This proposal seeks to link two important risk factors for type 2 diabetes, tissue iron stores and disruption of the circadian rhythm. Large epidemiologic studies have shown that dietary iron is a significant risk factor for diabetes. More recently, intervention studies have shown that the risk s causal and reversible. The body of work from our laboratory in the past decade has shown several mechanisms by which iron affects metabolism, including damaging -cells, down regulating adiponectin and leptin, and mediating multiple effects on the signaling pathways that regulate glucose and lipid metabolism. A second nonconventional risk factor for diabetes is disruption of the circadian rhythm of metabolism. Circadian rhythms allow organisms to anticipate and prepare for environmental changes. They coordinate metabolic changes needed as we shift from being asleep to being awake, from fasting to being fed, and from storing energy to using energy. It is therefore not surprising that many studies have shown these rhythms' importance to obesity and diabetes, whose pathogenesis incorporates derangements of all of those processes. Disruption of this normal cycle is felt to be a major factor in the increased prevalence of diabetes and obesity among night shift workers. Our work in the previous funding period has demonstrated that dietary iron, even within the broad range of normal, has significant effects on the circadian clock, specifically the shift from hepatic gluconeogenesis to hepatic fuel storage. In the course of these studies, it also emerged that dietary iron also affected the circadian rhythmicity of thermoregulation. Besides iron, another important input to the regulation of these cycles is oxygen. These two factors are necessary for fuel metabolism, so their availability needs to be part of the regulation of this fundamental rhythm. Deficiencies i both are common: Iron deficiency is the most common nutritional disease in the world, and hypoxia occurs commonly in diabetes, both systemically (associated with sleep apnea) as well as in tissues such as fat that outgrow their blood/oxygen supply in obesity. With deficiency of either, the organism must respond by limiting oxidative metabolism, which in turn will limit thermogenesis and the normal oscillations of body temperature that entrain the circadian clock. When in excess, we have shown that iron may also allow escape from the constraints of those rhythms, but at the expense of increased levels of oxidant stress. Importantly, we have shown that these effects occur across the very broad range of normal dietary iron intake and tissue iron levels. Thus, once the effects of different levels of dietary iron are understood, we will be able to verify the same effects in humans and begin to determine the optimal levels of iron that will best prevent obesity and diabetes. (In fact, we are currently working on a clinical trial to teat diabetes with bloodletting.) At the same time, we will uncover novel targets that can be potentially used to treat those conditions. This application builds upon our discoveries on the mechanisms and importance of dietary iron in the circadian rhythm of gluconeogenesis, and extends them into studies of thermoregulation, brown adipose function, and the novel underlying signaling mechanisms, including generation of microRNAs,

Public Health Relevance

Diabetes and obesity are common among Veterans, so attempts to discover novel pathways toward their prevention and treatment are an important mission of VA research. Understanding the contribution of circadian rhythms to these pathways is important for the general population of the US, where our society is becoming increasingly unbounded by the clock and the normal dark/light cycle of our planet. This issue has special relevance for the military, which is by its nature is on duty 24 hours per day. Might there be simple measures (modulating iron by controlling intake or by phlebotomy, for example) to minimize the impact of such shift work? Finally, given the fact that clinical trials are currently underway to determine if decreasing iron will improve glycemic control in diabetes or delay the onset of steatohepatitis, it is imperative that we understand the full ramifications of altering iron on metabolism. Our aim is to define the 'sweet spot' within the 20-30-fold range of 'normal' human iron that is optimal for the metabolic health of the Veteran population.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocriniology A (ENDA)
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W G Hefner VA Medical Center
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