April 12, 2021

Lipid mediators and biomarkers associated with type 1 diabetes development

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featured discovery

Ramandham FD article resizeSasanka Ramanadham, Ph.D.Sasanka Ramanadham, Ph.D., professor in the Department of Cell, Developmental and Integrative Biology (CDIB) and senior scientist in the Comprehensive Diabetes Center (UCDC), is the latest winner of the School of Medicine’s Featured Discovery.

This initiative celebrates important research from School of Medicine faculty members.

Working with first author, Alexander Nelson, and other colleagues from UAB, Ramanadham’s paper “Lipid mediators and biomarkers associated with type 1 diabetes development” was recently published in JCI Insight.

Ramanadham and his team are focused on understanding how lipids impact beta-cell function and survival.

“Humans have one pancreas, which contains about one million islets,” Ramanadham explains. “Each islet contains close to 2000 beta-cells. The beta-cells secrete insulin, which is the body’s major regulator of blood glucose (sugar) levels. In type 1 diabetes (T1D), the beta-cells are destroyed through a series of events involving the immune system. We have found that lipids produced by beta-cells and immune cells (e.g.: macrophages, T-cells, and B-cells) can have a profound impact on the survival of the beta-cells.”

The team identified an enzyme in beta-cells and immune cells integral to the generation of these lipids. The enzyme of interest is a calcium-independent phospholipase—A2beta or iPLA2β—and its expression is increased in prediabetic rodent models and humans that are at high risk for developing T1D.

In the current study, Ramanadham says their team explored the consequences of reducing the activity of iPLA2β on T1D incidence, and examined whether that correlated with reduced lipid production.

FD first author T1DFirst author, Alexander Nelson“We, in fact, found that with chemical inhibition or genetic reduction of iPLA2β, there is a dramatic decrease in T1D incidence in a widely used model of T1D, the non-obese diabetic mouse (NOD). This was associated with select changes in lipid production by immune cells and, translationally relevant, a similar lipid signature was evident in children that were at high risk for developing T1D.”

Therefore, their findings offer the possibility of targeting these select lipids with therapeutics to counter T1D development—a huge breakthrough in diabetes research.

Read more from UAB News here.

The School of Medicine communications staff sat down with Dr. Ramanadham to gain insights about the research of this study, UAB, and the science community.

Q: What was your most unexpected finding?

The findings in this study clearly identified a strong correlation between iPLA2β-derived lipids (iDLs) from immune cells and T1D incidence. There were a few unexpected findings like 1) the lipid changes occurred in the pre-diabetic phase, suggesting that iPLA2β activity was most important in contributing to the onset of T1D, 2) paradoxical increases in lipids which can affect resolution of inflammation, suggesting that the body produces “counter lipids” in an attempt to resolve the inflammatory state; when this fails, disease ensues, and 3) a similar plasma lipid signature in children that are at high risk for developing diabetes, suggesting that these lipids could serve as early biomarkers of T1D development.

Q: How do you feel your research will impact the science community?

The T1D field has traditionally been driven, justifiably, in the direction of specifically understanding immune processes that contribute to T1D development. Our ongoing work, along with a few others outside UAB, provide an understanding of lipid signaling pathways that can impinge on the immune system network to cause effect. Together, we are identifying important and novel concepts in the field that are likely to lead to alternate or adjunct therapeutics to counter the onset of T1D.

Q: What is your research’s relevance to human disease?

According to the CDC, approximately 1.6 million adults and children were diagnosed with T1D in 2020. This represents a 30% increase since 2017. A fundamental question is, what processes lead to beta-cell death, thus significantly reducing insulin availability and promoting increases in blood glucose (sugar) levels. Our work addresses a much-neglected arm in the field—lipid signaling. More specifically, lipid signaling that is derived from the very sources (immune cells and beta-cells) that participate in beta-cell death. Gaining a better understanding of such lipid signaling will offer new therapeutic avenues and significantly enhance the possibility of countering T1D development and/or progression.

Q: When did you know you had an important discovery?

From the time we started in this area in 2004, we knew that iPLA2β participated in beta-cell death. However, in 2015, when Robert Bone (co-author on our JCI publication and a Ph.D. candidate in my lab at that time), completed a study demonstrating that reducing iPLA2β activity dramatically mitigated T1D in the NOD, that was a source of great excitement and motivation for further study. The current JCI publication, spearheaded by Alexander Nelson who was a Sci Tech Honors student at the time, and Rob, who had moved on to do a post-doctoral fellowship at IU, took it a few steps forward by identifying select lipid changes associated with T1D development and, more importantly, revealing that there were similar changes associated with children, not yet diabetic but with multiple autoantibodies (i.e., they are at high risk for developing T1D). These findings strengthened our hypothesis that iPLA2β participates in T1D onset.

Q: How has being at UAB and living in Birmingham affected your research?

UAB has a reputation for significant collaborative efforts and our lab, as others, has benefited from such opportunities. As in any other field of research, it is easy to proceed in a myopic fashion but UAB offers sufficient triggers to consider other directions. However, in general, the lipid field is an enigma to many, as they feel overwhelmed by the sheer number of lipids with bioactivity, which can be daunting. This leads to a lesser appreciation of crucial signals that contribute to a variety of clinical disorders. In some respects, this has steered me towards collaborations with distinguished PIs outside UAB, some of whom are co-authors on this JCI paper. They were instrumental in the generation of our rodent models (Mathews), clinical samples analyses (Hessner and Park), providing select inhibitors (Kokotos), and performing the crucial lipidomics analyses (Chalfant). Their continual support and enthusiasm for our work is a significant source of motivation for our group. Overall, moving to UAB from WUSM has been a very positive move and comes with great support from my CDIB department and several PIs in the UCDC.

Read the full publication in JCI Insight.