Calcium-dependent Signal Transduction in Pancreatic Beta-cells: All cellular processes are controlled by signals. Defects in the transduction of these signals cause disease. Although we have learned a great deal about the events that control a variety of functions in pancreatic beta-cells, the signalling defects that cause diabetes remain to be elucidated. A major interest in the laboratory is the role of intracellular calcium stores, including those sensitive to IP3, ryanodine and NAADP, in beta-cell survival and function. Intracellular calcium homeostasis is vital to the survival of all cell types. We are particularly interested in the mechanisms by which dysfunctional intracellular calcium signalling leads to programmed cell death. Intracellular calcium stores have been linked to diabetes in previous studies. There is also emerging evidence that ER-stress, resulting from lowered ER calcium levels in the beta-cell, plays a significant role in both rare and common forms of diabetes. We are currently using advanced biochemical and molecular techniques, including FRET-based imaging for calcium signals, to further this research. Mathematical modelling of calcium handling is also used in our analysis. These projects are supported by grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association, and the Natural Sciences and Engineering Research Council of Canada.

Insulin ‘feedback’ signaling in type 1 and type 2 diabetes: Insulin is both a metabolic hormone and growth factor. The signal transduction cascades activated by insulin have been well studied in ‘insulin target tissues’ such as muscle and fat. However, recent studies have revealed unexpected tissues where blocking insulin signaling has adverse consequences to glucose homeostasis. Surprisingly, along with the liver and brain, these studies show that the pancreatic beta-cell itself an important site of insulin action. In addition, islets from human type 2 diabetics appear to be ‘insulin resistant’. We have investigated the role and mechanism of insulin signaling in the beta-cell and we have uncovered exciting differences compared to other tissues. We are continuing to study the effects of insulin on primary human and mouse islets, focusing on the anti-apoptotic effects of insulin and the mechanism of these effects. We are testing the hypothesis that altered insulin expression plays a role in type 1 diabetes. This project is supported by grants from the Juvenile Diabetes Research Foundation.

Human Diabetes Genes and Gene-Environment Interactions in Type 2 Diabetes. We have recently discovered that calpain-10, a type 2 diabetes susceptibility gene, is responsible beta-cell death in response to high fatty acids (a known risk factor for type 2 diabetes) and blocking the RyR2 calcium release channel. We have now used proteomics and gene chip analysis to determine possible pathways that could mediate the effects of fatty acids and ryanodine in beta-cells. This project is supported by a grant-in-aid from the Canadian Diabetes Association.

Screening for molecules that promote beta-cell survival or function. We are using high-throughput imaging and functional assays to determine whether known or novel islet secreted factors can be used to promote beta-cell growth or survival. We employ bioinformatic analysis of islet specific genes in these studies. This project is supported by the Canadian Diabetes Association. In collaboration with Dr. Kieffer and several other UBC investigators, we are also examining novel compound libraries for molecules that may eventually be used to induce beta-cell growth or survival. We develop new high-through, high content imaging-based screening methods and impliment robust statistical analyses for large data sets. This work is supported by the Stem Cell Network.

Molecular and functional consequences of cardiac ryanodine receptor deficiency in normal physiology and diabetic cardiomyopathy. Every heartbeat is composed of a complex cycle of highly orchestrated events. The ryanodine receptor calcium channel is central to this cycle, releasing calcium to cause heart muscle cell contraction with each heartbeat. Diseases such as arrhythmias and diabetic cardiomyopathy are associated with partial loss of RyR2 function. However, it has remained unclear whether the other cellular symptoms of these conditions are causes or consequences of the loss of RyR2 function. Working in other cell types, we have recently described unexpected roles for RyR2, namely the control of gene expression and cell survival. In these studies, we proposed for the first time to selectively delete all or half of the RyR2 calcium channels in heart muscle cells and determine which cellular functions are changed most directly as a result. These experiments will employ genetically engineered mice and direct analysis of single heart cells. The proposed studies will provide new insight into the dysfunction and death of heart cells in disease. Such insight is urgently needed given the dramatic increase in the incidence of diabetic cardiomyopathy, the number one cause of death in people with diabetes.

Hyperinsulinemia and insulin signalling in pancreatic cancer. Pancreatic cancer is one of the most deadly forms of cancer, but it is also one of the least well understood. We cannot design an intelligent cure for a disease that we know so little about. In particular, the exact events that initiate pancreatic cancer and accelerate its progression  remain unclear. A growing body of evidence indicates that type 2 diabetes can be a risk factor for pancreatic cancer. It has been suggested that the elevated levels of insulin assocated with diabetes might promote rapid growth of cells in the pancreas, an event that could contribute to the development of pancreatic cancer. Over the past 5 years, our research team has made important discoveries on the effects of insulin on a small subset of pancreas cells that are not associated with the most common forms of pancreatic cancer. We now plan to leverage our expertise and resources to better understand the effects of insulin on pancreatic cancer cells and their precursors. The overall goals of the proposed research is to determine whether elevated insulin increases pancreatic cell growth and/or tumorigenesis and to understand how insulin produces these effects in both humans and experimental animal models of pancreatic cancer. Given the alarming rising incidence of type 2 diabetes, it is critical to know exactly how this metabolic syndrome affects pancreatic cancer risk. Together, these studies have the potential to increase our understanding of this devastating disease.  Therefore, these investigations will improve our chances of finding effective treatments for pancreatic cancer.

Effects of insulin gene dosage on mammalian longevity. Both genetic and environmental factors are thought to contribute to growth, healthy aging and longevity. Studies in worms and flies have clearly demonstrated that the insulin gene plays key roles in the control of tissue growth and longevity. Similarly, evidence has been presented that mice lacking the insulin receptor in fat or insulin receptor substrates also have improved lifespan, but some of these results are controversial. To date, there has been no direct demonstration that the insulin gene modulates tissue growth or longevity in mammals. An ideal way to test this hypothesis would be to vary the amount of insulin in genetically engineered mice. Mice have two separate Insulin genes, Insulin 1 and Insulin 2. Thus, since the mother and father each contribute one copy of each Insulin gene, normal mice have four possible copies of the Insulin gene. The total lack of Insulin genes leads to diabetes at birth, but mice live normally with only one copy of the Insulin gene. We have taken advantage of this and begun to characterize mice with two of the four Insulin copies, as well as mice with only one Insulin gene copy. Our preliminary data suggest that mice lacking all but one Insulin gene allele are smaller but healthier than controls with reduced fat and lower blood sugar levels. Since these are all features of mice with extended lifespan, there is strong rationale to properly examine longevity in a controlled study. Interestingly, different phenotypes were observed depending on whether a single allele of Insulin 1 or Insulin 2 remained, strongly suggesting that the two Insulin genes have distinct biological roles in mice. These fundamental experiments will answer critical questions surrounding aging and growth in mammals. The findings are likely to translate to humans, where high circulating insulin is a prominent feature of the emerging worldwide epidemics of obesity and type 2 diabetes.

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