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Publications of the Week

CD248 Promotes Insulin Resistance by Binding to the Insulin Receptor and Dampening Its Insulin-Induced Autophosphorylation

By January 12, 2024No Comments

This week we profile a recent publication in EBioMedicine from the laboratory of
Dr. Edward Conway (pictured) at the UBC Centre for Blood Research. Dr. Conway is a Professor of Medicine, Director of the Centre for Blood Research (CBR), and a Scientist at the Life Sciences Institute at UBC.

Can you provide a brief overview of your lab’s current research focus?

The goal of my lab is to delineate molecular mechanisms underlying vascular and inflammatory disorders with a view to developing novel diagnostic and therapeutic approaches.

Our current focus is on characterizing the structure and function of a cell-surface expressed protein, CD248, which promotes inflammation, coagulation, cell proliferation and fibrosis. By using molecular/cell biology techniques and genetically modified mice, in conjunction with human studies, we are aiming to gain new insights into how this protein impacts the risk of developing venous and arterial thrombosis, atherosclerosis, cancer and type 2 diabetes.

What is the significance of the findings in this publication?

Type 2 diabetes (T2D) is a common, chronic inflammatory disorder that is associated with a high risk of vascular disease, stroke, heart disease, kidney failure, retinopathy and cancer. Critical in the development of T2D is the resistance of key organs, such as adipose, liver and muscle, to the activities of insulin. Insulin normally exerts its glucose and lipid metabolic effects by binding to the cell surface-expressed insulin receptor which is thus autophosphorylated, triggering a cascade of intracellular events that maintain metabolic homeostasis. The mechanisms of insulin resistance in T2D are incompletely understood, but have almost entirely been attributed to alterations in insulin-induced signaling pathways inside the cell. These pathways have been challenging to pharmacologically target, which explains why there are currently no drugs that specifically reverse insulin resistance. More accessible therapeutic targets would predictably be of huge value.

We previously showed that CD248 is highly expressed by white adipocytes, with levels that are positively correlated to obesity and insulin resistance in humans. The potential therapeutic relevance was highlighted by our finding that deletion of the CD248 gene in adipocytes and other cells reverses insulin resistance and T2D. Led by PDF Dr. Patricia Benedet and with the help of many collaborators, we have now extended these observations by delineating the mechanisms by which CD248 promotes insulin resistance, thereby uncovering a novel potential therapeutic strategy.

Using gold-standard insulin clamps in diet-induced insulin-resistant mice, we first showed that a lack of CD248 improves glucose metabolism by enhancing insulin sensitivity in the liver and in white adipose tissue. The effects of CD248 on insulin-triggered intracellular signaling were then characterized in cell and explant tissues from mice and humans. This led to our finding that CD248 promotes insulin resistance by blocking insulin from binding to the insulin receptor, preventing the latter’s autophosphorylation. Notably, CD248 achieves this via the direct interaction of its extracellular domain with the extracellular domain of the insulin receptor.

The implication of our work is that reversal of the insulin-resistant state may be achieved by reducing CD248 expression and/or by blocking the interaction of CD248 with the insulin receptor. That this CD248-insulin receptor interaction occurs on the cell surface provides a uniquely accessible potential therapeutic target to restore insulin sensitivity and to improve metabolic health.

What are the next steps for this research?

We are currently working with colleagues at the CBR and UBC, at the University of Alberta, in the USA and in Sweden to 1. resolve the structures of CD248, the insulin receptor and insulin to identify key sites involved in their interactions, and 2. to screen for, identify, and ultimately clinically assess compounds that reverse the CD248-insulin receptor interaction and improve insulin signaling and insulin sensitivity.

In addition to the potential of developing a direct therapy to reverse the glucometabolic disturbances of T2D, we are also exploring approaches to reduce the heightened CD248-dependent T2D/obesity-associated risk of cancer, renal dysfunction and vascular disease/thrombosis.

This research was funded by:

The Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.