During the Scientific Sessions symposium Beta-Cell Senescence/Stress, a panel of investigators discussed how emerging and ongoing research into the mechanisms of beta cell senescence is providing new insight into the roles of beta cell aging and stress in the development and progression of diabetes.

The session, which was originally presented Saturday, June 26, can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Billy Tsai, PhD, the Corydon Ford Collegiate Professor, Department of Cell and Developmental Biology, University of Michigan Medical School, discussed insulin misfolding and the activation of beta cell “ER-phagy” (autophagy of the endoplasmic reticulum).

“In the ER, proteins undergo folding. When life is good, the folded material is then secreted out to the extracellular milieu,” Dr. Tsai explained. “But, unfortunately, life is not always perfect, and when proteins undergo misfolding, cells must figure out a way to get rid of these proteins.”

The ER-phagy pathway for removal of these proteins to the lysosome for lysosomal degradation is a recent discovery, he said.

“The way to get rid of misfolded cargo is through the action of an ER-phagy receptor complex,” Dr. Tsai said. “This receptor complex effectively binds and engages the misfolded protein and targets it for degradation by physically coupling the misfolded cargo to the phagophore membrane.”

The identity of the ER-phagy receptor complex is the least understood step in this pathway and is the primary focus of Dr. Tsai’s research.

“Over the last few years, my lab has identified components of the ER-phagy machinery that are important for the removal of misfolded proinsulin,” he said. “One of the components that we identified is referred to as reticulon 3 (RTN3). It is a component of the ER-phagy receptor complex that physically couples this misfolded protein to the ER-phagy pathway that then routes the cargo for lysosomal degradation.”

An increased understanding of the ER-phagy pathway may provide important insight into the development and potential treatments for mutant INS-gene induced diabetes of youth (MIDY), Dr. Tsai said.

Peter Thompson, MSc, PhD, Assistant Professor, Department of Physiology and Pathophysiology, University of Manitoba, Canada, explained how beta cell senescence relates to other forms of beta cell stress, including the therapeutic potential for this stress response, particularly in the prevention of type 1 diabetes.

“Because we have a framework of understanding the natural history of the disease, we have a better way of understanding the different windows that we can use to investigate to intervene and prevent beta cell dysfunction and death,” Dr. Thompson said. “And what has really emerged in the last few years is that beta cell dysfunction is really an early manifestation in type 1 diabetes, and it’s occurring as early as stage 1 and stage 2, despite the fact that the disease is not overtly manifested until stage 3.”

A recent study using an anti-CD3 monoclonal antibody demonstrated that the onset of type 1 diabetes could be delayed in people who were at high risk for developing the disease, he noted.

“We think that beta cell senescence is a novel stress response in type 1 diabetes and is a potential therapeutic target,” Dr. Thompson added. “We’re following up on understanding how senescence develops and the role of autoimmunity in NOD (nonobese diabetic) mice, as well in the human islet culture model that we developed. We believe that this may have some implications for understanding how certain immunotherapies may be working and may have consequences on the beta cells as well.”

Emily May Walker, PhD, Research Investigator, University of Michigan, described the development of the MafA S64F missense mutation mouse model and how it became a model of beta cell senescence.

“We know that transcription factors are essential to human beta cell function, and the role of many of these transcription factors were discovered by studying genes that lead to maturity onset diabetes of the young (MODY),” Dr. Walker said.

While a majority of the genes that lead to MODY are caused by mutations in glucokinase, she said a significant percentage of them are actually transcription factors, such as hepatocyte nuclear factor (HNF) 1 alpha, HNF4 alpha and beta, pancreatic and duodenal homeobox 1, and potentially MafA.

In preliminary findings, Dr. Walker and her colleagues have demonstrated that MafA S64F expression leads to beta cell dysfunction due to senescence as well as Ca2+ signaling changes in male mice. The researchers are investigating molecular changes that lead to increased secretion in female islets and whether the expression of MafA S64F in human beta cells has sex-dependent consequences.

Ernesto Nakayasu, PhD, BS, Senior Scientist, Biological Sciences Division, Pacific Northwest National Laboratory, explained how multi-omics analyses of stressed human islets have led to the identification of tristetraprolin (TTP) as a potential regulator of GDF15 expression. TTP recognizes adenyl and uracyl-rich element of mRNAs, which is present in GDF15 mRNA and targets mRNAs to degradation, stabilization, or translation, he said.

“GDF15 is a therapeutic molecule for metabolic diseases and has potential to be also a treatment for type 1 diabetes,” Dr. Nakayasu said.