Type II diabetes is a multifactorial disease that results when insulin secretion from pancreatic beta cells can no longer compensate for insulin resistance in peripheral tissues. My research is focussed on understanding the cellular and molecular mechanisms that regulate insulin secretion in both the healthy and the diabetic states. For decades, scientists have been elucidating the mechanisms that couple glucose metabolism to the secretion of insulin from the beta cell. The “triggering pathway” of insulin secretion has been well-studied and puts ATP at the centre of its control; however, recent studies have shown that reactive oxygen species (ROS) also play an important signaling role in amplifying insulin secretion, allowing maximal secretion in response to a glucose stimulus. Insulin secretion over a 24-hr period is a highly dynamic and regulated process that includes phases of stimulated insulin secretion during the “fed-state” as well as phases of insulin secretion inhibition during the “fasted-state”; however, the mechanisms that control insulin secretion from the pancreatic beta cell over a 24 hour period are still incompletely understood. The long-term objectives of my research program are to identify novel metabolic and molecular mechanisms that control the dynamic daily cycles of insulin secretion from the pancreatic beta cell, which include mechanisms by which glucose stimulates insulin secretion as well as mechanisms by which fatty acids (FAs), which are the primary metabolic fuels during fasting, inhibit insulin secretion.

Currently, we have two specific research interests:

1. To determine the physiological role that mitochondrial uncoupling protein 2 (UCP2) plays in the regulation of insulin secretion in response to various metabolic fuels over 24 hours.
   Since its discovery over 15 years ago, scientists have been trying to discern the physiological function of UCP2 in the pancreatic β cell. At a biochemical level, we know that UCP2 plays a mild uncoupling role in the β cell that has limited impact on ATP production, but has a greater impact on the regulation of mitochondrial ROS signals, which we now know contributes significantly to the control of insulin secretion. Most of what we know about UCP2 function in the β cell and its control of insulin secretion comes from studies of chronic overexpression or chronic knockdown of UCP2 as well as from studies of UCP2 in extreme stress conditions, e.g. long term starvation/fasting, glucolipotoxicity, diabetes and obesity. What we currently do not know is what the role of UCP2 is in the daily control of beta cell function (i.e. in the absence of stress)? When is UCP2 active and inactive on a daily basis and how does this contribute to the regulation of insulin secretion? What controls the expression of UCP2?
   
2. To determine how ROS signalling contributes to the regulation of insulin secretion in response to various metabolic fuels over a 24-hour cycle
   We now know that ROS contributes to the control of insulin secretion. We would like to investigate which species of ROS regulates the stimulation and inhibition of insulin secretion and how ROS species production by the mitochondrion is altered by changing fuel sources over a 24-hour period. We would also like to determine the targets of ROS signaling within the insulin secretory pathways. And finally, we are interested in determining how the antioxidant background of the cell contributes to the control of ROS signals and ultimately insulin secretion. 
   For both of these research interests, we plan to define these mechanisms in healthy pancreatic beta cells and then look at how these pathways/mechanisms are altered or interrupted in a diabetic state, mainly using diabetic mouse models.

Academic Achievements

B.Sc. (Cell & Molecular Biology), University of Toronto, 2000
Ph.D. (Cell & Systems Biology), University of Toronto, 2007
Post-Doctoral Fellow (Physiology), University of Toronto, 2012
Assistant Professor (Physiology), University of Manitoba, 2012 - present

Recent Publications

• Tang C, Koulajian K, Schuiki I, Zhang L, Desai T, Ivovic A, Wang P, Robson-Doucette CA, Wheeler MB, Minassian B, Volchuk A, GiaccaA (2012) Glucose-induced beta cell dysfunction in vivo: link between oxidative stress and endoplasmic reticulum stress. Diabetelogia 55(5):1366-79
• Robson-Doucette CA, Sultan S, Allister EM, Wikstrom JD, Koshkin V, Bhatacharjee A, Prentice KJ, Sareda SB, Shirihai OS, Wheeler MB (2011) Beta cell uncoupling protein regulates reactive oxygen species production, which influences both insulin and glucagon secretion. Diabetes 60(11):2710-9
  Lee SC, Robson-Doucette CA, Wheeler MB (2009) Uncoupling Protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin. Journal of Endocrinology 203:33-43
• Koshkin VK, Dai FF, Robson-Doucette CA, Chan CB, Wheeler MB (2008) Limited mitochondrial permeability of palmitate-induced lipotoxicity in pancreatic beta-cells. J Biol Chem 283(12): 7936-7948