Research Highlights

Bioengineering adipocytes

Despite the advancements made for treating T1D patients, insulin injections using a needle remain the most common form of treatment. Cell therapies are continually improving but any form of allo-transplantation is prone to recipient rejection of donor islets and the need for long term immunosuppression. Dr Peter Light and his PhD students Neermeen Youssef and Katarina Ondrusova took a unique approach to cell therapy, starting with the observation that fat cells already have the machinery necessary to produce hormones, such as leptin and adiponectin.

They wondered whether a person's own fat cells, which most of us have in excess anyway, could be reprogrammed to secrete an insulin bolus in a way that was controlled by a simple and noninvasive signal - a pulse of light. To explore the feasibility of this idea the researchers utilized an adenoviral construct to encode a leptin leader linked with a preproinsulin gene and a light-gated cation-selective channelrhodopsin known to be sensitive to blue light. When tested in culture, they successfully demonstrated that insulin release from the bioengineered fat cells could be regulated using pulses of blue light.

This has set the stage for studies examining the controlled release of insulin from subcutaneous, bioengineered cells in an in vivo model. The significance of their research was recognized at the 2014 Falling Walls international competition in Berlin, Germany, winning second place overall.

Brain signaling in diabetes
Dr Jessica Yue joined the Alberta Diabetes Institute in 2015 after relocating from the Toronto General Research Institute where she trained under physiologist Dr Tony Lam. Yue's research looks at how the brain plays an important role in the pathogenesis of diabetes through neuronal signaling that controls various risk factors.
Her recent research describes how the brain can regulate fat metabolism and mitigate the development of cardiovascular disease, a risk factor for obesity and diabetes. She examined how the infusion of oleic acid, a naturally occurring monounsaturated fatty acid, triggered a signal from the hypothalamus to the liver to lower its secretion of triglyceride-rich, very-low-density lipoproteins, a protective effect against overproduction. When this trigger fails to work, such as with obesity, the risk of insulin resistance and diabetes rises.
Yue's findings also demonstrate how this faulty signal can be bypassed, unveiling potential pathways for regaining normal control in obese patients and opening the door for therapeutic intervention. Yue's research findings were published in Nature Communications (Jan 2015;65970) and were co-authored by Dr Peter Light.
Dimmer Switch in Islets

T2D can be characterized by a reduction in insulin production, a reduction in the body's response to insulin, or both. Insulin supply can be managed by drugs that boost production from the pancreatic islets of patients, but there has never been a clear understanding of why insulin production falls in the first place. Dr Patrick MacDonald changed that with research that identified a key mechanism for the elusive "dimmer switch", postulated to exist as far back as 25 years ago.

MacDonald and his research team that included Drs Mourad Ferdaoussi, Xiaoqing Dai, Joceylyn Manning Fox, Kunimasa Suzuki, PhD student Catherine Hamjrle, undergraduate student Robert Wright, and lab specialists Gregory Plummer, Aliya Spigelman and Nancy Smith examined islet cells from 99 human organ donors and identified a new molecular pathway that manages the amount of insulin produced and adjusts how much of the hormone is secreted when blood sugar rises.

They focused on isocitrate and showed that the cytosolic enzyme isocitrate dehydrogenase (ICDc) produces signals that contributes to the amplification of insulin exocytosis via another enzyme that MacDonald has studied extensively - sentrin/SUMO-specific protease-1 (SENP1). Deletion of SENP1 in mice caused impaired glucose tolerance by reducing insulin secretion and activating this enzyme in islets from human donors with T2D rescued insulin production.

Together, these results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues ϐ-cell function in diabetes. Results of MacDonald's research were published in The Journal of Clinical Investigation (125:3847-3860, 2015) and received considerable attention globally.

Innovation for tissue engineering research
While working as a research associate at the University of Toronto's Institute of Biomaterials & Biomedical Engineering, Dr Mark Ungrin recognized that researchers lacked a tool for the efficient, large-scale formation of uniform, size-controlled microtissues. To resolve this challenge, he developed a deceptively simple-looking device that starts with cells in a central reservoir and then employs centrifugal forced aggregation to capture them in tiny "micro-wells." These micro-wells represent a controlled environment for creating uniform aggregates of cells and the device has led to a new means of tissue assembly useful in a wide range of applications, from tissue engineering to toxicology to studies of tumour cell behaviour in a more realistic 3-dimensional environment. Now an Assistant Professor at the University of Calgary and a member of Alberta Diabetes Institute since 2013, Ungrin remains active in advancing this technology. One recent advance they made was in response to the potential displacement of certain types of microtissues from the micro-wells during long-term cultures, leading to a loss of material or inadvertent mixing of cells. They were able to bond a nylon mesh over the micro-well opening, allowing single cells to pass through the mesh into the wells during the seeding process, but then retaining the assembled microtissues within discrete microwells. The new technology was tested in a successful proof of concept study using bone marrow-derived mesenchymal stem cells for the production of cartilage microtissues over a 21 day period involving multiple medium exchanges (Biomaterials, 62:1-12, 2015). The original microwell technology, under the AggreWell™ brand name, is now a successful commercial product with Stem Cell Technologies Inc. of Vancouver. It is in use around the world, on every continent except Antarctica; and is mentioned in over 370 publications (with over 130 of those coming in the 2015-2016 period so far). In 2015, Ungrin was named a University of Calgary PEAK Scholar for his work in this area. He is presently applying it to the formation of pseudoislets (pancreatic islet microtissues) specifically engineered for optimized performance after transplantation, to enhance the efficiency of the Edmonton Protocol for the treatment of T1D.
New role for tumour suppressing gene in ϐ-Cell Apoptosis
While advances are continually being made in the treatment of T2D, research led by Dr Jean Buteau aims to prevent and reverse the disease after early onset. Buteau's recent research has resulted in the identification of a number of proteins and genes that are related to the proliferation and survival of islet cells and are targets for therapeutic intervention. An earlier genomic study conducted in his laboratory identified suppression of tumorigenicity18 (ST18) as a potentially important regulator of beta-cell mass and function. However, the biological roles of ST18, a neural zinc finger transcription factor, remained poorly characterized and its action in beta-cells has never been explored. Research done by Buteau and his team that included PhD student Anne-Françoise Close demonstrated that, in the pancreas, ST18 expression was restricted to endocrine cells and that expression and activity in ϐ-cells were increased by cytotoxic concentrations of fatty acids and cytokines. In addition ST18 was also increased in the islets of diet-induced obese animals. They found that ST18 overexpression induces ϐ-cell apoptosis and restricts replication. Furthermore, they also found a correlation between ST18 expression and impaired insulin secretion, suggesting that this gene acts as a potentially important transcriptional mediator of lipotoxicity and cytokine-induced ϐ-cell apoptosis. Their findings were published in The Journal of Biological Chemistry in 2014 (doi:10.1074/jbc.M114.554915)