Type II
diabetes mellitus (T2DM) is characterized by
insulin resistance, β-cell dysfunction and
hyperglycemia. In addition to well known risk factors such as lifestyle and
genetic risk score, accumulation of environmental toxicants in organs relevant to
glucose metabolism is increasingly recognized as additional risk factors for T2DM. Here, we describe the development of an in vivo oral
cadmium (Cd) exposure model. It was shown that oral Cd exposure in
drinking water followed by washout and high fat diet (HFD) in C57BL/6N mice results in islet Cd bioaccumulation comparable to that found in native human islets while mitigating the anorexic effects of Cd to achieve the same
weight gain required to induce
insulin resistance as in Cd naïve control mice. Inter individual variation in plasma
glucose and
insulin levels as well as islet Cd bioaccumulation was observed in both female and male mice. Regression analysis showed an inverse correlation between islet Cd level and plasma
insulin following a
glucose challenge in males but not in females. This finding highlights the need to account for inter individual target tissue Cd concentrations when interpreting results from in vivo Cd exposure models. No effect of Cd on insulin secretion was observed in islets ex vivo, highlighting differences between in vivo and ex vivo
cadmium exposure models. In summary, our oral in vivo Cd exposure-washout with HFD model resulted in islet Cd bioaccumulation that is relevant in the context of environmental
cadmium exposure in humans. Here, we showed that islet Cd bioaccumulation is associated with complex
cadmium-mediated changes in
glucose clearance and β-cell function. The model described here will serve as a useful tool to further examine the relationship between Cd exposure, islet Cd bioaccumulation, dysglycemia and their underlying mechanisms.