We aimed to identify metabolites that predict the loss of glycemic control in youth-onset T2D (Y-T2D), a disease characterized by more rapid decline in β-cell function than adults-onset T2D. The increasing incidence of Y-T2D highlights the need to understand its pathophysiology and develop appropriate interventions. We measured 40 plasma metabolites in 374 baseline and 10-year follow-up samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using mass spectrometry with a targeted ZipChip based assay. Loss of glycemic control was defined as HbA1c ≥8% for 6 months or inability to wean from temporary insulin after acute metabolic decompensation. We evaluated associations with time to loss of glycemic control in Cox proportional hazards models adjusted for HbA1c, triglycerides, systolic blood pressure, and estimated insulin sensitivity. Participants were 14±2 years of age, 63% female; 72% experienced loss of glycemic control. Five baseline plasma metabolites (threonine, asparagine, glycine, glutamine, L-alpha-aminobutyrate) associated with lower risk of loss of glycemic control, and one baseline plasma metabolite (citrate) associated with higher risk of loss of glycemic control. After multivariable adjustments, only plasma citrate remained statistically significant (HR: 1.16 per 1 SD [95% CI 1.04, 1.30]). At 10-year follow-up, of these plasma metabolites only threonine (logFC: -0.28, p=3.8×10-11) and glycine (logFC: -0.17, p=5.7×10-5) were significantly lower. Plasma metabolites, such as citrate that might originate from an excess of fatty acids, predicted loss of glycemic control in youth with T2D. Future work should validate these findings and investigate their response to promising therapies. Disclosure P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. R.Gubitosi-klug: None. K.Drews: None. K.L.Tommerdahl: None. J.B.Tryggestad: None. E.M.Isganaitis: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. L.Pyle: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. T.B.Vigers: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. L.El ghormli: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. J.R.Ryder: None. A.S.Shah: None. J.L.Lynch: Research Support; Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases

In youth-onset type 2 diabetes (YO-T2D; diabetes diagnosed <20 years-old) loss of glycemic control is more rapid than in adults, partly attributed to accelerated beta cell decline. However, no studies have investigated the potential heterogeneity in the longitudinal trajectories of beta cell function and whether genetic factors might contribute to heterogeneity. We derived longitudinal trajectories of fasting C-peptide (FCP) levels, a surrogate measure of beta cell function, via discrete mixture modeling of repeated measures collected over 15 years of follow-up in youth with YO-T2D (antibody negative and insulin resistant; n=266) from the SEARCH for Diabetes in Youth cohort study. We tested the association between the derived trajectories and T2D genetic risk score (GRS) using a multinomial logistic regression model with adjustment for relevant covariates. A four-trajectory model best fit the data, classifying youth with YO-T2D as having either “initial low FCP and stable over time” (32%), “initial high FCP and slow incline” (8%), “initial high FCP and slow decline” (53%), or “initial very high FCP and rapid decline” (7%) (Figure). T2D GRS was not associated with FCP trajectory membership. These data demonstrate substantial heterogeneity in trajectories of FCP in YO-T2D and suggest that genetic predisposition to T2D is not a significant determinant of this heterogeneity. Disclosure A.Shapiro: None. A.Bellatorre: None. J.M.Stafford: None. A.S.Shah: None. C.Pihoker: None. F.Malik: None. A.D.Liese: None. D.J.Pettitt: None. D.Dabelea: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK127208-01, 1UC4DK108173); Centers for Disease Control and Prevention (U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, U18DP006139)

The basis for the more aggressive loss of β-cell function in youth-onset type 2 diabetes (Y-T2D) compared to adult-onset T2D and its unresponsiveness to interventions remain incompletely understood. Given the increasing incidence of Y-T2D, there is an urgent need to better understand its pathophysiology and develop appropriate interventions. Accordingly, we sought to identify multiprotein signatures that predict loss of glycemic control in Y-T2D. We measured 7604 Aptamers in 374 baseline plasma samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using the SomaScan 7K Proteomic (SomaLogic) platform. Loss of glycemic control was defined as HbA1c ≥8% for 6 months or inability to wean from temporary insulin after acute metabolic decompensation. We evaluated associations with time to loss of glycemic control in Cox proportional hazards models adjusted for body mass index (BMI) and estimated insulin sensitivity. Gene set enrichment analysis identified pathways of interest. The false discovery rate was controlled at 5% and we report q-values. Participants were 14±2 years of age, 37% male; 72% experienced loss of glycemic control. Seventy-four proteins were associated with time to loss of glycemic control, with sixty-seven proteins remaining associated with time to loss of glycemic control after multivariable adjustments, such as: plexin-B2 (HR: 1.54 per 1 SD [95% CI 1.35, 1.76], q<0.0001) and Ephrin-A3 (HR: 1.25 [1.13, 1.39], q=0.012). Twenty gene sets, including HIF-1 signaling, metabolic and cell adhesion pathways, were positively related and 13 gene sets were negatively related to time to loss of glycemic control. Novel proteins, including those involved in regulation of insulin secretion and ligand-receptor pairing in β-cells, predict loss of glycemic control in Y-T2D, independently of BMI and estimated insulin sensitivity. Future work should include validation of these findings and investigating potential therapeutic targets. Disclosure T.B.Vigers: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. A.S.Shah: None. K.Drews: None. J.R.Ryder: None. R.Gubitosi-klug: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. L.Pyle: None. L.El ghormli: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. R.G.Nelson: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. S.Waikar: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.White: None. K.L.Tommerdahl: None.

