1211-OR: ADA Presidents' Select Abstract: Impaired Metabolic Flexibility in Type 1 Diabetes May Be Offset by Greater Physical Activity

Introduction and Objective: Metabolic inflexibility, or an inability to switch between fat and carbohydrate oxidation, has not been thoroughly investigated in T1D despite its close link with skeletal muscle insulin resistance—an established feature of T1D. We investigated whether T1D is characterized by metabolic inflexibility relative to controls without diabetes, and whether physical activity (PA), sedentary time, and HbA1c mediate the association between T1D status and metabolic flexibility (MetFlex). Methods: We computed a comprehensive battery of MetFlex indices based on change in respiratory exchange ratio (RER; whole-room indirect calorimetry) during a breakfast meal (~15% protein, ~35% fat, ~50% carbohydrate) following 1 day of domiciled scripted activity in 19 adults with T1D aged 23.9±3.1 years (HbA1c 8.6±1.3%) and 24 controls aged 29.0±7.3 years with similar sex and BMI distribution. Age and race-adjusted linear regression estimated cross-sectional MetFlex differences and bootstrapped 95% CIs between cohorts and mediation by moderate-to-vigorous PA (MVPA), total PA, and sedentary time (7-day wrist-worn accelerometry); and HbA1c. Results: Adults with T1D had lower MetFlex responses to breakfast than controls based on a shallower slope of RER increase between the lowest and first peak RER (β: -0.99; 95% CI -1.7, -0.3 log-units/minute), longer time to first peak RER (β: 20; 95% CI 10.3, 29.9 minutes), lower RER AUC (β: -4.1; 95% CI -7.0, -1.2), and smaller delta between min. and max. RER (β: -0.04; 95% CI -0.07, -0.0006), but no differences in 4 other MetFlex indices. Simulating higher MVPA (+35 min/day) and higher total PA (+120 min/day) to counteract the PA deficit in T1D fully negated (i.e., mediated) the lower RER AUC whereas sedentary time and HbA1c were not mediators despite being higher in T1D vs. controls. Conclusion: Adults with T1D display impaired substrate switching from fat to carbohydrate during a meal challenge relative to controls. This impairment may be offset by increasing MVPA and total PA, which should be confirmed prospectively. Disclosure D. Igudesman: Other - Received travel stipend to attend consortium meeting to present original scientific research unrelated to the company but may inform future research; Current; Endogenex. A. Collins: None. D. Zaharieva: Speaker's Bureau; Ended; Dexcom, Inc., Medtronic. Speaker's Bureau; Current; Insulet Corporation. Research Support; Current; Leona M. and Harry B. Helmsley Charitable Trust. M. Talbo: Other - Honorarium for presenting at Deep Dive on hypoglycemia (2024); Ended; Dexcom, Inc. A. Bilal: None. A. Casu: Research Support; Current; Enable Biosciences. K. Corbin: Research Support; Current; Eli Lilly and Company, Boehringer Ingelheim International GmbH, Novo Nordisk. D. Maahs: Advisory Panel; Current; Abbott Diabetes, Sanofi, Medtronic, biospex, enable biosciences, kriya. R. Pratley: Consultant; Current; Lilly USA LLC. Research Support; Current; National Institutes of Health, Novo Nordisk. Speaker's Bureau; Current; Novo Nordisk. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Novo Nordisk. Consultant; Current; Pfizer Inc., Recordati Rare Diseases Inc., Regeneron Pharmaceuticals Inc., Response Pharmaceuticals, Rona Therapeutics Ltd. Research Support; Current; Sanofi. Consultant; Current; Scholar Rock Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Sun Pharmaceutical Industries Ltd. Consultant; Current; Third Rock Ventures, Verdiva Bio Dev Limited. Research Support; Current; AstraZeneca AB, Boehringer Ingelheim International GmbH, Abbott Laboratories. Consultant; Current; Abbott Laboratories, AbbVie Inc. Other - Consulting; stock options; Current; Altanine, Inc. Consultant; Current; Amgen Inc., AstraZeneca Pharmaceuticals LP. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Bayer AG, Bayer HealthCare Pharmaceuticals Inc. Research Support; Current; Biomea Fusion. Consultant; Current; Boehringer Ingelheim Pharmaceuticals Inc., Carmot Therapeutics, Inc., Corcept Therapeutics. Research Support; Current; Dompé, Eli Lilly and Company. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Eli Lilly and Company. Research Support; Current; Endogenex Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Endogenex Inc. Consultant; Current; F. Hoffmann-La Roche Ltd. Research Support; Current; Fractyl Health, Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Gasherbrum Bio Inc., Genprex. Consultant; Current; Hanmi Pharm. Co., Ltd. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Intas Pharmaceuticals Ltd. Research Support; Current; Lexicon Pharmaceuticals, Inc. Consultant; Current; Lexicon Pharmaceuticals, Inc. Speaker's Bureau; Current; Lilly USA LLC. E. Alvarez Carnero: None. Funding DP3DK113358