A Molecular Quest for Understanding Type 2 Diabetes and Insulin Resistance

A Molecular Quest for Understanding Type 2 Diabetes and Insulin Resistance

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By: Tamadher Alghamdi

Although the groundbreaking discovery of insulin by Banting and Best in 1922 at the University of Toronto has saved millions of lives, there is still no cure for diabetes. Today, almost half a billion people live with diabetes (1). In Canada alone, it is estimated that the number of people with diabetes will increase to 5 million by 2025 (2). Moreover, the costs for medications and supplies to manage diabetes are estimated to range from $1,000 to $15,000 per year per person with diabetes (2). The substantial health and economic burden of diabetes in Canada and worldwide continues to demand novel effective therapies and urges for more fundamental research to better understand the causes of diabetes.

At the forefront of this research is Dr. Minna Woo, who holds the Canada Research Chair in Signal Transduction in Diabetes Pathogenesis. For almost 20 years Dr. Woo and her team have aimed to provide a clearer picture of exactly how diabetes, particularly type 2 diabetes, develops. She believes understanding the complexities of this disease will be the key to finding the most effective treatments.

Dr. Woo is a scientist at the Toronto General Hospital Research Institute (TGHRI) and a professor in the Departments of Medicine, Immunology and Institute of Medical Science at the University of Toronto, where she completed her medical degree and residency in general internal medicine with subspecialty training in endocrinology. She is the head of the Division of Endocrinology and Metabolism at University Health Network and Mount Sinai Hospital. During her clinical training, she became interested in academic medicine and basic science research. She decided to pursue her PhD in immunology under the supervision of Dr. Tak Mak, a world-renowned Canadian scientist and the discoverer of the T cell receptor. After completing her PhD, she decided to employ her clinical and research background to understand the molecular mechanisms implicated in diabetes pathogenesis using the powerful tools of genetics and in vivo models.

“Diabetes as we define it today is really poor and its diagnosis is still glucose-centric,” says Dr. Woo. It is commonly known as a chronic disease characterized by elevated levels of glucose in the blood, either due to lack of insulin or resistance of the body to insulin.1 However, diabetes is far more complex than that and its pathogenesis is not fully understood.

Diabetes comes in multiple forms. Typically, there are two main forms of diabetes, commonly known as type 1 and type 2. Type 1 is an autoimmune disease which results in destruction of insulin-producing beta cells in the pancreatic islets, and often affects children and adolescents (1). Type 2 is the most common type and is often associated with obesity, poor diet and physical inactivity. Hyperglycaemia in type 2 diabetes results from relative deficiency in insulin and the inability of the body to respond to insulin, which is known as insulin resistance. This initially leads to an increase in insulin to compensate for the high levels of glucose, and over time, the pancreatic beta cells fail to produce adequate insulin (1). Dr. Woo’s research was inspired by the many patients she sees with type 2 diabetes. The challenge with type 2 diabetes is that its onset is often difficult to determine at an early stage and it is clinically asymptomatic.

There is a growing body of evidence suggesting that inflammation is implicated in the pathogenesis of type 2 diabetes and insulin resistance (3). Work from Dr. Woo’s lab has highlighted several inflammatory pathways that could serve as potential therapeutic targets for type 2 diabetes and insulin resistance. Using genetically engineered mice, her group unraveled the role of an important negative regulator that prevents activation of the insulin signalling pathway known as phosphatase with tensin homology (PTEN). Initially, they showed that deletion of PTEN in muscles, one of the insulin target tissues, increased glucose uptake and protected against type 2 diabetes (4).

Interestingly, in a separate study, deletion of PTEN from pancreatic beta cells in mouse models of type 2 diabetes also exhibited protective effects against hyperglycemia and insulin resistance (5). Following these studies, Dr. Woo’s group showed novel findings, published in Nature Medicine, about the role of PTEN in inflammation and type 2 diabetes. They demonstrated that in vivo deletion of PTEN in select neurons not only enhanced insulin sensitivity and completely protected against type 2 diabetes, but it also reduced inflammation through activation of the anti-inflammatory reflex, a neural circuit that controls the immune responses and inflammation during pathogen invasion and tissue injury (6).

