For answers to type 2 diabetes, look for multitaskers
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Type 2 diabetes is a multi-tissue disease, affecting cells in the pancreas, liver, skeletal muscle and fat deposits. As a result, research in the field will benefit substantially if we broaden our view beyond a focus on single cell types.
There are strides waiting to be made in studies across tissue types in search of multitaskers — molecular targets that affect multiple systems, either directly or through beneficial signaling cascades. And then, most importantly, we must be ready to pursue the changes we find, no matter how unexpected.
This diverges from the pervasive approach of looking for unique, cell type-specific elements we can target for diabetes. In the context of type 2 diabetes, if we look for a pathway whose activity is very selective to the beta cell, for example, and no other cell in the body, we may fix the beta cells, but dysfunction in the liver or skeletal muscle will continue to torture these “fixed” beta cells, reversing the benefit.
In my lab, we’ve conducted comparison/contrast studies among the major cell types that contribute to prediabetes and type 2 diabetes. Based on the commonalities, we have found targets that could play a positive role in reregulating dysregulated cells. We are in search of a single “pill” to fix at once the major problems that contribute type 2 diabetes.
Think like a patient
One of the biggest complaints about diabetes treatment I hear from patients and their caregivers is that there are so many different pills required. The status quo is expensive and burdensome, and it opens up the risk for potentially dangerous medication errors.
Our goal should be to minimize medications and make regimens simpler. That requires a perspective on type 2 diabetes that takes into account the orchestration involved in metabolism.
As a lifelong musician and music lover, I’m partial to this metaphor: In an orchestra, each player has to listen to the other sections to know when to play. If somebody misses a cue and a musician fails to adjust, the whole piece falls apart.
The body is the same way. Our organ systems crosstalk with one another; they listen to one another. If one system starts sending a miscue and the others aren’t listening and compensating appropriately, you get a disease like type 2 diabetes. To bring the body back into balance, we must address dysregulations across multiple systems.
Listening for crosstalk
With orchestration in mind, my research group intentionally undertook comparison/contrast studies, making us one of the few labs looking at islet, skeletal muscle, fat and liver cells at the same time. When we screened the literature, we found we were studying more potential multitaskers than any other research group.
This approach has paid dividends. In lab models, we have identified syntaxin 4 and double C2 beta — which are suppressed in type 2 diabetes — as pathways whose activation protects beta cells and improves glucose uptake in skeletal muscle cells.
There are other like-minded scientists out there, and they provide further inspiration to my colleagues and me. For instance, Amira Klip, PhD, professor of biochemistry at the Hospital for Sick Children at the University of Toronto, has been studying crosstalk between skeletal muscle and inflammatory cell types that impinge on each other’s functionality. A symposium she led prompted me to look at the immune system in my research as well. These investigations have generated interesting data so far.
Broaden your scope
Clinical endocrinologists are incredibly well equipped to join the search for multitaskers because they are already thinking about the multitude of hormone changes that occur over time, as well as the interrelations among them.
One key step enables the search for multitaskers — cultivating a research group with the diverse competencies to do so and mentoring lab members to pick up the additional skills they need.
Most trainees in my laboratory came from different realms. For example, a virologist will bring a superior skillset in molecular biology but start off with little experience conducting in vivo metabolism-based studies in diabetic mice.
When somebody joins my research group, they know they will be training in several different cell types. The first 6 months can be pretty tough for those who have jumped into an entirely new area of research, but these junior colleagues come with great brains and great capabilities in other areas. Ultimately, both the team as a whole and its individual members are enriched.
Of course, by nature, we scientists tend to be extremely specialized. I encourage students and other early-career investigators to expand their set of tools and research interests. Seek training in new areas either directly or indirectly through collaborations.
For my part, I intentionally amassed a toolbelt during my own training. My goal as a scientist was that when I see a problem or an interesting phenomenon, I would be ready to tackle it without hesitation.
I trained in adipocyte biology, skeletal muscle biology and hepatocyte biology as a matter of serendipity. On the advice of one of my mentors, Jeffrey Pessin, PhD, now the Judy R. and Alfred A. Rosenberg Professorial Chair in Diabetes Research at the Albert Einstein College of Medicine, I purposely added islet biology as a postdoc. When I started my own lab in diabetes research, I had pretty much the whole orchestra right there.
Breadth is ultimately the key. As scientists look to broaden their skillsets; as labs recruit for a broader range of expertise; and as studies incorporate a broader set of cell types, the field of type 2 diabetes research will gain momentum for turning multitaskers into broadly applicable solutions for this disease whose detriments to the body are so broad as well.
For more information:
Debbie Thurmond, PhD, is director of the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope near Los Angeles. She is also the Ruth B. and Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research, professor and founding chair of the department of molecular and cellular endocrinology. She can be reached at dthurmond@coh.org.
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