Microplastic and nanoplastic exposure and risk of diabetes mellitus

Abstract

The issue of plastic pollutants has become a growing concern. Both microplastics (MPs) (particle size < 5 mm) and nanoplastics (NPs) (particle size < 1 µm) can cause DNA damage, cytotoxicity, and oxidative stress in various organisms. The primary known impacts of microplastic/nanoplastic are observed in the liver and respiratory system, leading to hepatotoxicity and chronic obstructive pulmonary disease. Although research on the effects of MPs and NPs on diabetes is still in its early stages, there are potential concerns. This editorial highlights the risk to diabetics from co-exposure to contaminants and MPs/NPs, supported by evidence from animal studies and the various chemical compositions of MPs/NPs.

Key Words: Microplastics; Nanoplastics; Plastic pollution, Diabetes mellitus; Insulin resistance

Core Tip: Laboratory studies provide strong evidence of the impacts of microplastic and nanoplastic exposure on glycolysis, blood glucose levels, insulin secretion, and insulin resistance. However, the lack of long-term human studies results in inconclusive conclusions regarding the direct effects of microplastics/nanoplastics on the risk of developing diabetes.

INTRODUCTION

Microplastics (MPs) (MPs < 5 mm) and nanoplastics (NPs) (NPs < 1 μm) are small plastic particles produced by industry or degraded by physical and chemical activities[1]. Negative influences of the exposure of MPs or NPs on human health include oxidative stress, inflammation, endocrine disturbance, liver metabolism, kidney damage, and even carcinogenicity[2]. Most of the studies focus on hepatoxicity and immunotoxicity since the liver and immune system are highly susceptible to potential toxicity from environmental pollutants. In contrast, the findings on the impacts of MPs/NPs causing the development of diabetic mellitus are limited. When MPs or NPs contain endocrine-disrupting compounds, such as bisphenol A or phthalates, their impacts on rapid elevation in plasma insulin and increase the risk of developing type 2 diabetes are foreseeable[3]. Mostly, like plastics, MPs/NPs can be made of polyethylene, polypropylene, polystyrene, and polyvinyl chloride[4]. Polystyrene MPs/NPs have been found to accumulate in the food chain and have exhibited various impacts on human organs[5]. Here, we summarize the shreds of evidence on the potential risks of diabetes mellitus under the exposure of MPs/NPs (Figure 1).

Figure 1 Microplastic and nanoplastic exposure and risk of diabetes mellitus. Humans are exposed to microplastic and nanoplastic from takeaway or drink containers. Microplastics (MPs) and nanoplastics (NPs) carry different functional groups, bringing different effects on diabetic symptoms. Animal evidences support the potential risks of diabetes mellitus under the exposure of MPs and NPs.

THE EXPOSURE OF MPS/NPS ON THE RISK OF DIABETES

Diabetes mellitus is caused by a combination of genetic and environmental factors. The environmental factors that might increase the risk of diabetes mellitus encompass lack of physical activity, obesity, exposure to medicines and toxins, virus infection, geographic areas, etc.[6,7]. MPs are released from takeaway containers, and individuals who order takeaway food 5–10 times a month may consume 145–5520 microplastic particles from these containers[8]. NPs are defined as the size ranging between 1 nm and 1 μm[9]. MPs/NPs are evenly distributed within the aquatic environment. The effect of MPs/NPs influences the growth rate of the shrimps, that might due to the change of their gut microbial diversity[10]. In addition, exposure to MPs/NPs presented endocrine-disrupting effects, reproductive hormones, or even gene expression patterns[11]. NP exposure impaired hepatic function and lipid metabolism. NPs affected the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, disrupting glucose metabolism[12]. The increased phosphorylation of insulin receptor substrate-1 leads to the decrease of Akt in the PI3K/Akt pathway, resulting in insulin resistance and increased plasma glucose in the mouse liver[12]. Huang et al[13] demonstrated that incorporating polystyrene MPs into the diet of mice induced insulin resistance and increased levels of plasma lipopolysaccharides and pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin (IL)-1β. Similar to aquatic animals, the diversity of gut microbes changed with an increase in the population of Gram-negative bacteria[13]. These findings suggest that exposure to MPs and NPs leads to elevated blood glucose levels and insulin resistance. This negative outcome may result from alterations in gut microbial diversity, which trigger an inflammatory response and inhibit the insulin signaling pathway. Not only oral exposure to NPs but airborne NPs also presented harmful effects on human health, such as respiration systems, endocrine system, and cardiovascular system etc.[14]. Although inhalation exposure to NPs is known to trigger the development of chronic pulmonary disease[15], emerging studies have also indicated that mice exposed to airborne NPs also exhibit impaired insulin resistance[16]. Nevertheless, there remains a lack of clinical study on the exposure of MPs/NPs and diabetic risk. Marfella et al[17] reported that presence of MPs/NPs in carotid plaques in clinical patients were correlated with cardiovascular events. Interestingly, MPs/NPs were found in the carotid plaques of 24% of the recruited patients with diabetes.

