Allen Volchuk Assistant Professor

B.Sc., University of Toronto, 1993
Ph.D., University of Toronto, 1998
PDF, Sloan-Kettering Institute, New York 1998 - 2004

MaRS Centre
Toronto Medical Discovery Tower
10th Floor Rm 10-707
101 College Street
Toronto, Ontario M5G 1L7

416-581-7675
avolchuk@uhnres.utoronto.ca


Molecular determinants of insulin secretion and cell death in type 2 diabetes

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Research Synopsis

Molecular basis of regulated insulin secretion
Type 2 diabetes is the most common metabolic disease in the world and is projected to double to some 300 million people by the year 2025. The primary cause of this disease in the majority of patients is unknown, although both insulin resistance in peripheral tissues and defects at the level of the pancreatic beta-cell contribute to the pathogenesis of the disease. It is generally believed that type 2 diabetes results when the pancreas fails to secrete sufficient insulin to compensate for developing insulin resistance. A deficient beta-cell insulin secretory response and/or death of beta-cells have been identified as the cause(s) of the insufficient pancreatic function. Aspects of both of these events are currently the focus of research in my laboratory.

    



Insulin secretion is a tightly regulated event whereby insulin storage granules inside the cell fuse with the cell surface releasing the processed hormone into the circulation. Glucose is the main stimulus that causes insulin secretion. The biochemical events that result in insulin secretion following stimulation by glucose are not completely understood. In general, upon entering the beta-cells glucose is metabolized to produce ATP, the production of which initiates a cascade of events that quickly results in elevated intracellular Ca+2 levels. A rise in Ca+2 triggers the fusion of insulin storage granules with the cell surface. Many proteins have been implicated in mediating this process. Research in my laboratory focuses on the final stages of insulin granule fusion with the cell surface, specifically the role of proteins that may regulate the fusion event. Using cell culture systems and in vitro assays, current biochemical, molecular and cell biological techniques are used to delineate the function of various proteins in the context of insulin secretion. These studies will further our understanding of this process at the molecular level and provide avenues for the development of therapeutics that can improve insulin secretion in conditions such as type 2 diabetes.
    


Insulin granule exocytosis events at the plasma membrane

 
The role of the Unfolded Protein Response in Type 2 Diabetes
In addition to insulin secretion defects, pancreatic beta-cell death also occurs during development of type 2 diabetes. Because beta-cells produce large amounts of insulin to overcome peripheral tissue insulin resistance during the development of the disease, the endoplasmic reticulum (ER) is believed to be chronically stressed. ER stress is known to activate the Unfolded Protein Response (UPR), a signal transduction cascade that senses ER stress and tranduces signals to the nucleus resulting in gene expression changes that help alleviate the stress conditions (see Figure). Persistent ER stress however, can lead to induction of apoptosis and cell death. Recently, induction of ER stress has also been suggested to cause insulin resistance in some peripheral tissues like the liver. The molecular details of UPR signaling leading to beta-cell apoptosis and insulin resistance in liver, and potentially beta-cells, remains largely unknown. A molecular understanding of this system will be beneficial to the development of therapeutic approaches that improve beta-cell function and alleviate the progression towards the diabetic state. Research in my laboratory will focus on the molecular mechanism of chronic activation of the UPR in pancreatic beta-cells leading to cell death. Current projects underway include developing beta-cell culture models of chronic ER stress and examining the role of free fatty acids on ER stress in beta-cells. Future studies will also make use of transgenic and knock-out mouse models.

   

Signal transduction pathways in the Unfolded Protein Response

 


Selected Publications

Lai E, Teodoro T, Volchuk A. (2007) Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology 22:193-201. Review.

Kaniuk NA, Kiraly M, Bates H, Vranic M, Volchuk A, Brumell JH. (2007) Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes 56:930-9.

Karaskov E, Scott C, Zhang L, Teodoro T, Ravazzola M, Volchuk A. (2006) Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology 147:3398-407.

Volchuk A., Ravazzola M., Perrelet A., Eng W., Di Liberto M., Varlamov O., Fukasawa M., Engel T., Sollner T.H., Rothman J.E., Orci L. (2004) Countercurrent distribution of two distinct SNARE complexes mediating transport within the Golgi stack. Mol. Biol. Cell. 4:1506-1518.

Varlamov O., Volchuk A., Rahimian V., Doege C.A., Paumet F., Eng W.S., Arango N., Parlati F., Ravazzola M., Orci L., Sollner T.H., and Rothman J.E. (2004) i-SNAREs: inhibitory SNAREs that fine-tune the specificity of membrane fusion. J. Cell Biol. 164:79-88.

Orci L., Ravazzola M., Volchuk A., Engel T., Gmachl M., Amherdt M., Perrelet A., Sollner T., and Rothman J.E. (2000) Anterograde flow of cargo across the Golgi stack potentially mediated via bidirectional “percolating” COPI vesicles. Proc Natl Acad Sci USA, 97:10400-10405.

Randhawa V.K., Bilan P.J., Khayat Z.A., Daneman N., Liu Z., Ramlal T., Volchuk A., Coppola T., Regazzi R., Trimble W.S., and Klip A. (2000) VAMP2, but not cellubrevin, mediates insulin-dependent incorporation of GLUT4 into the plasma membrane of L6 myotubes. Mol. Biol. Cell. 11:2403-2417.

Volchuk A., Amherdt M., Ravazzola M., Brugger B., Rivera V.M., Clackson T., Perrelet A., Sollner T.H., Rothman J.E., and Orci L. (2000) Megavesicles implicated in the rapid transport of intracisternal aggregates across the Golgi stack. Cell 102:335-348.

Rivera V.M., Wang X., Wardwell S., Courage N.L., Volchuk A., Keenan T., Holt D.A., Gilman M., Orci L., Cerasoli Jr. F., Rothman J.E., Clackson T. (2000) Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum. Science 287:826-830.

    

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