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

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Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes Diabetes Volume 68, October 2019 2035 Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes Anna V. Mathew,1 Mamta Jaiswal,2 Lynn Ang,2 George Michailidis,3 Subramaniam Pennathur,1,4 and Rodica Pop-Busui2 Diabetes 2019;68:2035–2044 | https://doi.org/10.2337/db19-0145 GENETICS/GENOMES/PROTEOMICS/METABOLOMICS While diabetes is characterized by hyperglycemia, nutri- Cardiovascular autonomic neuropathy (CAN) is a widely ent metabolic pathways like amino acid and tricarboxylic prevalent chronic diabetes complication that is character- acid (TCA) cycle are also profoundly perturbed. As gly- ized by impaired autonomic control of the cardiovascular cemic control alone does not prevent complications, we system (1). Although the initial prevalence of CAN in hypothesized that these metabolic disruptions are re- patients newly diagnosed with type 1 diabetes is low, later sponsible for the development and progression of di- prevalence after 15 years of diabetes increases to 35% in abetic cardiovascular autonomic neuropathy (CAN). We patients with type 1 diabetes and 60% in patients with performed standardized cardiovascular autonomic re- type 2 diabetes (1–4). CAN is an independent predictor of fl ex tests and targeted fasting plasma metabolomic chronic kidney disease progression and of cardiovascular analysis of amino acids and TCA cycle intermediates disease morbidity and mortality in patients with diabetes in subjects with type 1 diabetes and healthy control (5–8). CAN is also associated with an increased risk of subjects followed for 3 years. Forty-seven participants cardiac arrhythmias, silent myocardial ischemia, myocar- with type 1 diabetes (60% female and mean 6 SD age dial dysfunction, and sudden death (1,2,4,5,8). The earliest 35 6 13 years, diabetes duration 13 6 7 years, and HbA 1c clinical manifestations of CAN are insidious and include 7.9 6 1.2%) had lower fumarate levels and higher thre- onine, serine, proline, asparagine, aspartic acid, phenyl- reduced heart rate variability (HRV) at rest and during alanine, tyrosine, and histidine levels compared with several challenges such as standing, deep breathing, and 10 age-matched healthy control subjects. Higher base- the Valsalva maneuver. Currently, objective measures of line fumarate levels and lower baseline amino acid levels— HRV using recommended standard cardiovascular auto- asparagine and glutamine—correlate with CAN (lower nomic testing for research studies or clinical care remain baseline SD of normal R-R interval [SDNN]). Baseline the gold standard diagnostic (1). Given the critical prog- glutamine and ornithine levels also associated with the nostic consequences of CAN, its targeted and timely di- progression of CAN (lower SDNN at 3 years) and change in agnosis is paramount. However, the current cardiovascular fl SDNN, respectively, after adjustment for baseline HbA1c, autonomic testing and other tests such as the barore ex or blood glucose, BMI, cholesterol, urine microalbumin-to- imaging studies remain both cumbersome and expensive. creatinine ratio, estimated glomerular filtration rate, and Several risk factors play essential roles in the develop- years of diabetes. Therefore, significant changes in the ment of CAN including chronic hyperglycemia, diabetes anaplerotic flux into the TCA cycle could be the critical duration, hypertension, hyperlipidemia, chronic inflam- defect underlying CAN progression. mation, oxidative stress, and, more recently, glucose 1Division of Nephrology, Department of Internal Medicine, University of Michigan, Received 11 February 2019 and accepted 17 July 2019 Ann Arbor, MI This article contains Supplementary Data online at http://diabetes 2 Division of Metabolism, Endocrinology, and Diabetes, Department of Internal .diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0145/-/DC1. Medicine, University of Michigan, Ann Arbor, MI A.V.M. and M.J. contributed to this work equally. 3Department of Statistics, University of Florida, Gainesville, FL 4Department of Molecular and Integrative Physiology, University of Michigan, Ann © 2019 by the American Diabetes Association. Readers may use this article as Arbor, MI long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals Corresponding authors: Anna V. Mathew, [email protected], Subramaniam .org/content/license. Pennathur, [email protected], or Rodica Pop-Busui, rpbusui@med .umich.edu 2036 Metabolites and CAN in Type 1 Diabetes Diabetes Volume 68, October 2019 variability (1,2,4,9). While CAN progression is prevented diabetes duration; and no signs of microvascular compli- with tight glucose control in type 1 diabetes (2,9) and cations or uncontrolled