The micronutrient iron is a risk factor for type II diabetes (T2D) . The effects of iron are, in part, mediated by the iron-sensing hypoxia inducible factor (HIF) pathway. The interactions of iron and hypoxia in the progression of T2D are not fully understood. Mice were fed a fast-food (FF) diet supplemented with either normal iron (35 mg/kg) or high iron (2000 mg/kg) under normoxia and hypoxia. Hypoxic mice had a significant reduction in weight compared to normoxic mice (by 16% for 35mg-Fe diet and 14% for 2000mg-Fe diet, p<0.001) . There was an interactive effect of iron and hypoxia on fasting glucose and glucose tolerance (p=0.016, p=0.41 respectively) in which the combination of hypoxia and normal iron yielded the best improvement. For insulin-mediated glucose uptake mechanisms, insulin sensitivity was observed with high iron and also under hypoxia when using the homeostatic model assessment (HOMA-IR) . Direct measurement using the insulin tolerance test showed no additional sensitivity was observed with hypoxia, suggesting non-insulin mediated glucose uptake (NIMGU) mechanisms. Indirect calorimetry demonstrates that hypoxia and iron interact to increase carbohydrate utilization and energy expenditure (p<0.001 and p=0.005, respectively) . Measured eWAT tissue mass showed significant reduction in tissue mass for hypoxic mice. Transcriptional profile of mouse eWAT shows significant upregulation of classic HIF target genes involved in glycolysis, mitochondrial metabolism, and intracellular iron homeostasis in hypoxic mice and interestingly also in normoxic high iron mice. Lastly, protein expression of HIF regulators FIH1 and PHD2 were significantly reduced (25-40% reduction, p<0.05 for FIH and p<0.01 for PHD2) under hypoxia. We conclude that the observed effects of dietary iron are dependent on oxygen levels, with the best protection against T2D offered by normal iron and hypoxia. Enhanced glucose disposal is due to NIMGU mechanisms, with the two HIF regulatory arms, PHD2 and FIH1, also mediating effects. Results from this study support novel targeted therapies and dietary changes to treat T2D.
A. V. Harrison: None. D. A. Mcclain: None. S. T. Sink: None. F. Lorenzo: None.
NIDDK Research Service of the Veterans Administration