Heavy metals are well-known environmental pollutants with widespread distribution associated with natural and man-made sources. Within the previous few decades, persistent discharge of sewage and untreated industrial effluents into the environment has drastically heightened heavy metal contamination to a manifold [1]. On entrance into the human body, these ubiquitous substances accumulate preferably in vital organs (e.g., liver, kidneys and pancreas) of metabolic interest [2]. Such accumulation has a deleterious impact on glucose metabolic pathways, including those for the production of glucose from non-carbohydrate sources (i.e., gluconeogenesis), production of glucose from carbohydrate materials (i.e., glucogenesis), and the breakdown of glucose (i.e., glycolysis) by altering and/or inhibiting the activity of key enzymes [3]. Such alterations disrupt hepatic glucose homeostasis and are linked to the development of eye disorders [4]. Heavy metals are known to produce free radicals or oxidants (e.g., ROS and RNS) which weaken the body’s antioxidative defence mechanism [5]. Thus, they are considered “contributory hallmarks” seen in virtually all human diseases. Exposure to high-pressured oxygen, ultraviolet rays, ionizing radiation, irritants, chemical pollutants, and pathogenic microbes potentiates the susceptibility of the eye to the damaging effects of ROS and RNS [6].

Carbohydrate metabolism often starts with glycolysis — “the breakdown or splitting of sugars” and the primary organ involved is the liver [7]. This process converts glucose into pyruvate and is mediated by the catalytic actions of about ten enzymes [2, 8]. When glucose homeostasis is impaired or distorted, glucose accumulates in the blood with a characteristic feature of causing diabetes, which if not properly managed leads to secondary pathologies such as diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, and metabolic syndrome. Due to their effect on carbohydrate metabolism, several heavy metals have been implicated in eye diseases. For example, the glycolytic pathway can be impaired by the effect of cadmium on the activities of phosphofructokinase in the retinal muscles of the eyes [9]. Additionally, previous reports have linked cadmium to the elevated activities of xanthine oxidase, glutamate dehydrogenase, and amino acid oxidase, which are involved in amino acid catabolism in Cory catfish [10]. Eye diseases may be aggravated by the derangement of carbohydrate metabolism, in which heavy metals are directly or indirectly implicated. For instance, oxidative exhaustion is a major factor in the pathogenesis of many vision-impairing diseases such as cataracts and retinal degeneration and is linked to the intraocular generation of ROS [11]. ROS especially from extra-mitochondrial sources facilitates the oxidative deactivation of numerous glycolysis-regulating enzymes, of which the most susceptible ones are pyruvate kinase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [12]. With the prevalence of poorly controlled diabetes especially in underdeveloped nations, its complications including diabetic retinopathy and other eye diseases increase to a manifold, especially among the elderly. Therefore, it is pertinent that the underlying mechanisms and the contributory factors to the pathogenesis of eye diseases be properly understood. Such understanding may uncover drug targets, and proffer non-pharmacological advice as well as other preventive measures against heavy metal pollution. Therefore, the current systematic review is aimed at addressing these questions:

1. What is the link between toxic heavy metal exposures, glucose metabolism and the occurrence of eye diseases secondary to altered glucose metabolism (diabetes) in humans?

2. What precautionary measures can be instituted to reduce the exposure, disease progression and burden?

Aim of the study. The purpose of this study is to uncover the negative impacts of heavy metals on carbohydrate metabolism, their mechanisms and contributory factors as well as the effects of these on the aetiogenesis, pathophysiology and progression of eye diseases.

Methods

Strategy for search of literature. In January and March 2023, three authors conducted independent multiple online searches on 10 databases (Scopus, Cochrane Library, CINAHL, National Library of Medicine, Biomed Central, PubMed, ScienceDirect, Embase, Google Scholar, and MEDLINE). In July 2024, we updated our search on these databases to include recent publications. The search prevailed on studies that reported the association between heavy metals, carbohydrate metabolism and eye diseases in humans. The search was performed using the following keywords “heavy metals and carbohydrate metabolism”, “carbohydrate metabolism and eye diseases”, “heavy metals and hyperglycaemia in eye diseases”, “role of heavy metals in diabetic retinopathy”, “ocular pathologies and toxic metals”, and “altered carbohydrate metabolism and eye health”. These keywords were arranged using Boolean operators. The search was limited to papers published in the English language. Additionally, relevant publications were hand-picked from the references of searched articles.

