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Timothy Graham

Assistant Professor of Biochemistry and of Medicine and of Nutrition

B.S. St. John's College

M.D. University of New Mexico School of Medicine

Research

References

 

Tim Graham's PubMed Literature Search

Research

Our laboratory studies the pathogenesis of insulin resistance, the Metabolic Syndrome, and Type 2 diabetes, with a particular focus on how obesity and adipocyte dysfunction contribute to these conditions.   The laboratory is highly translational and develops projects that span multiple levels of inquiry from the test tube to cell culture to animal models and human subjects.   Because metabolic diseases frequently arise from defects within coordinated actions of multiple tissues, the laboratory places a particular focus on biochemical interactions as they pertain to inter-tissue communication and the systemic physiology of the intact organism.   

The laboratory presently has two principal areas of investigation:

1. Mechanisms of serum retinol binding protein (RBP4)-induced systemic insulin resistance and glucose intolerance.  Previous work identified serum retinol binding protein (RBP4) as an adipocyte-secreted protein increased in serum of obese and insulin resistant humans and mice.  RBP4 is the sole specific transport protein for retinol (Vitamin A) in blood.  RBP4 acts on liver and muscle to cause insulin resistance and glucose intolerance systemically.  Recent evidence suggests a potential role for RBP4 in cardiovascular disease, microvascular disease, and neoplasia associated with insulin resistance and Type 2 diabetes.  Despite evidence that RBP4 is an important target for treatment and/or prevention of insulin resistance associated conditions, relatively little is known about how RBP4 acts at the cellular level to cause insulin resistance.  Several projects in the laboratory focus on the biochemistry of RBP4 interactions with other serum proteins and cell surface receptors.  In addition, the laboratory studies how other alterations in retinoid homeostasis, including carotene metabolism, may influence systemic insulin-glucose homeostasis.

a. Regulation of RBP4 serum concentration and biological activity by post translational modifications of its serum binding partner, transthyretin (TTR)
b. Requirement of retinol binding/retinol transport function in RBP4 action in vitro and in vivo.
c. Interactions of RBP4 with putative cell surface receptors and retinol transporters, including Stra6, RBPR2, and others; including the role of these receptors in retinol homeostasis and insulin-glucose homeostasis in vivo. 
d. Alternate processing of beta carotene to form apo-carotenoids by asymmetric cleavage, and potential role of apo-carotenoids as mediators of insulin resistance.

2. Impaired autophagy in insulin resistant states as a cause of cellular injury, accelerated aging, and increased susceptibility to infection and cancer.   The laboratory recently determined that chronically elevated plasma insulin concentrations (hyperinsulinemia) which occur in insulin resistant states suppress basal and stress-induced autophagy in adipocytes and other target tissues of insulin action. Macroautophagy is a critical intracellular pathway  through which aged or damaged intracellular materials and organelles are isolated, sequestered, and degraded or recycled; this process is particularly critical for mitochondrial turnover (mitophagy).   Several projects in the laboratory focus on mechanisms by which insulin inhibits autophagy and the consequences of impaired autophagy on mitochondrial function and systemic metabolism. 

a. mTOR-independent regulation of Ulk1 and Ulk2 Ser/Thr kinases by insulin.
b. Development of the Rosella reporter as a novel tool for monitoring mitophagy in mammalian cell culture and in mice in vivo.
c. Mitochondrial dysfunction due to impaired mitochondrial turnover (mitophagy) in the setting of chronic hyperinsulinemia.

 

References