Another major signalling pathway implicated in inflammation that has been the focus of Dr. Woo’s research group is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, or more simply, the JAK/STAT pathway. This pathway is an important downstream mediator for a wide array of cytokines and growth factors essential for various cellular functions including cell proliferation, differentiation, formation of blood cells (hematopoiesis), and immune response. Improper regulation of the JAK/STAT pathway contributes to hematopoietic malignancies and inflammatory conditions, which led to the development of drugs that target this pathway for treatment.

However, in the context of type 2 diabetes, the role of the JAK/STAT pathway has yet to be elucidated. Several studies from Dr. Woo’s research group helped identify the role of the JAK/STAT pathway in the peripheral metabolic organs such as adipose tissue, liver, muscle, pancreas, and the immune system, using tissue-specific knockout mouse models. The findings of these studies suggest that the role of this pathway is highly context-dependant (7). For example, deficiency of JAK2 in macrophages–white blood cells with a role in the immune response–improves insulin sensitivity and reduces inflammation (8). In the liver, however, JAK2 expression plays a protective role against fatty liver and it is essential for growth hormone signalling (9).

Although modulation of the JAK/STAT pathway provides potential therapeutic targets, the tissue-specific role of this pathway needs to be fully understood. “It is a small piece of a puzzle, but it is a critical one, especially for ubiquitous pathways. As technologies advance, these data will help in identifying the best therapeutic strategy,” says Dr. Woo.

Dr. Woo’s research seeks to dissect underlying mechanisms of type 2 diabetes and unravel insulin resistance at the molecular and cellular level. When she was asked how far we are from finding a cure for diabetes, she said, “I think more research is needed for a clear understanding of this incredibly complex disease, and only by progress in good science will we find the answer.”

References:

  1. International Diabetes Federation. (2017). IDF Diabetes Atlas. 8th ed.
  2. Canadian Diabetes Association. The Prevalence and Costs of Diabetes. Available at www.diabetes.ca/about-diabetes/what/prevalence
  3. Donath, M. Y. and S. E. Shoelson (2011). Type 2 diabetes as an inflammatory disease. Nature Reviews Immunology. 11(2): 98-107
  4. Wijesekara, N., D. Konrad, M. Eweida, C. Jefferies, N. Liadis, A. Giacca, M. Crackower, A. Suzuki, T. W. Mak, C. R. Kahn, A. Klip, and M. Woo (2005). Muscle-specific Pten deletion protects against insulin resistance and diabetes. Molecular and cellular biology 25(3): 1135-1145
  5. Wang, L., Y. Liu, S. Yan Lu, K. T. Nguyen, S. A. Schroer, A. Suzuki, T. W. Mak, H. Gaisano and M. Woo (2010). Deletion of Pten in pancreatic beta cells protects against deficient beta cell mass and function in mouse models of type 2 diabetes. Diabetes. 59(12): 3117-3126
  6. Wang, L., D. Opland, S. Tsai, C. T. Luk, S. A. Schroer, M. B. Allison, A. J. Elia, C. Furlonger, A. Suzuki and C. J. Paige (2014). Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex. Nature Medicine. 20(5): 484-492
  7. Dodington, D. W., H. R. Desai and M. Woo (2017). JAK/STAT–Emerging Players in Metabolism. Trends in Endocrinology & Metabolism
  8. Desai, H. R., T. Sivasubramaniyam, X. S. Revelo, S. A. Schroer, C. T. Luk, P. R. Rikkala, A. H. Metherel, D. W. Dodington, Y. J. Park and M. J. Kim (2017). Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation. Scientific Reports 7(1): 7653
  9. Sivasubramaniyam, T., S. A. Schroer, A. Li, C. T. Luk, S. Y. Shi, R. Besla, D. W. Dodington, A. H. Metherel, A. P. Kitson and J. J. Brunt (2017). Hepatic JAK2 protects against atherosclerosis through circulating IGF-1. JCI Insight 2(14)