Sex-specific associations of blood and urinary manganese levels with glucose levels, insulin resistance and kidney function in US adults: National health and nutrition examination survey 2011–2016
Introduction
Noncommunicable diseases, mainly cardiovascular diseases (CVD), cancer, chronic respiratory diseases, and diabetes, accounted for three-quarters of global deaths in 2017 (Collaborators., 2018). Because diabetes independently increases the risk of death by cardiovascular and renal diseases up to 1.3- to 3-fold, prevention and control of diabetes is a top priority for the prevention of noncommunicable diseases (Rao Kondapally Seshasai et al., 2011). Diabetes is a complex, chronic illness requiring continuous medical care with multifactorial risk-reduction (ADA, 2019b). Epidemiological and mechanistic studies have begun to investigate the roles of environmental chemicals, particularly heavy metals, in diabetes development (Kuo and Navas-Acien, 2015; Yang et al., 2017), but these studies are far fewer than the extensive literature focusing on traditional risk factors of diabetes, such as body mass index, fasting plasma glucose (FPG), etc (Ding et al., 2019).
Manganese (Mn), a nutrient trace element both essential and toxic to humans, is involved in the regulation of blood glucose and cellular energy, digestion, and protection from free radicals. Previous studies reported the link between exposure to Mn and increased risk of type 2 diabetes (T2D), kidney disease (or damage of kidney function), insulin resistance, as well as altered FPG and hemoglobin A1c (HbA1c) (Jomova and Valko, 2011; Wang et al., 2016; Zhou et al., 2016; Li and Yang, 2018). Mn plays important roles in glucose, lipid, and protein metabolism, dysfunctions in which have been linked to diabetes and chronic kidney disease (CKD) (Wang et al., 2016; Riaz et al., 2019). CKD is associated with a decline in kidney function that is often progressive and estimated by glomerular filtration rate (eGFR). However, when the estimation of exposures is based on urinary analysis, the disease outcome is potentially associated with glomerular hyper- or hypofiltration (Weaver et al., 2016; Dhingra et al., 2017). The possibility of reverse causality in the exposure-outcome relationship poses a serious challenge for researchers investigating the association between environmental exposure to urinary chemicals and diabetes (Kuo and Navas-Acien, 2015).
Although previous studies (Shan et al., 2016; Du et al., 2018; Shah et al., 2018) have suggested a potential relationship between exposure to Mn and risk of diabetes, sex-specific heterogeneities and interaction among metals in the associations were rarely evaluated. In the present study, we analyzed the associations of both blood and urinary Mn with FPG, HbA1c, HOMA-IR, insulin and eGFR, as well as potential sex-dependent heterogeneities and interaction of metals among adults participating in US National Health and Nutrition Examination Survey (NHANES) between 2011 and 2016.
Section snippets
Study population
The NHANES program is a series of cross-sectional surveys conducted on the US general population to collect data on the diet, nutritional status, health, and health behaviors (Zipf et al., 2013). In the present study, we included data (n = 29,902) from surveys conducted in 2011–2012, 2013–2014, and 2015–2016 cycles because other cycles did not test blood and urinary Mn levels. A random subsample was selected for blood and urinary Mn and other metal assays during the three cycles. These
Clinical and demographic characteristics of the study participants
Table 1 shows the clinical and demographic characteristics of the1417 study participants (801 men and 616 women), of whom 39.2% were 18–39 years old, 43.1% white, and 60.9% had at least some college education. The median clinical values (25th, 75th): was 5.55 (5.16, 6.05) mmol/L of FPG, 141.99 (134.63, 150.91) ml/min per 1.73 m2 of eGFR, 5.50 (5.20, 5.80) % of HbA1c, 9.17 (5.70, 14.72) μU/mL of insulin, 2.38 (1.39, 4.01) of HOMA-IR. The level of blood and urinary Mn was 9.34 (7.52, 11.60) μg/L
Discussion
In this study, we comprehensively evaluated the associations of both blood and urinary Mn with FPG, HbA1c, HOMA-IR, insulin and eGFR, as well as potential sex-dependent heterogeneities and interactions of metals among adults in NHANES 2011–2016. We observed positive linear relationships between urinary Mn with FPG and HbA1c among women, while we detected J-shaped non-linear relationships of blood Mn with HOMA-IR and insulin among men. We also found a positive linear relationship between blood
CRediT authorship contribution statement
Jingli Yang: Methodology, Software, Writing - original draft, Validation. Aimin Yang: Conceptualization, Methodology, Software, Writing - review & editing. Ning Cheng: Writing - review & editing. Wenya Huang: Validation. Peiyao Huang: Data curation. Nian Liu: Data curation. Yana Bai: Conceptualization, Writing - review & editing.
Declaration of competing interest
None.
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Aimin Yang, co-first author, the author contributed to this article equally.