKGROUND: We conducted exploratory analyses to identify distinct trajectories of estimated glomerular filtration rate (eGFR) and their relationship with hyperfiltration, subsequent rapid eGFR decline, and albuminuria in participants with youth-onset type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Annual serum creatinine, cystatin C, urine albumin, and creatinine measurements were obtained from 377 participants followed for ≥ 10 years. Albuminuria and eGFR were calculated. Hyperfiltration peak is the greatest eGFR inflection point during follow-up. Latent class modeling was applied to identify distinct eGFR trajectories. RESULTS: At baseline, participants' mean age was 14 years, type 2 diabetes duration was 6 months, mean HbA1c was 6%, and mean eGFR was 120 ml/min/1.73 m2. Five eGFR trajectories associated with different rates of albuminuria were identified, including a "progressive increasing eGFR" group (10%), three "stable eGFR" groups with varying starting mean eGFR, and an "eGFR steady decline" group (1%). Participants who exhibited the greatest peak eGFR also had the highest levels of elevated albuminuria at year 10. This group membership was characterized by a greater proportion of female and Hispanic participants. CONCLUSIONS: Distinct eGFR trajectories that associate with albuminuria risk were identified, with the eGFR trajectory characterized by increasing eGFR over time associating with the highest level of albuminuria. These descriptive data support the current recommendations to estimate GFR annually in young persons with type 2 diabetes and provide insight into eGFR-related factors which may contribute to predictive risk strategies for kidney disease therapies in youth with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00081328, date registered 2002. A higher resolution version of the Graphical abstract is available as Supplementary information.

Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS: Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006). CONCLUSIONS: By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

Elevated Serum Uric Acid Is Associated With Greater Risk for Hypertension and Diabetic Kidney Diseases in Obese Adolescents With Type 2 Diabetes: An Observational Analysis From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study.

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.

Depressive symptoms and quality of life in adolescents with type 2 diabetes: baseline data from the TODAY study.

OBJECTIVE: The study objective was to examine the prevalence of depressive symptoms and relationships to quality of life and demographics in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study's large, ethnically diverse youth with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 704 youth with type 2 diabetes <2 years' duration, aged 10-17 years, and BMI ≥85th percentile completed depressive symptoms and quality of life measures. RESULTS: Some 14.8% reported clinically significant depressive symptoms, and older girls had significantly higher rates than older boys. CONCLUSIONS: Rates of significant depressive symptoms were similar to those of healthy adolescents and lower than those of teens with type 1 diabetes. Elevated depressive symptoms, particularly in older girls, suggest clinicians assess vulnerability.

The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study.

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.