Debbie C. Thurmond, Ph.D.

Associate Director of Basic Diabetes Research Group, Herman B. Wells Center for Pediatric Research
Professor of Biochemistry & Molecular Biology
Professor of Cellular & Integrative Physiology

Education/ Training:
Ph.D. University of Iowa (1997)

Regulatory mechanisms underlying insulin granule trafficking and GLUT4 vesicle translocation.

The long-term goal of my research is to determine the molecular mechanisms involved in the regulation of glucose homoeostasis, in particular the role of vesicular trafficking. In various states of insulin resistance and diabetes there is a defect in the maintenance of glucose homeostasis which is thought to occur from the inability to recruit the insulin-responsive GLUT4 glucose transporters to the plasma membrane or sarcolemma/t-tubule system in adipose or muscle, respectively. Since insulin-stimulated GLUT4 translocation accounts for the majority of post-prandial glucose uptake, trafficking of the GLUT4-storage vesicles is a quantitatively critical factor in glucose metabolism. Similarly, insulin secretion from the pancreatic beta cells is also a vesicular trafficking event, utilizing many of the same molecular pathways as GLUT4 vesicle translocation in adipocytes and muscle. Since the quantity of insulin in beta cells is not limiting, one of the most important steps in insulin secretion is getting granules primed and ready to release their cargo at the plasma membrane. Thus, the general focus of my research is on these common mechanisms that have tremendous importance to whole body glucose homoeostasis and to our understanding of diabetes and insulin resistance.
Vesicular translocation from an interior compartment to the cell surface involves at least four main steps: signaling, trafficking, docking/tethering and subsequent fusion of the vesicle with the plasma membrane. We have recently begun to gain molecular insight into the docking and fusion of the GLUT4-containing vesicles and insulin-containing granules; enough to recognize that these events have several features in common with the regulated exocytosis pathway of synaptic vesicle trafficking in neurotransmitter release. In the case of synaptic vesicle docking and fusion, this system entails the pairing of protein complexes in the vesicle compartment (v-SNAREs, for vesicle SNAP receptors) with their cognate receptor complexes at the target membrane (t-SNAREs, for target membrane SNAP receptors). There are multiple isoforms of the proteins that make up the core SNARE complex, and it is this specific pairing and compartmentalization of these proteins that are believed to impart the specificity of vesicle targeting. Since this SNARE-mediated paradigm has been so well established in synaptic vesicle trafficking, I will focus my research program on applying and extending this knowledge to the study of both GLUT4 vesicle and insulin-containing granule movement, in an effort to derive detailed mechanistic models for these processes.

Recent Publications:

Oh, E., and Thurmond, D.C. (2006). The stimulus-induced tyrosine-phosphorylation of Munc18c facilitates vesicle exocytosis. J Biol Chem 281:17624-17634.

Nevins, A. K., and Thurmond, D.C. (2006). Caveolin-1 functions as a novel Cdc42 guanine nucleotide dissociation inhibitor (GDI) in pancreatic beta cells. J Biol Chem 281:18961-18972.

Wang, Z., Oh, E., and Thurmond, D.C. (2007). Glucose-stimulated Cdc42 signaling is essential for the second phase of insulin secretion. J Biol Chem 282:9536-9546.

Ke, B., Oh, E., and Thurmond, D.C. (2007). Doc2? is a novel Munc18c-interacting partner and positive effector of Syntaxin-4 mediated exocytosis. J Biol Chem 282:21786-97.

Oh, E., Heise, C.J., English, J.M., Cobb, M.H. and Thurmond, D.C. (2007). WNK1 is a Novel Regulator of Munc18c-Syntaxin 4 Complex Formation in SNARE-mediated Vesicle Exocytosis. J Biol Chem 282:32613-22.

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