Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 68; no. 10; pp. 2035 - 2044
• Main Authors: Mathew, Anna V., Jaiswal, Mamta, Ang, Lynn, Michailidis, George, Pennathur, Subramaniam, Pop-Busui, Rodica
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.10.2019
• Subjects: Adult; Amino acids; Amino Acids - metabolism; Asparagine; Aspartic acid; Autonomic nervous system; Autonomic Nervous System - metabolism; Autonomic Nervous System - physiopathology; Blood Glucose; Cardiovascular System - metabolism; Cardiovascular System - physiopathology; Cholesterol; Citric Acid Cycle - physiology; Creatinine; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - physiopathology; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - physiopathology; Diabetic neuropathy; Disease Progression; Female; Genetics/Genomes/Proteomics/Metabolomics; Glomerular filtration rate; Glucose monitoring; Glutamine; Histidine; Humans; Hyperglycemia; Intermediates; Male; Metabolic pathways; Metabolism; Metabolomics; Middle Aged; Ornithine; Phenylalanine; Proline; Serine; Threonine; Tricarboxylic acid cycle; Tyrosine; Urine; Young Adult
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db19-0145

While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean ± SD age 35 ± 13 years, diabetes duration 13 ± 7 years, and HbA1c 7.9 ± 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels—asparagine and glutamine—correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA1c, blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.