Study inclusion and exclusion criteria. Study inclusion was based on the following criteria: (1) studies in which the role of heavy metals in carbohydrate metabolism was discussed, (2) reported the role of carbohydrate metabolism in eye diseases, (3) reported the association of toxic metals with eye diseases, (4) reported the relationship between heavy metals and hyperglycaemia, (5) published in peer-reviewed journals, and (6) written and published in the English language. The exclusion criteria were: (1) study design (brief report, blog post, letter to editor, commentary, editorial), (2) unavailability of full texts, and (3) English language was not the language of communication.

Selection and eligibility of studies. In line with the inclusion and exclusion criteria, the selection of studies was conducted in two phases: (1) title and abstract screening, and (2) full-text assessment for specific inclusions. Included studies were screened for eligibility in tandem with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines as described by Moher et al. [13] with modifications by O’Dea et al. [14] and Page et al. [15].

Assessment of quality. Papers included in this study were assessed for quality using the Critical Appraisal Skills Programme (CASP) checklists [16]. The checklists provide a careful evaluation of the methods, results’ validity, application, and utility of the included articles. They are made up of 10—12 questions with three possible responses (“yes”, “no”, and “can’t tell”).

Data extraction and analysis. In adherence to the CASP checklists, the following data: study information (i.e., authors, location and date of publication); design of the study; and major findings of the study amongst other important information were extracted from each study included in this systematic review (Supplementary file 1), and analysed using the narrative synthesis method.

Results

Selection of studies. A total of 128 studies were retrieved from the databases searched. Of these, 69 duplicates were removed during the data cleaning process. Five papers were excluded for not being published in the English language. Screening by title and abstract removed 28 articles that did not match the inclusion requirements. Thus, 26 papers were further assessed for eligibility and specific inclusion, after which 24 studies [17—40] were considered “eligible” for inclusion in this narrative synthesis as illustrated in the PRISMA flow chart (Fig. 1).

Study characteristics. Of the 24 studies, five [18, 20, 29, 32, 37] were laboratory investigations (original research). Eleven studies [19, 21, 24—28, 30, 31, 33, 39], four [22, 34, 35, 40], and four [17, 23, 36, 38] were designed as reviews, cohort and cross-sectional studies, respectively. All studies reported any of the following or a combination of two or more; heavy metals, carbohydrate metabolism, hyperglycaemia, eye diseases, diabetic retinopathy, and interaction of heavy metals with enzymes such as glucokinase and pyruvate kinase as well as metal-induced insulin insensitivity. No clinical trial was found among the studies in this systematic review (Table).

Quality and risk of bias assessment. After critically appraising the quality of studies in the present study, all studies [17—40] included were of high quality (see supplementary Table). Reporting bias and duplication were minimised by searching the registers of PROSPERO (the International Prospective Register of Systematic Reviews) for overlapping reviews. In all cohort studies included in this study, we specifically looked for selection bias which might compromise the generalisability of the findings. The representativeness of the cohort for a defined population was also checked. To ensure quality, we included highly rated journal articles which were critically appraised using the Critical Appraisal Skills Programme checklists. To minimise the risk of individual bias, studies included in this review were assessed independently for quality by 3 reviewers, and any disagreements were resolved by a fourth reviewer.

