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

Abstract

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 HbA_1c 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 HbA_1c, 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.

Figure 1

Correlation of baseline SDNN with baseline glutamine levels (A), asparagine levels (B), and fumarate levels (C). Correlation of 3-year SDNN with baseline glutamine levels (D) and baseline ornithine levels (E). Panel F demonstrates the correlation between the change in SDNN over 3-year follow-up with baseline ornithine levels. All metabolite levels in μmol/L and SDNN in seconds. Pearson correlation represented as r. yr, year. *P value <0.05.

Figure 2

A: Schematic diagram of the altered metabolites that associate with CAN parameters. Metabolites highlighted in red ovals are increased in subjects with type 1 diabetes and positively related to baseline SDNN and RMSSD, those in green-filled ovals are decreased in subjects with diabetes and positively related to SDNN and RMSSD at baseline and follow-up [r values by Pearson correlation to baseline CAN parameters, represented in parentheses as (SDNN/RMSSD)], and those in yellow-filled ovals are decreased in subjects with diabetes and positively related to SDNN and RMSSD at follow-up and the difference in SDNN and RMSSD from baseline and follow-up [r values by Pearson correlation to 3-year follow-up CAN parameters, represented in parentheses as (SDNN/RMSSD)]. OAT, ornithine amino transferase; P5CS, pyrroline 5-carboxylate synthetase.