Our Research Members

Dr. Calvin Ke received his Doctor of Medicine from the University of Toronto. He completed his residency training in Internal Medicine at the University of British Columbia and Endocrinology and Metabolism at the University of Toronto. He completed his PhD in clinical epidemiology and global health as a Global Scholar at the Institute of Health Policy, Management and Evaluation, University of Toronto. He served as an Honorary Visiting Scholar at The Chinese University of Hong Kong. He provides clinical outreach services for Chinese-speaking communities with the CareFirst Family Health Team.

Dr. Ke’s research focuses on young-onset type 2 diabetes (individuals diagnosed with type 2 diabetes before the age of 40 years), and on type 2 diabetes in Chinese and South Asian populations. He applies clinical epidemiological methods to characterize the burden, management, and outcomes of type 2 diabetes in both local and global populations across China and India. He is a member of the International Diabetes Federation Atlas Committee and the NCD Risk Factor Collaboration.

My research interest is focused on Fibroblast Growth Factor receptor (FGFR) expression and signaling in adult beta cells. We have identified control of FGFR1-expression and -signaling by modifications in the beta-cell extracellular microenvironment. We are now investigating the role of the novel kinase-deficient FGFR5 isoform in the regulation of beta-cell FGFR1-signalling. Using insulin-secreting cell lines, we have expression of FGFR5 at both the cell membrane as well as in association with insulin secretory granules. Expression of FGFR5 enhances classical intracellular FGF-mediated signaling pathways, cellular matrix adhesion as well as insulin content. Expression of a ‘dominant-negative’ (kinase-deficient) isoform of classical FGFR1 (similar in structure to FGFR5) has been shown to induce a diabetic phenotype in mice. Taken together, these data promote our interest in defining the role that FGFRs play in normal beta-cell maintenance and insulin secretion. We currently examine this receptor signaling system using methods of fluorescence microscopy (live-cell and fixed) both in vitro as well as in vivo (whole islet), and verify our results in combination with traditional biochemical techniques.

I am an organelle cell biologist who focuses on understanding cellular processes in the perceptive of organelles to understand human diseases. One of my main focus is understanding the role of the metabolic organelles, the peroxisomes. Peroxisomes are metabolic organelles are critical for metabolism of lipids and redox homeostasis. One of our goal is to understand the role of peroxisomes in pathogenesis of obesity and type 2 diabetes mellitus (T2DM). For this reason, my lab has two area of interest in respect to T2DM:

1) There is growing evidence to suggest a potential involvement of peroxisomes in pathogenesis of obesity and type 2 diabetes mellitus (T2DM). For example, plasma levels of nonesterified fatty acids (NEFAs) are increased under the conditions of obesity and adipose dysfunction, which ultimately exert lipotoxicity and promote insulin resistance. Since peroxisomes may play a pivotal role in regulating plasma NEFA levels through governing lipid droplet (LD) formation and fatty acid oxidation in adipocytes, we are studying the role of adipose-peroxisomes can be directly associated with pathogenesis of T2DM.
 
2) Recently it has been demonstrated that H2O2 generated in peroxisomes rather than in the mitochondria is responsible for NEFA-induced lipotoxicity in pancreatic beta-cells. Therefore, when the elevated levels of NEFAs in obesity exceed the capacity of mitochondrial beta-oxidation, the excess fatty acids will be metabolized via peroxisomal beta-oxidation, leading to increased production of H2O2. Therefore, we are studying whether a lack of peroxisomes in pancreatic beta-cells impedes the inactivation of H2O2, resulting in b-cell dysfunction due to ROS-mediated lipotoxicity.

Although mesenchymal-epithelial interactions play a critical role in organ development and stem cells, little is known about digestive organ-specific stromal signals. Utilizing reporter mice that label pancreatic, stomach and intestinal stromal cells, we analyzed their gene expression and identified pancreatic stroma-specific downregulation of Hh signaling. To investigate how mesenchymal Hh signaling is tightly regulated, we conditionally deleted two Hh negative regulators, Sufu and Spop, in the pancreatic mesenchyme and demonstrated their critical roles in beta cell differentiation during pancreatic development. Since Hh activation increases the expression of gut mesenchymal Wnt ligands, leading to severe defects in beta cell development, in collaboration with Dr. Cristina Nostro’s group, we examined the role of Wnt signaling in hESC differentiation. Notably, Wnt inhibitors such as WIKI4 significantly increased the number of C-PEP+/NKX6.1+ beta-like cells, whereas its agonist, CHIR99021, impaired the expression of pancreatic progenitors and endocrine lineage markers. Our goal is to define the signaling and epigenetic mechanisms of pancreatic niche signals for beta cell maturation and function.