Impact of heavy metals on carbohydrate metabolism. The impact of heavy metals on bodily processes and functions can never be overemphasised. Cai et al. [17] estimated the association of six heavy metals (As, Cd, Cu, Ni, Pb, and Zn) with glycated haemoglobin (HbA1c) levels using both single-metal exposure and multi-metal co-exposure models. Based on their findings, there were significant associations between copper and nickel with HbA1c levels in all study participants. HbA1c is a bioindicator of prolonged carbohydrate (glucose) metabolism and is readily not affected by short-term changes in blood glucose levels. After adjusting key clinical parameters (i.e., fasting blood glucose, age, body mass index, triglyceride, and total cholesterol levels), Chang et al. [40] reported a strong correlation between HbA1c and Log blood Pb, such that even a slight increase in blood Pb levels gave a corresponding increase in HbA1c levels. The authors concluded that HbA1c serves as both a valuable diagnostic and prognostic indicator in individuals with diabetes, as well as a useful tool for predicting the future risk of diabetes in non-diabetic persons. Similarly, Trouiller-Gerfaux et al. [38] reported a positive interaction between serum levels of Cd and HbA1c levels. Thus, this provides a mechanistic insight into the onset of hyperglycaemia. Even at low exposure levels, cadmium exaggerates gluconeogenesis, hinders the direct secretion of insulin into the bloodstream, and insulin insensitivity at the target sites, particularly the adipocytes, culminating in a drastic decline in the uptake of blood glucose, and hyperglycaemia. Furthermore, Strydom et al. [31] reported that heavy metals (As, Cd, Cr, Ni, and Pb) commonly found in groundwater in South Africa are known to interfere with xenobiotic metabolic pathways including carbohydrate metabolism (glycolysis, the Krebs cycle, and oxidative phosphorylation), protein, and lipid metabolism. Based on their findings, the authors concluded that these and other toxic metals cause environmental pollution, complicate human and animal health, and potentiate numerous diseases as consequences of their impacts on the central metabolic pathways.

Ocular pathologies: consequences of distorted carbohydrate metabolism. Santos et al. [30] reported retinopathy which is one of the complications of diabetes to be a major cause of acquired blindness in young adults. According to these authors, hyperglycaemia is pivotal to the aetiogenesis of retinopathy, especially as the microvasculature of the retina steadily interfaces with high glucose, leading to distorted metabolic, structural and functional outcomes.

Hyperglycaemia causes mitochondrial dysfunction of the retina and compromises the electron transport chain system with a resultant generation of superoxide ions. Thus, the retina is not relieved from a continuous cycle of damage. As reported by Lutty [24], ophthalmic complications of hyperglycaemia are prominently seen in the cornea and retina of the eyes. Complications of the cornea are in about 75% of diabetic patients and are collectively known as diabetic keratopathy. In another study, Poll-The and Wenniger-Prick [28] linked ocular pathologies and inborn error of metabolism (IEM), particularly errors in carbohydrate metabolism, metal metabolism, protein metabolism, and lipid metabolism. Notably, disorders due to inborn error of metabolism linked to ocular motor malfunctioning and eye diseases are neurotransmitter disorders, lipid storage diseases, and respiratory chain disorders. Accumulation of intermediates of metabolism and/or abnormal by-products of metabolism secondary to errors of synthetic pathways or deficient energy metabolism impact negatively on the eyes’ physiology and are all implicated in the pathogenesis and pathophysiology of eye diseases. Zhao et al. [36] reported a 43.4 and 4.2% prevalence of insulin resistance and glaucoma, respectively among older men with high blood pressure, increased waist circumference, fasting glucose and HbA1c levels. Additionally, the authors reported the prevalence of metabolic syndrome, pre-diabetes, and diabetes to be 32.1, 49, and 17.1, respectively. Also, there was a significant association between the duration of diabetes and the occurrence of glaucoma in the study population. Study participants with 5 years of poorly controlled diabetes had a higher prevalence of glaucoma.

High glycaemic diet and age-related eye diseases. Francisco et al. [19] reported the influence of dietary habits on the occurrence and advancement of age-related eye conditions, specifically AMD, cataracts, diabetic retinopathy, and glaucoma. Several studies have associated several ocular pathologies (e.g., age-related macular degeneration (AMD), cataracts, and retinopathy) with high glycaemic diets and glycation-mediated products [i.e., advanced glycation end products (AGEs)]. According to Francisco et al. [19], AGEs are produced when carbohydrates and their metabolites are non-enzymatically added to proteins. AGEs are generated both endogenously and exogenously (e.g., from cigarette smoke) and initiate oxidative stress and mediate inflammatory processes. When accumulated, especially in the event of persistent hyperglycaemia, AGEs exert their toxicities, majorly cytotoxicities. Similarly, Rowan et al. [37] investigated the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model and reported that high glycaemic diets caused photoreceptor degradation and other characteristics related to macular degeneration including the atrophy and hypopigmentation of the retinal pigment epithelium, and accumulation of lipofuscin in the retina, leading to the progressive loss of function of the retinal pigment epithelium and retinal degeneration. Conversely, consumption of low glycaemic diets was not associated with features of age-related macular degeneration.

