NIH funds study of type 1 diabetes development

(Press-News.org) Weill Cornell Medicine has received a four-year, $3.4 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, for a study of the details and dynamics of the autoimmune process that causes type 1 diabetes. Dr. Shuibing Chen, the Kilts Family Professor of Surgery and director of the Center for Genomic Health at Weill Cornell Medicine, will lead the project. Dr. Chen’s long-time collaborator, Dr. Stephen Parker, professor of computational medicine and bioinformatics, human genetics and biostatistics, and director of the Epigenomic Metabolic Medicine Center (EM2C) at the Caswell Diabetes Institute at the University of Michigan, is the multi-principal investigator.

According to the American Diabetes Association, about two million Americans have type 1 diabetes, representing 5% to 10% of all diabetes cases in the United States. The disorder arises, typically in childhood or early adulthood, when the immune system attacks insulin-producing cells—known as beta cells—in the pancreas. With regular injections or infusions of insulin, people with type 1 diabetes can have near-normal lifespans, but they often cannot control blood sugar levels optimally, leaving them with relatively high risks of diabetes-related complications such as heart, kidney and retinal disease.

How and why beta cells are attacked by immune cells and antibodies has never been well understood, though there is evidence that the process generally requires a genetic susceptibility as well as one or more environmental triggers.

Dr. Chen and Dr. Parker and their teams will explore both genetic and environmental factors in the disease process, and these factors’ interactions, using advanced and powerful laboratory and computational tools—for example, recording how the molecular details of individual beta cells and immune cells differ between patients with type 1 diabetes and healthy individuals.

The team will study how these differences manifest and change over time, using three-dimensional cell cultures called “organoids”—essentially modeling the parts of the pancreas where beta cells are found and are attacked by immune cells.

Prior genetic studies have illuminated more than 100 specific locations on the human genome where abnormalities or variants are associated with a higher risk of type 1 diabetes. Most of these “risk loci” are not within the protein-coding regions of genes, which suggests that they normally have indirect, regulatory functions—such as dialing up or down a gene’s activity in a specific context, or controlling how the segments of a gene’s transcripts are spliced together to encode proteins of different length. Dr. Chen and her team plan to use their collective expertise in cell profiling and organoid modeling to identify the specific regulatory roles of many of these risk variants.

Understanding, at this level of detail, what makes people susceptible to type 1 diabetes and ultimately triggers it could transform the clinical management of this disorder. Beta cells can take months to years to die out entirely, and thus it should be possible, in principle, to detect and then stop the disease process while patients still retain some natural insulin-response capability.

“Our interdisciplinary collaboration brings together expertise in genetics, genomics, organoid biology and computational methods to discover the relationship between genetic and environmental influences in type 1 diabetes,” said Dr. Parker.

“We expect these findings to have a substantial impact on the development of new disease progression markers and therapeutic strategies,” said Dr. Chen, who is also a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine.

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