The Scientific Sessions symposium The Islet and Type 1 Diabetes featured a panel of investigators who discussed recent and emerging research that sheds new light on the role of beta cells in the development and progression of type 1 diabetes.

The session, first presented Tuesday, June 29, 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.

Carmella Evans-Molina, MD, PhD, the Eli Lilly and Company Professor of Pediatric Diabetes and Director, IU Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, reviewed recent analyses looking at the association between beta cell function and immune therapy efficacy.

A subgroup analysis of data from the Type 1 Diabetes TrialNet Teplizumab Prevention Study suggested that teplizumab was more efficacious in individuals with lower baseline beta cell function, she said.

“Somewhat counterintuitive to what you might predict, what this subgroup analysis found is that individuals with C-peptide below the median—or, in other words, those with lower C-peptide responses during an oral glucose tolerance test, or worse beta cell function—had a better response to drug therapy,” Dr. Evans-Molina said. “What’s notable though is that this is not the only prevention trial in TrialNet where those with worse beta cell function appeared to do better.”

In the TrialNet Oral Insulin Study, oral insulin showed no effect on the development of type 1 diabetes across the study cohort, but Dr. Evans-Molina noted that an interesting effect was observed in one of the study’s predefined secondary strata.

“This stratum was composed of individuals with reduced first-phase insulin responses measured during IVGTT (intravenous glucose tolerance test) and, notably, among these individuals there was a delayed progression to type 1 diabetes with oral insulin therapy,” she said. “So again, very similar to the teplizumab results, those with worse beta cell function seemed to have some benefit to oral insulin therapy. Taken together, these analyses would suggest that those with accelerated active disease may be uniquely poised to respond to immune interventions.”

These and other findings suggest a therapeutic “window of opportunity” based on metabolic staging, Dr. Evans-Molina said.

“Identifying and understanding this window is really important because a better understanding of this concept of accelerated active disease has the potential to improve trial design and allow us to design trials that are potentially shorter in duration,” she explained.

Golnaz Vahedi, PhD, Associate Professor of Genetics, Perelman School of Medicine, University of Pennsylvania, discussed multiomics single-cell profiling of human pancreatic islets, including recently published novel findings from a study examining the transcriptional perturbations of islets in type 1 diabetes.

“As things are evolving in the field, there are many ways of measuring molecular features of cells using single-cell assays, but each of these strategies has advantages and disadvantages,” Dr. Vahedi said. “Our approach to beat the limitations of an individual assay was to combine them and use multiple—in this particular case, four—distinct molecular assays to measure various features of cells in human type 1 diabetes individuals.”

Dr. Vahedi and her colleagues found that type 1 diabetes cells are indicative of an inflammatory environment and express major histocompatibility complex class II proteins, which could represent new pathogenic cells in type 1 diabetes and a new link to type 1 diabetes genetics, she said.

“Surprisingly, we also found that endocrine and non-endocrine cells from autoantibody-positive donors had a lot of transcriptional similarities with type 1 diabetes donors,” she said.

Lorenzo Pasquali, MD, PhD, Professor of Human Genetics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Spain, shared research looking at the impact of pro-inflammatory cytokines on pancreatic regulatory networks, including which gene regulatory networks are activated or suppressed.

“Our hypothesis is that perhaps, at least in part, the genetic predisposition to type 1 diabetes may reflect a decreased capacity of the beta cell to react to an inflammatory environment,” he said.

Dr. Pasquali explained that he and his colleagues observed that exposure to pro-inflammatory cytokines causes profound remodeling of the beta cell regulatory landscape and that beta cell cytokine responsive enhancers are enriched in type 1 diabetes risk variants. These findings could make it possible to identify new disease candidate genes, he noted.

“Identification and characterization of type 1 diabetes genes acting at the beta cell level could allow discovery of new drug targets,” he added. “Our findings could apply by extension to other autoimmune diseases.”

Amelia K. Linnemann, PhD, Assistant Professor, Department of Pediatrics, Indiana University School of Medicine, discussed research looking at pancreatic beta cell autophagy in type 1 diabetes.

“Because effectively nothing is known about alterations in beta cell autophagy in the context of autoimmune diabetes, we wanted to ask whether autophagy is perturbed or not in type 1 diabetes,” Dr. Linnemann said. “There is quite a lot of evidence now that beta cells are not completely destroyed in type 1 diabetes.”

Dr. Linnemann and her research colleagues have demonstrated that autophagic flux is impaired in the islets of nonobese diabetic (NOD) mice, and that there is impairment in both autophagy and crinophagy in the beta cells of human donors with type 1 diabetes.

“Although our data is suggestive, in our current study we aren’t able to fully answer the question of whether impaired autophagy or crinophagy is a cause or consequence of hyperglycemia, and how autophagy dysfunction fits into the immune infiltration timeline,” she said. “So, what we’re starting to do now is to longitudinally monitor this impairment of autophagy in NOD mice using fluorescent biosensors to measure the autophagic flux coupled to intravital microscopy.”