Dietary iron overload is linked to increase risk of type 2 diabetes (T2D), with iron significantly affecting insulin sensitivity/secretion, hepatic glucose production, as well as other physiological responses altered in T2D. These effects are in part mediated through the iron-dependent hypoxia sensing pathway. The interactions between iron and hypoxia in T2D have yet to be elucidated. 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 30% for 4mg-Fe diet, 20% for 35mg-Fe diet, and 15% for 2000mg-Fe diet; p<0.05) as compared to normoxic mice, independent of food consumption. ECHO-MRI measurements revealed higher fat mass with increased iron in normoxic mice. Hypoxic mice had significantly lower fat mass and increased leaner muscle mass. Both fasting glucose (FG) and glucose tolerance were significantly improved under hypoxia (improvement of 15-45% for FG, p<0.05 and 25-40% 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. Consistent with the HOMA-B results, islet perifusion shows that glucose-stimulated insulin secretion (GSIS) is comparatively lower under the combination of high iron and hypoxia. We conclude that while iron is able to independently affect glucose tolerance in mice on a FF diet, the effects of dietary iron still depend on oxygen level. Our perifusion data suggests that iron and hypoxia work in synergy to alter β-cell activity. The synergistic effects of iron and hypoxia may be mediated by the two HIF regulatory arms, iron-dependent dioxygenases prolyl-hydroxylase (PHD) and factor inhibiting HIF (FIH).


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

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