Diabetogenic and Obesogenic Effects of Cadmium in Db/Db Mice and Rats at a Clinically Relevant Level of Exposure

Abstract

Studies show an association between cadmium (Cd) exposure and prediabetes or type II diabetes mellitus. We have previously reported that Cd causes decreased levels of serum leptin in rats following 12 weeks of daily Cd dosing (0.6 mg/kg/b.w./day). Since leptin plays an important role in metabolism, we examined the effects of Cd on rats and db/db mice, which are deficient in leptin receptor activity. We gave rats and mice daily subcutaneous injections of saline (control) or CdCl2 at a dose of 0.6 mg/kg of Cd for 2 weeks, followed by 2 weeks of no dosing. At the end of the 4-week study, exposure to Cd resulted in a more rapid increase in blood glucose levels following an oral glucose tolerance test in db/db vs. lean mice. During the two weeks of no Cd dosing, individual rat bodyweight gain was greater (p ≤ 0.05) in Cd-treated animals. At this time point, the combined epididymal and retroperitoneal fat pad weight was significantly greater (p ≤ 0.05) in the Cd-treated lean mice compared to saline-treated controls. Although this pilot study had relatively low N values (4 per treatment group for mice and 6 for rats) the results show that clinically relevant levels of Cd exposure resulted in diabetogenic as well as obesogenic effects.

Modulation of Metabolic Pathways and Protection against Cadmium-Induced Disruptions with Taxifolin-Enriched Extract

“…Like previous findings, TFN treatment mitigated the Cd-induced increase in G6P levels markedly . Taxifolin’s robust antioxidant and anti-inflammatory potential has been established in the literature. − Similarly, in the current experimental design, TFN reduced oxidative stress induced by CdCl 2 through the modulation of first-line antioxidant enzymes and decreased inflammation by modulating key inflammatory cytokines IL-6 and TNF-α. , CdCl 2 is an obesogenic factor, as its administration led to increased levels of fatty acids, cholesterol, TGs, and FFAs, consistent with the literature . However, treatment with TEE mitigated hyperlipidemia by modulating hepatic lipoprotein synthesis and other multiple lipid-lowering pathways .…”

“…34 , 35 CdCl 2 is an obesogenic factor, as its administration led to increased levels of fatty acids, cholesterol, TGs, and FFAs, consistent with the literature. 36 However, treatment with TEE mitigated hyperlipidemia by modulating hepatic lipoprotein synthesis and other multiple lipid-lowering pathways. 37 Cd produced hepatotoxicity in the current study’s treatment groups, as evidenced by elevated levels of AST and ALT due to Cd 2 + binding with sulfhydryl groups in mitochondria, leading to oxidative stress, mitochondrial dysfunction, and ischemia to hepatocytes.…”

Report of the Scientific Committee of the Spanish Agency for Food Safety and Nutrition (AESAN) on the available evidence in relation to the potential obesogenic activity of certain chemical compounds that may be present in foods

“…Although Cd is primarily considered nephrotoxic, there are a large number of short-and longterm in vivo Cd exposure models demonstrating significant correlations between Cd exposure and the prevalence of prediabetes and/or type 2 diabetes mellitus (Schwartz et al, 2003). While the exact mechanism of action of Cd-induced alteration of glucose homoeostasis is unknown, it is likely related to general pancreatic β cell dysfunction and impaired glucose-stimulated insulin release in animal models (Nguyen et al, 2022).…”

“…However, other works have shown that exposure to Cd at levels reflecting human exposure over a lifetime, results in diabetogenic and obesogenic effects. Determining how Cd alters body weight and, specifically, white adipose tissue weeks after the last dose of Cd is of great interest (Nguyen et al, 2022). Green et al (2018) determined Cd levels in maternal blood samples from the first trimester and analysed the results cross-over with the weight gain trajectory of children up to 5 years.…”

Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease

“…Exposure to Cd appears to increase the risk of developing diabetes in some individuals [ 136 ]. Diabetic mice (db/db) exposed to Cd were found to be hyperglycemic and exhibited an increase in white adipose tissue and weight gain [ 137 ]. Interestingly, exposure of these mice to Cd also decreased serum leptin levels, which may enhance appetite and lead to weight gain.…”