Limited data exist examining arterial stiffness and heart rate variability (HRV) over time in young adults with youth-onset type 1 (T1D) and type 2 diabetes (T2D) . We compared arterial stiffness and HRV over time and by diabetes type and determined the risk factors associated with worsening arterial stiffness and HRV. Arterial stiffness (pulse wave velocity, augmentation index) and HRV (SDNN and PNN50) were measured twice (∼ 5 years apart) in the SEARCH for Diabetes in Youth Study. Linear regression models assessed risk factors overtime and with arterial stiffness and HRV at follow-up. Of 1159 participants studied, 949 had T1D (mean age 17.1 ± 4.7 years, 60.3% non-Hispanic White, 55% female) and 2had T2D (mean age 22.1 ± 3.5 years, 23.8% non-Hispanic White, 71% female) at initial assessment when diabetes duration was 7.9 years (both groups) . Participants with T2D vs. T1D had greater arterial stiffness and more abnormalities in HRV at initial and follow-up assessments (Figure) .For AIx and PNN50 T2D compared to T1D had a greater change over time (p<0.05) . Risk factors associated with worse arterial stiffness and HRV at follow-up in both T1D and T2D included higher BP, HbA1c, waist circumference, and triglycerides overtime, and longer diabetes duration. Arterial stiffness and HRV worsened over time with greater changes among those with T2D and features of the metabolic syndrome regardless of diabetes type. Disclosure A.S. Shah: None. R. Dagostino: Consultant; Aetion, Inc., AstraZeneca, Biogen, Bristol-Myers Squibb Company, Daiichi Sankyo, Merck & Co., Inc. L.M. Dolan: None. D. Dabelea: None. G. Imperatore: None. A.K. Mottl: Advisory Panel; Bayer AG. Board Member; Bayer AG. Research Support; Alexion Pharmaceuticals, Inc., Aurinia, Bayer AG, Boehringer Ingelheim International GmbH, Pfizer Inc. E. Lustigova: None. C. Pihoker: None. S.M. Marcovina: None. E.M. Urbina: Advisory Panel; Astellas Pharma Inc. Funding NIH and CDC

Arterial stiffness and echocardiograms were assessed in participants with youth-onset DM (N=399, 22.8 ± 5.1 years, duration 10.8 ± 3.2 years, 63% female, 45% non-Hispanic White; 33% non-Hispanic Black, 13.5% Hispanic, 8% Other, 44% type 2 DM (T2D)) . Cardiovascular risk factors (CVRF) , arterial stiffness and cardiac measures were compared between those with or without elevated arterial stiffness (stiff = Pulse Wave Velocity [PWV] ≥ 90th% for lean controls) . Association between PWV and cardiac parameters after adjusting for CVRF was assessed. Participants with high PWV were 4.6 yrs older, had 0.6 yrs longer diabetes duration, were more likely to be female (71.5 vs. 54.9%) , non-Hispanic White (68.8 v 42.3) , have T2D (72.0 v 20.2%) , higher BMI (35.6 v 26.3 kg/m2) , BP (122/79 v 109/72 mmHg) , LDL-C (113 v 100 mg/dl) , CRP (0.6 v 0.1mg/dL) , and HbA1c (9.6 v 8.9%; all p≤0.04) . Those with high PWV had higher left ventricular mass index (LVMI) and lower systolic and diastolic function. PWV remained a significant predictor of LVMI (R2 0.37) , systolic (EF, R2 0.235) and diastolic (e’/a’, R2 0.461) function after adjustment for CVRF, all p≤0.0002. Higher arterial stiffness is associated with adverse changes in cardiac structure and function and was more prevalent in persons with T2D compared to type 1 DM. Disclosure E.M. Urbina: Advisory Panel; Astellas Pharma Inc. D. Dabelea: None. R. Dagostino Jr: None. S.R. Daniels: None. L.M. Dolan: None. G. Imperatore: None. E. Lustigova: None. S.M. Marcovina: None. A.K. Mottl: Advisory Panel; Bayer AG. Board Member; Bayer AG. Research Support; Alexion Pharmaceuticals, Inc., Aurinia, Bayer AG, Boehringer Ingelheim International GmbH, Pfizer Inc. C. Pihoker: None. A.S. Shah: None. Funding Grant Support (SEARCH 4) : The SEARCH for Diabetes in Youth Cohort Study (1R01DK127208-01, 1UC4DK108173) is funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and supported by the Centers for Disease Control and Prevention. The Population Based Registry of Diabetes in Youth Study (1U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, and U18DP006139) is funded by the Centers for Disease Control and Prevention (DP-15-002) and supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Grant Support (SEARCH 1, 2, 3) : SEARCH for Diabetes in Youth is funded by the Centers for Disease Control and Prevention (PA numbers 00097, DP-05-069, and DP-10-001) and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Kaiser Permanente Southern California (U48/CCU919219, UDP000246, and U18DP002714) , University of Colorado Denver (U48/CCU819241-3, UDP000247, and U18DP000247-06A1) , Cincinnati's Children's Hospital Medical Center (U48/CCU519239, UDP000248, and 1U18DP002709) , University of North Carolina at Chapel Hill (U48/CCU419249, UDP000254, and U18DP002708) , Seattle Children's Hospital (U58/CCU019235-4, UDP000244, and U18DP002710-01] and Wake Forest University School of Medicine (U48/CCU919219, UDP000250, and 200-2010-35171) .