Pancreas–Liver–Adipose Axis: Target of Environmental Cadmium Exposure Linked to Metabolic Diseases

“

TL;DR

This narrative review examines how environmental cadmium (Cd) exposure disrupts the pancreas–liver–adipose axis, leading to metabolic diseases such as type 2 diabetes, dyslipidemia, and obesity. Cadmium accumulates in these tissues, inducing oxidative stress and inflammation, which impair insulin secretion, promote insulin resistance, and alter lipid metabolism. The clinical significance is that Cd should be considered a modifiable risk factor for metabolic syndrome and diabetes, though molecular mechanisms remain incompletely understood.

Full summary

3,783 CHARS

**Background:** Cadmium (Cd) is a nonessential heavy metal ranked among the top five most hazardous environmental contaminants by the ATSDR. With an elimination half-life of 20–40 years, Cd accumulates in multiple tissues including liver, kidney, and bone. The pancreas–liver–adipose axis is central to carbohydrate and lipid homeostasis, yet the impact of environmental Cd exposure on this axis is rarely discussed in the context of metabolic diseases. This review synthesizes evidence from epidemiological, in vivo, and in vitro studies to elucidate the biological and cellular mechanisms linking Cd exposure to metabolic disorders.

**Methods:** This is a narrative review summarizing studies on environmental Cd exposure and its effects on glucose and lipid homeostasis, focusing on the pancreas, liver, and adipose tissue. The authors discuss Cd toxicokinetics, minimal risk levels (MRLs), absorption pathways, and molecular mechanisms including oxidative stress, inflammation, and cell signaling impairment. Evidence is drawn from human epidemiological data (e.g., NHANES 1999–2010, studies in Thailand, China, and the US) and animal models (primarily rats and mice) exposed to Cd via oral, inhalation, or subcutaneous routes at environmental (NOAEL/LOAEL) and toxicological doses.

**Key Results:** The review reports that the gastrointestinal tract absorbs 5–10% of ingested Cd, while respiratory absorption is 10–40%. Average daily Cd intake in noncontaminated areas is 15–25 μg/day for a 70 kg person. In pancreatic β-cells, Cd enters via DMT1, ZIP, and calcium channels, displaces zinc in insulin hexamers, and promotes hyperinsulinemia through PDX-1 and MAPK pathway activation. β-cells express only about 50% of SOD and 5% of GPx and CAT compared to the liver, making them highly susceptible to oxidative stress. In the liver, Cd exposure at LOAEL doses increases gluconeogenic enzymes (pyruvate carboxylase, PEPCK, fructose-1,6-diphosphatase, glucose-6-phosphatase), impairs glycogen synthesis via GSK3β overactivation, and promotes de novo lipogenesis through SREBP-1c upregulation, leading to hepatic steatosis and overproduction of large VLDL1 and small LDL particles. In adipose tissue, chronic environmental Cd exposure causes adipocyte hypertrophy, reduced PPAR-γ and C/EBP expression, increased leptin release, and unchanged adiponectin levels. Epidemiological data show positive associations between urinary Cd (2–4.0 µg/g creatinine) and blood Cd (1.2–2.5 µg/L) with prediabetes and diabetes. The NHANES 1999–2010 cross-sectional study by Menke et al. (2016) found increased urinary Cd associated with type 2 diabetes. However, some studies report no relationship. Animal studies show sex-specific effects, with females more sensitive to glucose metabolism disruption.

**Clinical Implications:** The evidence strongly suggests that environmental Cd exposure is a risk factor for developing metabolic syndrome, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. The pancreas–liver–adipose axis is disrupted through oxidative stress (via Fenton/Haber–Weiss reactions, NADPH oxidase, and mitochondrial complex III), inflammation (TNF-α, IL-1β, IL-6, IL-8, NF-κB activation), and interference with insulin signaling (PI3K/Akt/mTOR, JNK, and MAPK pathways). The liver has robust antioxidant defenses (MT, GSH, Nrf2), while β-cells are particularly vulnerable due to low antioxidant enzyme expression. Adipose tissue exhibits limited antioxidant capacity, and Cd-induced hypertrophy promotes insulin resistance and chronic low-grade inflammation. The authors recommend that population risk analyses consider Cd exposure data and that future research focus on molecular mechanisms to develop therapeutic strategies minimizing metabolic alterations.