During the Scientific Sessions symposium Imagining How Genetics Alters Risk of Diabetes, four investigators discussed how molecular and genetic studies are providing new insight into the influence of genetics in the development and progression of diabetes and the potential for new therapies targeting diabetes risk factors.

The session, which was originally presented Monday, June 28, 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.

Marcela Brissova, PhD, Research Professor of Medicine and Director of the Islet Procurement and Analysis Core, Vanderbilt University, discussed findings from collaborative studies looking at the birth and growth of human beta cells and islets, and at how processes and events that occur during postnatal pancreas development relate to those in fetal pancreas development.

“What we found is that the multipotent pancreatic progenitor cells that give rise to both islets and exocrine tissue reside in specialized regions of the pancreas around the periphery of pancreatic lobes,” Dr. Brissova said. “And when we look during fetal development, these multipotent progenitors reside at the very tips of branching epithelial tubes, and they persist in the pancreas during neonatal and at least through infancy.”

Building on these and other findings, Dr. Brissova and her colleagues sought to determine whether young beta cells are capable of responding to proliferative cues, such as the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4.

“Beta cell proliferation almost doubled in the presence of exendin-4 treatment in young islets, but in adult islets, adult beta cells were unable to respond to exendin-4 treatment,” she explained. “This brings up a very exciting opportunity with emerging immunomodulatory therapies for type 1 diabetes, where you can envision a combination of immunomodulation with agents like exendin-4 to augment beta cell mass in young individuals to prevent or slow down progression of type 1 diabetes.”

Struan F.A. Grant, PhD, Professor of Pediatrics, the Daniel B. Burke Chair for Diabetes Research, and Director of the Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia and the University of Pennsylvania, discussed research using high-throughput omics technologies combined with statistical and bioinformatic approaches to identify gene targets of variants that have been found in genome-wide association studies (GWAS).

“What we’re really trying to ask is what the genetic variants at particular loci are doing,” Dr. Grant said. “They are invariably in noncoding regions. They’re either in an intron or they’re lying between genes. But are they driving the nearest gene promoter or are they driving a promoter further afield?”

Using RNA sequencing, assay for transposase-accessible chromatin with sequencing, and promoter-focused Capture C sequencing techniques, Dr. Grant and his colleagues are studying the differentiation of embryonic stem cell-derived hypothalamic neurons.

“When we look at the GWAS data that’s intersected with our data, we see an enrichment for a number of traits—in particular, age at menarche, bipolar disorder, body mass index, height, depression, and sleep traits,” he said. “We’re now doing variant-to-gene mapping in this setting and, given what we’re seeing—an overall enrichment—we think we have greater confidence of going in and pursuing individual loci in these particular traits.”

Maggie Ng, PhD, Associate Professor, Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, discussed the use of risk scores derived from genetic studies to improve prediction in diabetes. She said the goal is to incorporate the application of polygenic risk scores (PRS) into clinical applications.

“We will need to collect more studies of diverse ancestry to improve the power of PRS, as well as develop methods to incorporate functional annotations, and develop pathway-specific PRS and meta-PRS derived from GWAS of multiple cardiometabolic traits,” she said. “This PRS can then be used to evaluate the causal relationship of diabetes and other phenotypes using Mendelian randomization. And eventually we should be able to integrate this PRS, along with other omics and clinical risk factors, to stratify patients and predict disease risk, prognosis, and treatment response in clinical settings.”

Melina Claussnitzer, PhD, Assistant Professor and Director of the Biology of Aging Program, Beth Israel Deaconess Medical Center and Harvard Medical School, reviewed research focused on the relationship between disease-associated genetic variants and function in the context of type 2 diabetes and its complications.

“Genome-wide association studies have been incredibly successful in identifying hundreds of thousands of robust associations in the human genome with diverse traits and diseases,” Dr. Claussnitzer said. “But the reality is only a few of these hundreds of thousands of genetic associations have been converted into actionable therapeutic hypotheses.”

In systematic variant-to-function studies using process-specific PRS to inform mechanisms, Dr. Claussnitzer and her research colleagues have identified lipodystrophy-specific PRS that implicate mitochondrial impairment in subcutaneous adipocytes and lipid accumulation in visceral adipocytes.

“We found distinct cellular programs in both subcutaneous and visceral adipocytes, and these polygenic effects appeared to follow a certain differentiation dynamic,” she said. “This can really inform us in terms of what is going on at the level of the cellular processes that lead to disease progression. And [it] will hopefully help us in the future to connect these different layers and ask questions such as whether there is convergence on pathways that are driven by different type 2 diabetes genetic variants, how these play out across different cell types, and how they depend on different stimulatory conditions.”