Co-exposure of contaminants and MPs/NPs on the risk of diabetes

Environmental pollution caused by the suspension of MPs/NPs only is usually accompanied by metal or toxic chemicals. The high surface ratio and lipophilicity of polystyrene NPs make them easy to absorb heavy metals in the environment[18]. Cadmium is a common contaminant found in soil and water[19]. In addition to cadmium treatment, combined exposure to MPs enhanced zebrafish's toxicity, growth, and reactive oxygen species accumulation[18]. Furthermore, the combined treatment of cadmium and polystyrene NPs exhibited synergistic effects on oxidative stress and kidney damages[20]. The mice that were co-exposure to lead and MPs experienced insulin resistance and damaged glucose tolerance via the nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor-kappa B (NF-κB) signaling pathway by increase in phosphorylated p-NF-κB protein levels and reduction of Nrf2 mRNA and protein level[21].

THE FUNCTIONAL GROUPS OF MPS/NPS ON THE RISK OF DIABETES

Here are listed couples of studies that exhibited different functional group of NPs also brings different effects on diabetic symptoms.

Amino-modified polystyrene nanoparticles

Polystyrene nanoparticles (PS-NH2) nanoparticles are known to induce inflammation[22,23]. The nanoparticles (NH2)-based nanoparticles not only induced NOD-like receptor family pyrin domain containing 3 inflammasome and proinflammatory IL-1β release but also medicated apoptosis through the release of cathepsin B and damage to the mitochondrial membrane[23]. Besides, PS-NH2 nanoparticles particularly inhibited the phagocytosis of Escherichia coli by M1 and M2 microphage[24]. In liver slides, the downregulation of inflammation markers, IL-1β and IL-10, was observed, and the viability of the cells significantly decreased after exposure to NH2-based nanoparticles[25]. The NH2 group exhibited the most significant fasting blood glucose elevation, glycogen accumulation, and insulin resistance[26]. Those effects might be due to the positive group of NH2 based nanoparticles, which makes it easy to enter the cell by reducing the thickness of the lipid layer[27].

Metal-based NPs: Research has shown that exposure to certain metal-based nanoparticles, such as titanium dioxide or zinc oxide, can lead to oxidative stress and inflammation in animal models[28]. These effects can disrupt glucose homeostasis and potentially contribute to the development of insulin resistance and diabetes. MPs/NPs can act as vectors for heavy metals like copper and zinc to form a complex because they are easily absorbed by MPs/NPs[29]. The oxygen groups on NPs increase surface polarity, enhancing the absorption of metal ion[30]. The co-localization of silver and NPs in various cell compartments of Caco-2 cells (a human intestinal carcinoma cell line) was further confirmed by confocal analysis, suggesting the tendency of association between metal and NPs[31]. Zhong et al[32] found that co-exposure to metals and NPs elevated ferroptosis-related genes, leading to renal damage in mice. Ferroptosis, a novel form of programmed cell death, is involved in the development of diabetics[33]. In diabetic mice, there was an observed increase in the expression of ferroptosis markers, specifically acyl-coenzyme A synthetase long-chain family member, and a decrease in the expression of glutathione peroxidase 4. These changes further contributed to the dysfunction of pancreatic β cells[34].

