Emerging Links between Cadmium Exposure and Insulin Resistance: Human, Animal, and Cell Study Data

Abstract

Recent research has helped clarify the role of cadmium (Cd) in various pathological states. We have demonstrated Cd involvement in pancreatic cancer, as well as the bioaccumulation of Cd in the pancreas. Bioaccumulation and increased toxicity suggest that Cd may also be involved in other pancreas-mediated diseases, like diabetes. Cd falls into the category of “hyperglycemic” metals, i.e., metals that increase blood glucose levels, which could be due to increased gluconeogenesis, damage to β-cells leading to reduced insulin production, or insulin resistance at target tissue resulting in a lack of glucose uptake. This review addresses the current evidence for the role of Cd, leading to insulin resistance from human, animal, and in vitro studies. Available data have shown that Cd may affect normal insulin function through multiple pathways. There is evidence that Cd exposure results in the perturbation of the enzymes and modulatory proteins involved in insulin signal transduction at the target tissue and mutations of the insulin receptor. Cd, through well-described mechanisms of oxidative stress, inflammation, and mitochondrial damage, may also alter insulin production in β-cells. More work is necessary to elucidate the mechanisms associated with Cd-mediated insulin resistance.

Effects of arsenic and heavy metals on metabolic pathways in cells of human origin: Similarities and differences

“…Cadmium inhibits adipocyte differentiation by down-regulating PPARγ [ 52 ] and affects placental PPARγ-associated pathway [ 53 ]. In addition, cadmium-mediated abnormal adipocyte differentiation, expansion and function, along with hampered insulin signaling may cause insulin resistance, hypertension and cardiovascular diseases [ 54 , 55 ]. High fat diet, an independent factor for development of metabolic syndromes, also increases cadmium accumulation in several organs including testes in cadmium exposed male mice, resulting in increased infertility [ 56 ].…”

Prenatal cadmium exposure does not induce greater incidence or earlier onset of autoimmunity in the offspring

“…There are several indicators that Cd may be involved in developing susceptibility to autoimmune disease. For example, direct Cd exposure of adults has been implicated in diabetes development (reviewed in (37)). A relatively unexplored exposure paradigm is the possible epigenetic changes induced in the developing fetus when the parents are exposed to an environmental agent.…”

The Role of Toxic Metals and Metalloids in Nrf2 Signaling

“…It has been classified as a group 1 carcinogen by the IARC due to its firm linkage to kidney and prostatic cancers [ 62 ]; however, its linkage to pancreatic and breast cancer development has also been suggested [ 44 , 63 , 64 ]. Cadmium is also a well-known endocrine disruptor, its role in thyroid [ 47 ], metabolic [ 46 , 65 ], and reproductive disorders [ 66 , 67 , 68 ] has been suggested and shown in the literature. Mechanisms of Cd toxicity include changes in genes expression and the inhibition of DNA damage repair, interference with autophagy, apoptosis, and alteration of bioelements levels and inhibition of antioxidant defence [ 56 ].…”

“…Non-occupationally-exposed individuals can come into contact with these chemicals through a variety of sources, including air, drinking water, food, and tobacco smoke [ 40 , 42 , 43 ]. Hence, the relationship between environmental exposure to toxic elements, particularly lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), but also nickel (Ni), chromium (Cr), cobalt (Co), and antimony (Sb), and human diseases have been repeatedly investigated [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Some of these elements are known to damage the mental and central nervous activities, lungs, liver, kidneys, endocrine system, as well as other fundamental organs even at low concentrations, causing various diseases [ 42 ].…”