We study how insulin and exercise stimulate glucose entry into muscle and how this fails in insulin resistance and type 2 diabetes. We explore intracellular signals, movement of vesicles containing glucose transporter 4 (GLUT4) and strategies to render muscle cells insulin-resistant. We generated platforms of muscle cells in culture and transgenic mice expressing tagged GLUT4 in muscle, to test GLUT4 movement in vivo. We found that signals downstream of PI3-kinase bifurcate into activation of Akt leading to Rab8A and Rab13 activation, and Rac1 activation that controls actin filament remodelling. Orr collaborator Erik Richter (University of Copenhagen) found that mice lacking Rac1 in muscle become insulin-resistant. Mechanistically, we find that, in cells rendered insulin resistant by exposure to saturated fatty acids, GLUT4 translocation becomes defective along with alterations in Rac1 signalling to actin rather than in the Akt pathway. These studies will aid in identifying specific steps affected in muscle that curtail stimulation of glucose uptake by insulin in obesity.

Saturated fatty acids also render monocytes invasive and macrophages pro-inflammatory, producing cytokines that make muscle cells insulin-resistant. In vivo, high fat feeding of mice  causes direct activation of the NOD innate immunity recognition receptors in macrophages and that contributes to whole-body insulin resistance. We documented a particular infiltration of inflammatory macrophages and neutrophils in muscles of high fat-fed mice and of obese, insulin-resistant humans, and we find that an early feature of obesity is production of infiltrating monocytes in the bone marrow. These collective findings contribute to our understanding of the link between inflammation and insulin resistance. 

Finally, more recently we have investigated how glucose and insulin cross microvascular endothelial cells of capillaries, in an effort to understand the molecular underpinnings of their delivery to tissues. Defects in this step in obesity will have impact on insulin action on glucose uptake in muscle and fat cells in vivo.

My research program has three projects directly related to diabetes:

1) Angiotensin II is a peptide produced in the kidney that leads to progression of diabetic kidney disease. We have identified a group of proteins regulated by angiotensin II in kidney cells and demonstrated that these proteins were involved in kidney fibrosis. We have also demonstrated that measurements of these proteins in urine correlate with kidney fibrosis. We are now studying the mechanisms of regulation of these angiotensin II-activity proteins. Agents that inhibit these proteins may represent new potential treatments of diabetic and other kidney diseases.

2) The mechanisms leading to development of early diabetic nephropathy are still poorly understood. By studying the urinary peptidome of patients with juvenile diabetes mellitus type I and no known diabetic complications, we have identified several peptides of protein uromodulin. We are now investigating the potential function of these peptides and proteases that cleave them from uromodulin, in order to enhance our understanding of the early events leading to kidney injury in type I diabetes.

3) Male sex has been associated with increased risk of progression of kidney disease. We have recently discovered that male sex hormones affect metabolic enzymes in kidney cells and may result in maladaptive metabolic changes in the kidney. These effects were demonstrated in two different animal models of diabetes, where male animals had increased expression of these enzymes and increased kidney hypertrophy and oxidative stress. We are now investigating how sex hormones affect metabolism in kidney cells and whether we can modify the maladaptive effects of testosterone through manipulation of metabolism.

My clinical research focuses on:

1. The impact of obesity on metabolic dysfunction
2. The pathophysiology and risk factors for the development of type 2 diabetes mellitus (T2DM)
3. Risk factors for cardiovascular disease in individuals with metabolic abnormalities
4. Strategies for the treatment of T2DM. 

I am particularly interested in understanding the pathophysiology of T2DM in individuals with various degrees of obesity and differential patterns of body fat distribution.