Carbon-based NPs: Carbon-based nanoparticles, such as carbon nanotubes and graphene oxide, have also been studied for their impact on metabolic health[35]. Some animal studies suggest that exposure to these nanoparticles can lead to liver damage, changes in lipid metabolism, and impaired glucose tolerance, which are risk factors for diabetes[36]. The acute exposure of carboxyl NPs exhibited toxicity in daphnids and elevated the expression of metabolic enzymes, such as lactate dehydrogenase (LDH)[37]. LDH, involved in catalyzing pyruvate into lactic acid during glycolysis, has been determined to be an assessment of the progression of diabetics[38]. The level expression of LDH presented a positive correlation with glucose level, suggesting that exposure to carboxyl NPs presents the risk of developing diabetics.

THE ANIMAL STUDIES OF THE NP EXPOSURE ON THE RISK OF DIABETES

The mice exposed to polystyrene NPs for nine weeks presented the elevation in the fasting blood glucose levels, glucose intolerance, and insulin resistance[26]. Those conditions were more severe in diabetic mice. Blood glucose, glucose intolerance, and insulin resistance were increased under the condition of oral exposure to different dosages of polystyrene NPs for 8 weeks in a mouse model[39]. Even though the exposure time was shortened to two weeks, the liver tissue structure was abnormal and filled with inflammatory cells[40]. Using ultra-high-performance liquid chromatography coupled with orbitrap mass spectrometry analysis, 353 metabolites were identified in hepatic samples exposed to polystyrene NPs for two weeks[40]. Notably, levels of cortisol and acetylcholine were significantly reduced. Cortisol was found to be linked to insulin secretion[41], while acetylcholine played a direct role in mediating insulin secretion[42]. Besides oral exposure to NPs, airborne NPs also presented a similar effect on animal metabolism. Mice were kept in an airborne nanoplastic (NP) chamber with NP exposure doses ranging from 0.1 mg/day to 0.8 mg/day. Under two weeks of airborne NP exposure, the eating, drinking, and body weight were decreased while blood glucose was elevated[16]. The effect of elevated glucose was the consequence of insulin signaling impairment, in which FoxO1, the transcript factor of gluconeogenesis, was activated and subsequently promoted the expression of downstream genes, such as phosphoenolpyruvate carboxykinase 1, glucose-6-phosphatas, and peroxisome proliferator-activated receptor-γ coactivator-1α[16]. Consequently, exposure to polystyrene-NPs through oral or airborne exposure led to dysregulated insulin secretion and insulin resistance.

Synergistic effects of polystyrene NPs were observed in diabetic animals. The oral exposure of polystyrene NPs in the mice treated with streptozocin injection, which is commonly used to induce diabetic situations. The oxidative stress, glucose intolerance, and insulin resistance were aggravated than that of their health counterpart[39]. The oxidative stress could be alleviated by treating with Akt activator suggesting polystyrene NPs involving manipulating the level of reactive oxygen species through Akt phosphorylation pathway[39]. In type 2 diabetic mice, exposure to 0.5 mm (500 nm) NPs resulted in impairment in glucose tolerance and an increase in blood glucose level[43]. Furthermore, the hepatic lipid metabolism was distributed, and liver fibrosis was observed by activating the Wnt/β-catenin signaling pathway.

CONCLUSION

Animal studies provide strong evidence of the impacts of MPs and NPs exposure on glycolysis, blood glucose levels, insulin secretion, and insulin resistance. However, the lack of long-term human studies results in ambiguous conclusions regarding the direct effects of MPs/NPs on the risk of developing diabetes. Further research is essential to comprehensively understand the mechanisms of MPs/NPs toxicity in diabetic patients and to develop strategies for preventing these risks. With the risks of diabetes due to MPs/NPs exposure have been underscored, the significance and urgency of addressing MPs/NPs pollution for human health should be prioritized.