Mechanistic approach to heavy metals-induced altered carbohydrate metabolism. In carbohydrate metabolism, the conversion of glucose to sorbitol is catalyzed by aldose reductase (AR), part of the polyol pathway, which is implicated in diabetic retinopathy. AR reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase. This NADPH-dependent reaction leads to oxidative stress due to the production of reactive oxygen species (ROS). The elevated activity of AR depletes glutathione levels, making oxidative stress a major contributor to diabetic cataractogenesis (Fig. 2). The intracellular accumulation of sorbitol creates osmotic stress, leading to electrolyte imbalance, tissue degradation, and cataract formation [27]. Sorbitol’s sluggish conversion to fructose and its polar nature hinder its intracellular clearance. Experimental studies in animals reveal that polyols accumulate, leading to fibre liquefaction and lens opacities [27]. AR enhances diacylglycerol concentrations, which activate protein kinase C, regulating extracellular matrix synthesis and removal. As AR is present in tissues like the eyes, nerves, and nephrons — sites that develop diabetic complications — its inhibition has become a therapeutic target in diabetes management. Heavy metals, such as cadmium, bind covalently to cysteine-SH groups, inhibiting key enzymes like hexokinase and phosphofructokinase, which are essential for glucose metabolism. Glutathione, in its reduced form, scavenges free radicals, and its function depends on NADPH. The pentose phosphate pathway, a primary source of NADPH, converts glucose-6-phosphate into 6-phosphogluconate, producing NADPH in the process [27, 41]. Arsenic disrupts ATP generation during glycolysis by replacing phosphate anion with arsenate in a process called “arsenolysis” [42]. Heavy metals distort carbohydrate metabolism by inhibiting biochemical molecules crucial for glucose homeostasis, playing a key role in the progression of diabetes. For example, arsenic induces oxidative stress and insulin resistance, impairing glucose metabolism. Cadmium prevents insulin release, disrupts insulin receptors, and leads to hyperglycaemia. Mercury and lead destroy beta cells of the pancreas, decreasing insulin production [27]. Mitochondrial dysfunction plays a pivotal role in diabetic retinopathy, with heavy metals mediating ROS generation, leading to oxidative stress, decreased energy production, inflammation, and retinal neurodegeneration [39]. Miller et al. [39] linked changes in mitochondrial function and redox balance to stenosis of blood vessels in diabetic retinopathy, implicating these changes in the pathogenesis of microvascular diseases. Heavy metals-induced oxidative stress further exacerbates these issues, contributing to mitochondrial dysfunction, breakdown of the blood-retinal barrier, and neurodegeneration in the retina (Fig. 3).

Prevention of ocular pathologies secondary to altered carbohydrate metabolism. Rowan et al. [37] reported that consumption of low glycaemic diets reversed the high glycaemic diet-induced features of age-related macular degeneration, suggesting that lifestyle modifications, especially proper dieting are critical precautionary measures for eye diseases secondary to distorted carbohydrate metabolism. Additionally, the authors reported that untargeted metabolomic approaches strongly associated microbial cometabolites, especially serotonin with protection against features of age-related macular degeneration. While gut microbiota, especially those of the Clostridiales order responsive to high glycaemic diets were associated with features of age-related macular degeneration, the Bacteroidales order responsive to low glycaemic diets arrested and/or prevented features of age-related macular degeneration. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet- and age-induced features of age-related macular degeneration, implying a functional relationship between dietary carbohydrates, the metabolome, including microbial cometabolites, and age-related macular degeneration. Based on their findings, the authors concluded that a simple dietary intervention may be useful as an adjuvant in the management of AMD. According to Miller et al. [39], since the bioenergetics of the retina are impacted during the initial phases of diabetes, resulting in mitochondrial disease of the retina and other effects that go beyond alterations in ATP levels, preserving the integrity of mitochondria may help mitigate retinal illness. Additionally, since mitochondrial disease of the retina is implicated in DR, AMD, cataract, and glaucoma, research should be focused on novel mitochondria-targeted therapeutic options to reverse altered bioenergetics in diabetes.