hypertension at baseline. All sub- possibly with combined multifactorial interventions in jects had normal resting electrocardiogram and normal type 2 diabetes (10), to date there are no specificdisease- exercise treadmill test results before enrolling in the study. modifying therapies for CAN. Thus, a deeper understand- Patients with a history of cardiovascular disease were ing of the mechanisms that modulate CAN development excluded from the study. Healthy control subjects were and progression is crucial for both risk assessment and age matched with normal weight, normal glucose toler- therapeutic interventions. ance, and normal blood pressure (BP). Forty subjects with In addition to the changes in carbohydrate metabolism, type 1 diabetes completed the study. Demographic and diabetes is characterized by profound alterations in amino anthropometric measures were collected through ques- acid and lipid metabolism. In fact, elevated levels of tionnaires and physical examination; fasting blood and branched-chain amino acids (BCAAs) are a well-characterized urine samples were obtained for the measurement of risk predictor of future type 2 diabetes risk and insulin various metabolic parameters including HbA1c, lipid panel, resistance (11–13). While glycemic control as documented and renal function tests. The University of Michigan In- by hemoglobin A1c (HbA1c) has been the primary goal for stitutional Review Board approved the study, and written diabetes management, a broader understanding of nutri- informed consent was obtained from all subjects. ent metabolism can offer a potential mechanistic risk modifier in the care of patients with diabetes. Indeed, CAN Assessments microvascular complications like neuropathy, diabetic kid- Standardized CAN evaluations were performed on all sub- ney disease, and retinopathy are also associated with jects after an overnight fast. Subjects were asked to avoid increased oxidative stress and alterations in the levels caffeine and tobacco products for 8 h before testing and to of intermediary metabolites (14). There are tissue-specific hold any medication (except for basal insulin) until CAN patterns of altered metabolic flux through the glycolytic testing was completed. Subjects who experienced a hypogly- and tricarboxylic cycles in diabetic mouse models (15,16). cemic episode after midnight (blood glucose #50 mg/dL Importantly, diabetic neuropathy and retinopathy show [2.77 mmol/L]) before the testing were rescheduled. The a distinctly different metabolic signature compared with electrocardiogram recordings were obtained in the supine diabetic kidney disease in animal models (14,16,17). Re- position using a physiologic monitor (Nightingale PPM2; Zoe cent advancement in mass spectrometry techniques— Medical), and data were collected during a resting study both targeted and untargeted approaches—have made (5 min) and during several standardized cardiovascular simultaneous large-scale assessments of various metabolic autonomic reflex tests obtained under paced breathing pathways possible. Many studies have demonstrated that (R-R response to deep breathing, Valsalva maneuver, and these intermediary metabolites can predict the progression postural changes). Indices of CAN were derived using the and severity of disease in type 1 and type 2 diabetic kidney ANX 3.1 (ANSAR Medical Technologies) as previously de- – disease (16,18 20) and diabetic retinopathy (21). These scribed (22). All CAN variables were assessed for the entire fi studies have clari ed the pathophysiological mechanisms, cohort at baseline and for 40 subjects with type 1 diabetes fi highlighted biomarkers, and identi ed potential therapeu- (out of 47) who completed the study at 3 years of follow-up. tic targets. However, such targeted metabolomic profiling has not been used to characterize the metabolic perturba- CAN Outcome Measures tions associated with CAN in diabetes. Therefore, the The following measures of CAN were predefined as outcomes primary objective of this study was to evaluate the asso- of interests and analyzed: SD of normal R-R interval (SDNN), ciation between perturbations in metabolic intermediates root-mean square differences of successive R-R intervals (tricarboxylic acid [TCA] cycle metabolites and amino (RMSSD), expiration-to-inspiration (E:I) ratio during deep acids) and measures of CAN in subjects with type 1 di- breathing, Valsalva ratio (average of two measures), 30:15 abetes. The discovery of a distinct metabolomic biomarker ratio, low-frequency (LF) power (0.04–0.15 Hz), high- signature associated with CAN may provide insight into frequency (HF) power (0.15–0.4 Hz), and LF/HF at rest the pathogenic pathways that are currently unknown and and during cardiovascular autonomic
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