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DIETARY IRON INTERACTS WITH OTHER DIETARY NUTRIENTS, HYPOXIA SIGNALING, AND METFORMIN MONOTHERAPY IN MOUSE MODELS OF TYPE 2 DIABETES

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title
DIETARY IRON INTERACTS WITH OTHER DIETARY NUTRIENTS, HYPOXIA SIGNALING, AND METFORMIN MONOTHERAPY IN MOUSE MODELS OF TYPE 2 DIABETES
author
Harrison, Alexandria V
abstract
ABSTRACTDietary iron is an important factor in metabolic regulation and diabetes risk, but the underlying mechanisms are not fully understood. We demonstrate in mice that the effects of iron are distinct based on dietary macronutrient composition, for example with higher levels of iron promoting insulin resistance on normal chow but leanness and protection from obesity and insulin resistance on high fat diets. For its relevance to typical human diabetogenic diets, we chose to study further a diet high in both fat and carbohydrate (“fast food”), focusing on the effects of hypoxia signaling that have previously been shown to mediate some of iron’s metabolic effects. Both high iron and hypoxia result in decreased weight despite higher food intake, and improved glucose tolerance that is not fully accounted for by the lower weights. The improved glucose tolerance under hypoxia is associated with decreased homeostasis model indices of insulin resistance, although insulin sensitivity measured by insulin tolerance is not altered. Insulin secretion was also not affected. Rather, the mice on high iron or under hypoxia exhibit a shift toward increased energy expenditure and carbohydrate utilization, associated with upregulation of hypoxia pathway targets such as GLUT1 that support insulin-independent glucose uptake and increased glycolysis. Both high iron and hypoxia also induced genes that protect from oxidative stress and affected expression of the key asparaginyl- and prolyl-hydroxylase regulators of hypoxia sensing. We conclude that high iron and hypoxia signaling have interactive and similar effects on glucose homeostasis that are non-additive and operate at least in part through stimulation of hypoxia sensing pathways. We also investigated the interplay between iron and the monotherapy metformin. Action of metformin, the preferred pharmacologic treatment for type 2 diabetes (T2D), remains incompletely understood. Metformin induces an iron starvation response in yeast, so we hypothesized tissue iron might influence metformin responsiveness in mammals. We correlated metformin responsiveness with the iron biomarker ferritin by reviewing patient charts. Glycemia was also followed in mice on diabetogenic diets with different iron contents, treated with or without metformin. In humans, both high and low ferritin were associated with decreased HbA1c response to metformin. In mice, metformin responses (fasting glucose) were greatest on the normal iron diet compared to high or low iron. Low iron mimicked metformin, which was either not or less than additive with low iron in its effect on glycemia and downstream mediators of metformin action. Based on earlier work, we hypothesized that the effects of metformin are in part mediated by protein modification by O-linked N-Acetylglucosamine (O-GlcNAc). Increased O-GlcNAc in a genetic mouse model mimicked lower iron levels, abrogated the effect of high iron, and resulted in smaller relative metformin responses on glycemia and downstream mediators. We conclude that dietary iron and serum ferritin are predictors of the glycemic response to metformin, results that are consistent with the hypothesis that metformin induces an iron starvation response suggesting that metformin responsiveness in patients could be optimized by modulating iron, and that protein O-GlcNAcylation plays a role in mediating these interactions. Collectively, these results hopefully will prompt an intervention study to achieve an optimal rather than “normal” level of tissue iron in patients with diabetes as well as other diseases including cancer and Alzheimer’s.
contributor
McClain, Donald A (advisor)
Olivier, Michael (committee member)
Parks, John (committee member)
Solberg-Woods, Leah (committee member)
date
2023-09-08T08:35:27Z (accessioned)
2023 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2028-09-05 (terms)
2028-09-05 (liftdate)
identifier
http://hdl.handle.net/10339/102621 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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