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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001140-09
Application #
9551505
Study Section
Endocriniology A (ENDA)
Project Start
2011-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2020-03-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
W G Hefner VA Medical Center
Department
Type
DUNS #
023298611
City
Salisbury
State
NC
Country
United States
Zip Code
28144
McClain, Donald A; Sharma, Neeraj K; Jain, Shalini et al. (2018) Adipose Tissue Transferrin and Insulin Resistance. J Clin Endocrinol Metab 103:4197-4208
Nam, Hyeyoung; Jones, Deborah; Cooksey, Robert C et al. (2016) Synergistic Inhibitory Effects of Hypoxia and Iron Deficiency on Hepatic Glucose Response in Mouse Liver. Diabetes 65:1521-33
Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan et al. (2015) Dietary iron controls circadian hepatic glucose metabolism through heme synthesis. Diabetes 64:1108-19
Gao, Yan; Li, Zhonggang; Gabrielsen, J Scott et al. (2015) Adipocyte iron regulates leptin and food intake. J Clin Invest 125:3681-91
Kwon, Oh Sung; Tanner, Ruth E; Barrows, Katherine M et al. (2015) MyD88 regulates physical inactivity-induced skeletal muscle inflammation, ceramide biosynthesis signaling, and glucose intolerance. Am J Physiol Endocrinol Metab 309:E11-21
Bai, Zhenzhong; Wuren, Tana; Liu, Shou et al. (2015) Intermittent cold exposure results in visceral adipose tissue ""browning"" in the plateau pika (Ochotona curzoniae). Comp Biochem Physiol A Mol Integr Physiol 184:171-8
Ge, Ri-Li; Simonson, Tatum S; Gordeuk, Victor et al. (2015) Metabolic aspects of high-altitude adaptation in Tibetans. Exp Physiol 100:1247-55
Zhang, Xu; Zhang, Wei; Saraf, Santosh L et al. (2015) Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease. Hum Genet 134:895-904
Carlin, Matthew B; Tanner, Ruth E; Agergaard, Jakob et al. (2014) Skeletal muscle Ras-related GTP binding B mRNA and protein expression is increased after essential amino acid ingestion in healthy humans. J Nutr 144:1409-14
Addison, O; Drummond, M J; LaStayo, P C et al. (2014) Intramuscular fat and inflammation differ in older adults: the impact of frailty and inactivity. J Nutr Health Aging 18:532-8

Showing the most recent 10 out of 17 publications