Project Grant K23DK140641

MECHANISMS AND CONSEQUENCES OF ERYTHRITOL AND ERYTHRONATE EXCESS IN CARDIOMETABOLIC DISEASE - PROJECT SUMMARY/ABSTRACT THE OBESITY AND TYPE 2 DIABETES (T2D) EPIDEMICS PARALLEL A RISE IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD), AND HEART FAILURE (HF). ELEVATED SERUM ERYTHRITOL CONCENTRATIONS HAVE BEEN LINKED TO INCREASED ASCVD WITH ERYTHRITOL INGESTION AS AN ARTIFICIAL SWEETENER IMPLICATED. ERYTHRITOL HAS BEEN SHOWN TO BE ENDOGENOUSLY PRODUCED THROUGH THE PENTOSE PHOSPHATE PATHWAY (PPP) AND FURTHER METABOLIZED TO ERYTHRONATE. ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY ANALYSIS OF SAMPLES FROM PRIOR TO FDA APPROVAL OF ERYTHRITOL AS AN ARTIFICIAL SWEETENER FOUND ERYTHRITOL TO BE ASSOCIATED WITH CORONARY HEART DISEASE, INDEPENDENT OF DIABETES AND OBESITY, SUGGESTING A ROLE FOR ENDOGENOUS PRODUCTION. IT IS UNKNOWN WHETHER INCREASED ERYTHRITOL AND ERYTHRONATE ARE MARKERS OF PATHOPHYSIOLOGICAL CHANGES IN METABOLIC PATHWAYS OR CAUSAL MARKERS OF ASCVD THAT ARE IMPACTED BY GENETIC VARIABILITY. ABSOLUTE ERYTHRITOL AND ERYTHRONATE CONCENTRATIONS IN PEOPLE WITH AND WITHOUT T2D AND/OR OBESITY ALSO NEED TO BE ESTABLISHED. WE HYPOTHESIZE THAT (1) ERYTHRITOL, ERYTHRONATE, AND OTHER PPP ENZYMES AND METABOLITES HAVE STRONG ASSOCIATIONS WITH MACROVASCULAR AND MICROVASCULAR DISEASE AND HF; (2) ERYTHRITOL AND ERYTHRONATE CONCENTRATIONS ARE IMPACTED BY GENETIC VARIABILITY; AND (3) PERSONS WITH T2D AND OBESITY HAVE HIGHER ERYTHRITOL AND ERYTHRONATE CONCENTRATIONS IN THE FASTING STATE, WHICH ARE FURTHER EXAGGERATED IN RESPONSE TO EXOGENOUS GLUCOSE AND ERYTHRITOL. AIM 1 EXAMINES THE ASSOCIATION OF ERYTHRITOL, ERYTHRONATE AND OTHER PPP INTERMEDIATES TO INCIDENT MICRO- AND MACROVASCULAR DISEASE AND HF OUTCOMES IN MULTIETHNIC OBSERVATIONAL STUDIES. AIM 2 DETERMINES WHETHER T2D AND/OR OBESITY STATUS INCREASE PRODUCTION OF ERYTHRITOL AND ERYTHRONATE WHEN FASTING AND/OR IN RESPONSE TO GLUCOSE INFUSION AND ORAL ERYTHRITOL. UNDERSTANDING ERYTHRITOL AND ERYTHRONATE'S ENDOGENOUS PRODUCTION, GENETIC VARIABILITY, AND ASSOCIATION TO ASCVD IS KEY TO UNDERSTANDING CLINICAL PREDICTIVE UTILITY. THE EFFECT OF EXOGENOUS GLUCOSE AND ERYTHRITOL INTAKE ON ERYTHRITOL AND ERYTHRONATE CONCENTRATION IN PEOPLE WITH AND WITHOUT T2D AND/OR OBESITY WILL SHED LIGHT ON THE ROLE OF DIETARY INTAKE IN THESE GROUPS. DR. ABUSHAMAT IS A BOARD-CERTIFIED ADULT ENDOCRINOLOGIST AND TENURE-TRACK ASSISTANT PROFESSOR AT BAYLOR COLLEGE OF MEDICINE. HER LONG-TERM GOAL IS TO BECOME AN INDEPENDENT NIH-FUNDED PHYSICIAN-SCIENTIST IN CARDIOVASCULAR METABOLISM, FOCUSING ON GENETIC VARIABILITY IN METABOLIC PATHWAYS TO INFORM PERSONALIZED APPROACHES TO PREVENTION, DIAGNOSIS, AND TREATMENT. THE RESEARCH AIMS SUPPORT THE PI'S CAREER DEVELOPMENT BY AUGMENTING HER PAST TRAINING AS AN MD/MPH VIA MASTER'S LEVEL TRAINING IN CLINICAL INVESTIGATION WITH THE ADDITION OF SKILLS IN MULTI-OMIC ANALYSIS, MENDELIAN RANDOMIZATION, STABLE-ISOTOPE TRACER STUDIES AND INTERMEDIATE BIOSTATISTICS. THIS TRAINING PLAN WILL BE CARRIED OUT VIA A SUPERB MENTORING AND ADVISORY TEAM, ADVANCED COURSEWORK, AND SCHOLARLY ACTIVITIES WITHIN AN EXCELLENT RESEARCH ENVIRONMENT. THIS RESEARCH PROPOSAL AND TRAINING PLAN WILL PREPARE DR. ABUSHAMAT TO BECOME AN INDEPENDENTLY FUNDED PHYSICIAN-SCIENTIST.