Abstract and Introduction
Abstract
Context: The hyperglycemia condition disrupts metabolism of nitrate/nitrite and nitric oxide, and dietary nitrate intake can restore nitric oxide homeostasis.
Objective: This study aims to examine whether urinary nitrate is associated with diabetes complications and long-term survival among people with hyperglycemia.
Methods: A total of 6208 people with hyperglycemia who participated in the National Health and Nutrition Examination Survey from 2005 to 2014 were enrolled. Diabetes complications included congestive heart failure, coronary heart disease, angina, stroke, myocardial infarction, diabetic retinopathy, and nephropathy. Mortality was obtained from the National Death Index until 2015. Urinary nitrate was measured by ion chromatography coupled with electrospray tandem mass spectrometry, which was log-transformed and categorized into tertiles. Logistic regression models and Cox proportional hazards models were respectively performed to assess the association of urinary nitrate with the risk of diabetes complications and disease-specific mortalities.
Results: After adjustment for potential confounders, including urinary perchlorate and thiocyanate, compared with the participants in the lowest tertile of nitrate, the participants in the highest tertile had lower risks of congestive heart failure (odds ratio [OR] 0.41; 95% CI, 0.27–0.60) and diabetic nephropathy (OR 0.50; 95% CI, 0.41–0.62). Meanwhile, during a total follow-up period of 41 463 person-years, the participants in the highest tertile had lower mortality risk of all-cause (hazard ratio [HR] 0.78; 95% CI, 0.62–0.97), cardiovascular disease (CVD) (HR 0.56; 95% CI, 0.37–0.84), and diabetes (HR 0.47; 95% CI, 0.24–0.90), which showed dose-dependent linear relationships (P for nonlinearity > 0.05). Moreover, no association between nitrate and cancer mortality was observed (HR 1.13; 95% CI, 0.71–1.80).
Conclusion: Higher urinary nitrate is associated with lower risk of congestive heart failure and diabetic nephropathy, and lower risk of all-cause, CVD, and diabetes mortalities. These findings indicate that inorganic nitrate supplementation can be considered as a supplementary treatment for people with hyperglycemia.
Introduction
Nitrate is a natural chemical substance that exists widely in the environment and food. Accumulating evidence has shown that its major source in the general population is from drinking water and food, including plants, vegetables, fruits, dairy products, and meats.[1,2] Measurement of urinary nitrate has been frequently used to assess its intake levels in humans[3] Some in vivo studies in humans and mammals indicate that circulating nitrite rather than nitrate reflects endothelial-dependent NO synthesis in humans and mammals. It is clearly established that the major urinary metabolite of nitric oxide (NO) is nitrate.[4] Urinary and serum nitrate levels were associated with the progression of infection, gastroenterological conditions, hypertension, renal and cardiac disease, inflammatory diseases, transplant rejection, diseases of the central nervous system, and others.[5] It has been documented that circulating perchlorate and thiocyanate have internal competitive effects on nitrate metabolism.[6] Accumulating evidence has suggested that perchlorate, nitrate, and thiocyanate could competitively inhibit thyroid iodine uptake and exert potential adverse effects on thyroid function. Therefore, when analyzing one of the health effects, it is necessary to consider the influence of the other 2 factors.
Currently, there are reports from many animal and human studies that have examined the health impacts of perchlorate, nitrate, and thiocyanate, and the controversy is largely from the health effects of nitrate among people with hyperglycemia. The prevalence of diabetes has increased dramatically over the past 3 decades.[7] It has been demonstrated that the hyperglycemia condition can disrupt the metabolism of nitrate/nitrite and NO through increased oxidative stress, accumulation of advanced glycation end products, increased asymmetric dimethylarginine, and decreased L-arginine bioavailability and NO synthase, contributing to the consequent complications of hyperglycemia in metabolism and vascular.[8,9] Moreover, a previous study has demonstrated that with progressive development of hyperglycemia, more and more superoxides accumulate, which further inhibits endothelial nitric oxide synthase, forming a vicious cycle.[10] Therefore, inorganic nitrate supplementation is considered to be a supplementary treatment for patients with diabetes because animal studies found that dietary nitrate intake can restore NO homeostasis and maintain steady-state NO levels under the context of disrupted metabolism of NO.[11] However, while some randomized controlled trials of short-term interventions (2 weeks to 6 months) with supplementary nitrate have shown that dietary nitrate supplementation among patients with prediabetes or diabetes can significantly affect the level of serum glucose or insulin in the body, others have shown that nitrate supplementation has no significant effect on blood pressure, insulin sensitivity, and other metabolic parameters in patients. These results were inconsistent, probably because these studies mainly focused on the hypoglycemic effects with relative short intervention periods or small sample sizes, which makes it difficult to clarify the potential health impacts on the development of diabetes complication and long-term survival.[12–17] More importantly, evidence from large or long-term observation studies for clarifying the association of nitrate with diabetes complications and long-term survival among people with hyperglycemia is still lacking.
To fill this gap, this study aimed to simultaneously examine the association of urinary perchlorate, nitrate, and thiocyanate with complications of diabetes and mortality of all-cause, cardiovascular disease (CVD), and diabetes to elucidate whether and how nitrate is associated with the complications of diabetes and long-term survival among patients with hyperglycemia.
J Clin Endocrinol Metab. 2023;108(6):1318-1329. © 2023 Endocrine Society