Estefania Quesada-Masachs, M.D., Ph.D.

2020 Tullie and Rickey Families Spark Awards Winner

Estefania Quesada-Masachs, M.D., Ph.D.

“Winning a SPARK award would give me the opportunity to explore a possible cause of type 1 diabetes, which could open the door to better treatments and interventions.”

Exploring toxic effects of T1D patient’s serum in pancreatic β cells

Funded: January 2020
Funded By: The generosity of Larry & Tiki Spitcaufsky

What was the goal of your SPARK project?

Patients with type 1 diabetes (T1D) develop the disease when the immune system damages their insulin-producing beta cells, leading to loss of beta cell function and, ultimately, irreversible insulin deficiency. This autoimmune attack of insulin-producing beta cells is thought to be primarily mediated by autoreactive immune cells. Older studies have suggested that the blood serum of patients with T1D may directly harm beta cells, and scientists have hypothesized that autoantibodies and other unknown players in blood serum may be partly responsible for disease progression. For my SPARK project, we investigated whether serum derived from patients with T1D could alter the function of healthy islets and induce a different response than serum from non-diabetic patients.

Pivoting during a pandemic

The pandemic did prove to be a challenge for my project. We had difficulties sourcing some essential reagents, and the organ donor program that provides human islets was temporarily halted for a few months. Despite the setbacks, we were able to use the extra time to perfect our experimental plan. Thankfully, we received all of the necessary materials with enough time to successfully complete the study. I was very proud to be able to finish all of the experiments without sacrificing any essential parts, and this allowed me to obtain meaningful data.

SPARK project results:

We found that islets incubated in serum from patients with T1D make more insulin in response to conditions of high and low glucose, compared to islets incubated in serum from non-diabetic patients. Furthermore, the increased insulin secretion observed in the islets cultured with serum from the T1D group was similar to that observed in islets incubated with proinflammatory molecules. This suggests that the serum of patients with T1D may be stressing these islets, leading them to secrete more insulin.

Despite using state-of-the-art microscopy techniques, we didn’t observe differences in the presence of insulin, glucagon or inflammatory molecules, such as HLA-I, in the islets receiving the serum of T1D patients. To determine what may cause the altered islet insulin secretion, we next characterized the serum of the patients by measuring the levels of 97 different factors known to affect inflammation, immune-regulation, and cell growth. In our preliminary analysis, we found subtle differences in some of these molecules between the serum from T1D patients and the serum from non-diabetic patients, but not enough to justify the functional differences observed. Our more complex multivariate analysis is ongoing, which may yet uncover potential causes for these mysterious alterations in islet function.

What’s next for this project?

Prolonged durations of high levels of insulin secretion can lead to nonfunctional beta cells and/or insulin resistance. If the serum from patients with T1D can cause chronic elevated insulin secretion in islets, as we observed in our experiments, this could be a potential reason for dysfunction and eventual autoimmune recognition of beta cells, leading to diabetic symptoms in patients. In our preliminary characterization of the serum from T1D patients, we have not yet found the specific molecules that may cause this, but there may be other factors we have not studied that could impair islet function. Further studies will be required to determine the mechanism by which human serum from T1D patients dysregulates insulin secretion, and what specific factors are involved.

Given these preliminary findings, we plan to pursue a National Institutes of Health (NIH) R21 exploratory/developmental grant to further obtain proof-of-concept and to explore the mechanisms by which human serum from patients with T1D contribute to dysregulated insulin secretion in isolated islets (we hope to hear back by the end of 2021). With future funding, we will test more patients, and use different assays (e.g. cell death assays) to provide better readouts that will help us gain greater understanding of how the islets respond to serum treatment and which factors have the most influence. We hope this will provide greater insight into the potential factors responsible for the effects we observed on islet function.

What’s next for Estefania?

I’ve applied for a postdoctoral fellowship to the Juvenile Diabetes Research Foundation (JDRF). This fellowship would secure my position for the next few years, and serve as another important step in my career by demonstrating my ability to attract support for my research. I’ve also applied to the Sociedad Española de Reumatología (Spanish Society of Rheumatology) for a fellowship to support Spanish rheumatologists who are scientists pursuing research abroad.

My plans are to stay at LJI to continue to develop my research skills and mentor both technicians, graduate and undergraduate students. Also, this year I re-applied to the Tullie and Rickey Families SPARK Awards program with the hope of exploring a new question I have related to type 1 diabetes, and I’m honored to have been selected as a ‘22 SPARK finalist. I look forward to competing in the SPARK pitches again this fall, where I can build on my skills of communicating the importance of my research to the public and hopefully secure funding to pursue my new project.

Hear from Dr. Tom Riffelmacher, Dr. Katia Faliti, Dr. Alex Marki and Dr. Estefania Quesada-Masachs about their ambitious SPARK projects that could advance diagnostics and treatments for diseases ranging from heart disease to infectious diseases to type 1 diabetes.

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