Previous studies, mostly in animal models, have suggested that microRNAs (miRNAs) play a role in type 2 diabetes (T2D). However, there is limited knowledge of miRNA expression in human pancreatic islets (HPIs). Now, researchers at Cornell University, the University of Cambridge, and the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) have identified which miRNAs are associated with the disease in humans. The findings represent the largest study to date of diabetes-linked miRNAs found in human pancreatic islets.
The new study is published in Proceedings of the National Academy of Sciences in a paper titled, “Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis.”
“Genetic studies have identified ≥240 loci associated with the risk of T2D, yet most of these loci lie in noncoding regions, masking the underlying molecular mechanisms,” wrote the researchers. “Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating miRNA expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date.”
The study’s corresponding authors, Praveen Sethupathy, PhD, professor of biomedical sciences in the College of Veterinary Medicine and director of the Center for Vertebrate Genomics at Cornell University, and Francis Collins, MD, PhD, former director of the NIH and a senior investigator at the National Human Genome Research Institute at the NIH, had access to a network that supplied nearly 65 human pancreatic islet samples from cadavers for this study.
“We’ve defined in the largest cohort of human islets to date the miRNAs that might be most relevant for type 2 diabetes,” said Sethupathy, who was a postdoctoral researcher in Collins’ NIH lab from 2008–2011.
“We [also] found that some of the diabetes-associated miRNAs in humans are not ones that have been well-characterized in the previous two decades of studying islets and diabetes in rodent models,” he said.
“There’s been long-standing interest to better understand the molecular environment of the pancreas so that we could get a better handle on what goes awry in diabetes patients and then eventually be able to use that information to develop better therapeutics,” Sethupathy explained.
The relatively large sample size helps to reveal the extent of variation in the quantity of miRNAs in the islets, or expression level, across the human population. The researchers also had genetic information on all the patients, which helped them determine a handful of genomic loci underlying variability in miRNA expression, though ultimately this type of inquiry will require many hundreds of samples for a fuller picture. One of these loci was found in the same area of the genome that is associated with T2D-related traits, which could suggest a novel mechanism for how T2D develops.
Some of the most altered miRNAs in islets from individuals with T2D were consistent with those found in previous rodent studies, but there were also some notable differences. “These represent interesting candidates to investigate further in human models of pancreatic islets,” Sethupathy said.
Looking toward the future, the researchers will need to further invest in the development and study of human models of T2D, such as genetically-modified islets or organoids.