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Whereas selenium was found to act as an insulin-mimic and to be anti-diabetic in earlier studies, recent animal experiments and human trials have shown unexpected risk of prolonged high Se intake in potentiating insulin resistance and type 2 diabetes. Elevating dietary Se intakes (0.4 to 3.0 mg/kg of diet) above the nutrient requirements, similar to overproduction of selenoproteins, led to insulin resistance and(or) diabetes-like phenotypes in mice, rats, and pigs. Although its diabetogenic mechanism remains unclear, the high Se intake elevated activity or production of selenoproteins including GPx1, MsrB1, SelS, and SelP. This up-regulation diminished intracellular reactive oxygen species (ROS) and then dys-regulated key regulators of β cells and insulin synthesis and secretion, leading to chronic hyperinsulinaemia. Over-scavenging intracellular H2O2 also attenuated oxidative inhibition of protein tyrosine phosphatases and suppressed insulin signaling. High Se intake might affect expression and(or) function of key regulators for glycolysis, gluconeogenesis, and lipogenesis. Future research is needed to find out if certain forms of Se metabolites in addition to selenoproteins and if mechanisms other than intracellular redox control mediate the diabetogenic effect of high Se intakes. Furthermore, a potential interactive role of high Se intakes in the interphase of carcinogenesis and diabetogenesis should be explored to make the optimal use of Se in human nutrition and health.