Excess intake of the micronutrient iron has been associated with increased risk of type 2 diabetes (T2D). Sentinel abnormalities observed in T2D are reduced insulin sensitivity, impaired insulin secretion, and increased hepatic glucose production. All three hallmarks are significantly affected by tissue iron levels, with these effects in part being exerted through the iron-dependent hypoxia sensing pathway. The interplay between iron and hypoxia in the progression of T2D has not been thoroughly investigated. We therefore fed mice a fast food (FF) diet with varying iron concentrations, from a low 4 mg/kg to a high 2000 mg/kg, under normoxic and hypoxic conditions. There was a reduction in weight for hypoxic mice (by 23% for 4mg-Fe diet, 14% for 35mg-Fe diet, and 10% for 2000mg-Fe diet; p<0.05) as compared to normoxic mice, independent of food consumption. Although higher iron was generally associated with worsening of fasting glucose (FG) and glucose tolerance for both normoxic and hypoxic mice, these parameters were significantly improved under hypoxia (10-40% improvement for FG, p<0.05 and 24-36% improvement for glucose tolerance, p<0.01). High iron decreased the homeostasis model assessment of insulin resistance (HOMA-IR) in normoxic mice, and hypoxic mice were less insulin resistant than those in normoxia (p<0.05). Higher iron also decreased the homeostasis model assessment of beta-cell function (HOMA-B) for both normoxic and hypoxic mice, and hypoxic mice trended to have higher HOMA-B. Hypoxia-inducible factor 1-alpha (HIF1α) protein is stabilized under hypoxia, and expression increases with iron. We conclude that the effects of dietary iron to alter glucose homeostasis are, in part, dependent on oxygen levels. Both iron and hypoxia affect glucose tolerance in mice on a FF diet, and their synergistic effects may be mediated by the two regulatory arms of the hypoxia inducible factor (HIF) pathway, iron-dependent dioxygenases prolyl-hydroxylase (PHD) and factor inhibiting HIF (FIH).


A.V. Harrison: None. S. Jain: None. F. Lorenzo: None. D. McClain: None.


U.S. Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases

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