Discussion

Our findings, based on 24 selected articles, have linked heavy metals to the onset, progression, and complications of eye diseases, including diabetes. With the established connection between diabetes and non-communicable diseases, its prevention and control are crucial for preventing such pathologies [43]. Glycolysis provides the energy needed for retinal phototransduction and vision processing [39, 44]. Disruptions in the glycolytic pathway may impair the retina’s normal function, leading to eye diseases. ROS generated by heavy metals interferes with insulin receptor signalling and glucose transport, exacerbating insulin resistance [17, 45]. Furthermore, trace element exposure affects age-related eye disorders [46]. In pre-diabetes, insulin resistance leads to persistent hyperglycaemia, which triggers diabetes. Similarly, in diabetes, insulin resistance causes complications like retinopathy, cataracts, and optical pathologies. Numerous studies have established a link between high-glycaemic foods and the development of eye diseases, including cataracts and AMD [19, 47—52]. Moghaddam et al. [50] reported a significant correlation between glycaemic index, insulin load, and cataract risk. Heavy metal exposure occurs daily through the food chain, water, ambient air, and electronic devices [53], posing widespread health risks [54].

Heavy metals like cadmium, lead, zinc, arsenic, and nickel are associated with diabetes [17]. Arsenic exposure mainly comes from contaminated water due to industrial effluent, agrochemical wastes, and preservatives [55]. Cadmium exposure occurs through food and smoking [56], while zinc, copper, and nickel are encountered via water, food, and smoking [53]. Lead exposure is common in herbal products, water, household dust, and occupational environments [34]. Both essential and toxic metals are involved in diabetes. Trace elements like zinc, copper, and nickel are vital for physiological processes, but imbalances can trigger diabetes [40]. High copper levels act as a pro-oxidant, depleting antioxidant enzymes [57]. Excess nickel increases glucose metabolism and disrupts pancreatic functions, elevating blood glucose [56]. Toxic metals, including mercury, cadmium, lead, and arsenic, lack physiological benefits and instead induce oxidative stress (OS), a major factor in diabetes pathogenesis [58]. In the retina, melanosomes in retinal pigment epithelial cells are highly susceptible to heavy metal toxicity due to melanin’s affinity for metals. Common eye diseases, such as AMD, cataracts, and diabetic retinopathy, are linked to diabetes. The reviewed studies provide insights into the molecular events preceding hyperglycemia, diabetes, and related complications. Heavy metals disrupt carbohydrate metabolism, worsening diabetes and its complications [31]. Lee et al. [59] also linked Pb and Cd exposures to glaucoma. Additionally, Hg, Cd, and Pb are major risk factors for AMD, a leading cause of blindness in sub-Saharan Africa. The burden of heavy metal exposure is particularly high in low- and middle-income countries (LMICs), where nutrient deficiencies, such as vitamins E, A, and C, further aggravate eye health risks. Diets in these regions have shifted from nutrient-rich traditional foods to high-calorie, and low-nutrient diets, increasing the prevalence of lifestyle-related diseases like diabetes and cardiovascular conditions. Our findings highlight that although glucose is essential for normal eye physiology, distorted glucose homeostasis contributes to eye diseases. Persistent low-dose cadmium exposure is linked to insulin resistance and hyperglycaemia, which, if uncontrolled, leads to complications like retinopathy. The consumption of low-glycaemic diets and the use of metal chelators may offer non-pharmacological approaches to preventing eye diseases related to diabetes.

Limitation. There may be some publication bias in this analysis, especially as only publications published in English were considered.

Conclusion

Taken together, this review presents a comprehensive update on the role of toxic heavy metals in the derangement of glucose metabolism leading to hyperglycaemia, insulin insensitivity, diabetes and its complications — particularly diabetic cataracts and retinopathy. There are no safe exposure levels to toxic heavy metals. Furthermore, this systematic review shows that chronic and intermittent exposure to these ubiquitous pollutants may be implicated in the pathogenesis of metabolic disease. Therefore, policy formulation and implementation must be ensured to minimize toxic metal exposures among the human population.

Acknowledgments. The authors are grateful to anonymous reviewers for the comments provided in improving the manuscript.

Financing the work. The study received no funding.

Authors’ contribution:

Study concept and design: Orisakwe O.E.

Data collecting and analysis: Udom G.J.

Text writing: Udom G.J., Oritsemuelebi B.

Editing: Frazzoli C., Bocca B., Ruggieri F.