Human studies investigating the link between Cd exposure and IR are limited and have yielded somewhat conflicting data. The first association between Cd content, impaired fasting glucose (IFG), and diabetes was suggested by Schwartz et al. who analyzed the data of the third National Health and Nutrition Examination Survey (NHANES III). This large, cross-sectional study revealed a significant, dose-dependent association between Cd urinary levels and IFG/diabetes prevalence, regardless of the source of Cd exposure. Another study analyzing NHANES participants for the years 2005 through 2010 aged ≥40 years revealed a complex, non-linear association between higher Cd levels and prediabetes state. Since this association varied across smoking groups and age, the authors suggested a complex relationship between Cd exposure, age, smoking habits, and prediabetes odds. Nevertheless, since no differences in the Homeostatic Model Assessment for IR (HOMA-IR) were observed across the exposure quintiles, the authors marked changes in IR as an unlikely cause of Cd effects on glucose level. The relationship between Cd exposure and T2D occurrence was confirmed in the study comparing the levels of Cd in various biological samples (blood, urine, and scalp hair) of patients having T2D (age range 31–60) with the levels in control subjects. Significantly higher levels of Cd were observed in scalp hair samples from patients compared to control individuals, along with a similar trend in observed values obtained from blood and urine samples .Studies that followed tried to establish possible mechanisms of Cd in disturbing glucose metabolism. Pizzino et al. investigated glycemic control, oxidative stress markers, and urinary Cd levels from 111 males (aged 12–14 years) living in polluted areas of Sicily and control age-matched population of 60 males living 28–45 km from the contaminated site. The results revealed altered glycemic control in adolescents that was associated with higher Cd levels. Altered glycemic control was demonstrated by the robust correlation between Cd and the homeostatic model assessment of HOMA-IR, along with markers of disturbed oxidative status. The authors identified oxidative stress disturbance to play a role in Cd-induced IR .Apart from oxidative stress induction, Cd’s ability to induce inflammation was also investigated. In a case-control, cross-sectional study, including 120 healthy controls and 105 systemic lupus erythematosus (SLE) patients, the relationship between various trace elements with SLE diagnosis, disease activity, and IR was assessed .Serum levels of Cd were higher in patients with IR. Cd’s ability to impair insulin sensitivity was connected to the positive association between Cd and the C-reactive protein (CRP). Namely, CRP as an inflammatory marker was shown to have a role in the development of diabetes .

Conflicting results from multiple studies have complicated the interpretation of Cd-mediated hyperglycemia. Jacquet et al. provided a comprehensive review of these conflicting reports in a 2016 review, where they categorized the effects as having “associations”, “no association”, or “potentiation” in diabetes.Examples of this data variability is reflected in a study of Scandinavian Caucasian women, aged 64, which showed conflicting data with the previously mentioned studies. Two thousand five hundred and ninety-five women were screened with oral glucose tolerance tests to identify subjects with T2D, impaired glucose tolerance (IGT), and normal glucose tolerance (NGT), and samples were randomly chosen from each group. Cd concentration was measured in blood and urine samples, while the HOMA-IR calculations assessed the acute insulin response. A follow-up examination was also performed. Both cross-sectional and prospective studies showed no association between Cd exposure and increased risk of T2D, impaired insulin secretion, or insulin sensitivity. The discrepancies in these results with previously published data were explained by differences in the occurrence of T2D risk factors in investigated groups, such as age, obesity, smoking, lifestyle, and ethnic predispositions. Furthermore, all women studied were aged 64+, which does not inform on the behavior of other populations. Interestingly, however, Wu et al.in their PRISMA-compliant systematic review and meta-analysis based on 11 cohort/cross-sectional studies included in the meta-analysis, determined that high Cd exposure may not be a risk factor for diabetes development. Moreover, Anetor et al. found significantly lower Cd blood levels from diabetic patients when compared to controls. This conflicted finding was partly attributed to the observed higher Zn levels in the same group of patients and the relatively small sample size (65 participants). Indeed, Cd belongs to the same group of elements as zinc, and the number of common biological targets of the two metals abound .The role of zinc in insulin regulation has been extensively examined. Zinc associates with insulin in exocytosis granules, and a significant amount of zinc is subsequently released into the extracellular space. Zinc can act as an autocrine mediator, affecting the activity of surrounding β-cells .Defects in the transporters, such as SLC30A (ZNT) for the Zn provision for insulin secretion or SLC39A (ZIP) for replenishment, result in reduced intracellular zinc and a reduction in functional insulin release .Changes in functional insulin release and alterations in zinc homeostasis may thus combine to contribute to glucose intolerance and IR.

Swaddiwudhipong and associates conducted a series of studies in Cd-exposed adults from Mae Sot District, Tak Province, in northwestern Thailand. This region was contaminated by the Cd-rich waste of Zn mines, and the population was Cd-exposed by the consumption of rice and other crops irrigated by downstream water. No association between urinary Cd levels and an increase in diabetes prevalence and risk were found . The follow-up examination conducted on 436 persons who had urinary Cd levels >5 µg/g creatinine revealed a significant increase in the prevalence of diabetes compared to baseline .

The question of the role of kidneys in Cd-induced IR has been raised earlier. The kidney is responsible for up to 20% of all glucose production, and these figures are even higher in diabetic conditions . Moreover, IR represents an early metabolic alteration in chronic kidney disease (CKD) patients, with the skeletal muscle representing the primary site of IR . On the other hand, a recent study in a group of 395 subjects from low- and high-Cd exposure areas demonstrated that glomerular filtration rate could be linked to Cd exposure and tubular toxicity . This linkage was shown to act in both dose and toxicity severity-dependent manners. The association of Cd with CKD was recently highlighted in a review by Satarug , which addressed the connection between Cd dietary intake and its effects on kidneys. However, animal studies have shown that the Cd effect on fasting blood glucose elevation is evident before signs of renal dysfunction are overt . It is, nevertheless, highly plausible that Cd acts synergistically with chronic hyperglycemia seen in diabetic nephropathy. For example, research on 65 participants, consisting of 45 T2D and 20 healthy individuals, revealed the association between higher Cd levels in the poor glycemic control group . Thus, Cd should certainly be considered as the agent of high importance in the progression of diabetes-related kidney disease, and the toxic effects of Cd in the kidney certainly further contributes to the role of Cd in IR.

Studies conducted in human subjects have shown conflicting data on the role of Cd in IR development. The obtained results depend on many factors, and the actual prevalence of diabetes in the study population seems to have an important impact on them. Although questionable due to ethical reasons, prospective studies investigating the Cd levels, especially low-level exposure, before the presentation of pathologies/toxicity is warranted to establish the causality bases for this association.

Pancreatic disorders and Therapy is now accepting submissions on this topic. A standard EDITORIAL TRACKING SYSTEM is utilized for manuscript submission, review, editorial processing and tracking which can be securely accessed by the authors, reviewers and editors for monitoring and tracking the article processing. Manuscripts can be uploaded online at Editorial Tracking System (www.longdom.org/submissions/pancreatic-disorders-therapy.html ) or forwarded to the Editorial Office at manuscripts@longdom.org

Regards,

Jessica Celina

Managing Editor

Pancreatic disorders and Therapy