Don McClain

Professor of Biochemistry and Medicine

Don McClain

B.A. Haverford College

M.D. Cornell University Medical College

Ph.D. Rockefeller University

Research

References

donald.mcclain@hsc.utah.edu

Don McClain's PubMed Literature Search

Research

Our laboratory studies the molecular basis for the pathogenesis of obesity, type 2 diabetes mellitus and its complications, specifically how excess nutrients contribute to those processes. Our current work in this area includes three projects: (1) How glucose regulates transcription and protein function through the hexosamine pathway of glucose metabolism; (2) How excess iron, a risk factor for diabetes, regulated metabolism, and; (3) How hypoxia regulated metabolism. We study these factors in cell culture and animal models as well as in humans.

We have previously shown that artificially increasing hexosamine flux in the tissues responsible for fuel homeostasis recapitulates many of the central phenotypic characteristics of type 2 diabetes, including obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia, and elevations of leptin.  We have shown that the basis for these effects is the modification of cytosolic and nuclear proteins by O-linked GlcNAc. We are currently engaged in work to more fully characterize the biochemical basis for these changes, concentrating on the transcriptional regulation, activation and subcellular partitioning of key enzymes of fuel homeostasis such as glycogen synthase and AMP-dependent kinase.

Our laboratory also studies the mechanisms by which high levels of iron, such as are seen in some hereditary conditions (e.g. hemochromatosis) and also with simple dietary iron overload, are associated with diabetes. To this end, we have discovered novel mechanisms by which iron regulates fat metabolism and impairs mitochondrial function. Current projects focus on the regulation by iron of adipokines, the circadian rhythm, and cellular signaling pathways involved in metabolic regulation.

Finally, because iron can exert some of its effects through the hypoxia signaling pathway, we are also studying the effects of hypoxia on metabolism in animal models of high altitude adaptation as well as in humans that are so adapted.

References

  1. Huang J, Simcox J, Mitchell TC, Jones D, Cox J, Luo B, Cooksey RC, Boros LG, McClain DA (2013) Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice. FASEB J. Mar 20. [Epub ahead of print]
  2. Simcox JA, McClain DA (2013)  Iron and diabetes risk. Cell Metab. 17(3):329-41
  3. Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, Jones D, Cooksey RC, Gabrielsen D, Adams TD, Hunt SC, Hopkins PN, Cefalu WT, McClain DA (2012) Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest 122(10):3529-40
  4. Ge RL, Simonson TS, Cooksey RC, Tanna U, Qing G, Huff CD, Zheng-Zhong B, Witherspoon DJ, Xing J, Prchal JT, Jorde LB, McClain DA (2012) Metabolic insight into mechanisms of high-altitude adaptation in Tibetans. Molecular Genetics and Metabolism, ePub 17 March 2012
  5. Soesanto Y, Luo B, Parker G, Jones D, Cooksey RC, McClain DA (2011) Pleiotropic and age-dependent effects of decreased protein modification by o-linked n-acetyl glucosamine on pancreatic {beta}-cell function and vascularization. J Biol Chem, 286:26118
  6. Cooksey RC, McClain DA (2011) Increased Hexosamine Pathway Flux and High Fat Feeding are not Additive in Inducing Insulin Resistance: Evidence for a Shared Pathway. Amino Acids, 40:841
  7. Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED, Cooksey RC, McClain DA (2010) Iron overload and diabetes risk: A shift from glucose to fatty acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes, 60:80-7
  8. Cooksey RC, Jones D, Gabrielsen S, Huang J, Simcox JA, Luo B, Soesanto YA, Rienhoff H, Abel ED, McClain DA (2010) Dietary iron restriction or iron chelation protect from diabetes and loss of beta cell function in the obese (ob/ob lep-/-) mouse. Am J Physiol Endocrinol Metab, 298:E1236-43
  9. Taylor RP, Geisler TS, Chambers JH, McClain DA. 2009. Upregulation of O-GlcNAc transferase with glucose deprivation in HepG2 cells is mediated by decreased hexosamine pathway flux. J Biol Chem, 284(6):3425-32
  10. Huang J, Gabrielsen JS, Cooksey RC, Luo B, Boros LG, Jones DL, Jouihan HA, Soesanto Y, Knecht L, Hazel MW, Kushner JP, McClain DA (2007) Increased glucose disposal and AMP-dependent kinase signaling in a mouse model of hemochromatosis. J Biol Chem, 282:37501-7

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Last Updated: 6/13/13