Although it has long been believed that microRNA (miRNA) molecules in pancreatic islets play significant roles in Type 2 diabetes, no specific miRNAs have been definitively linked to the disease in humans.
The largest investigation on diabetes-related miRNAs discovered in human pancreatic islets—groups of cells in the pancreas that release insulin and control blood glucose levels—has just been published on February 9th, 2023 in the journal Proceedings of the National Academy of Sciences.
The majority of previous attempts to fully characterize miRNAs (which control which genes are switched on and off) in pancreatic islets have been carried out either in culture or using rodent models. The restricted number of samples used in a few research used human islets that were hard to acquire.
The study’s corresponding authors, Dr Francis Collins, Former Director of the National Institute of Health (2009-21) and Senior Investigator at the National Human Genome Research Institute at the NIH, and Praveen Sethupathy’03, Professor of biomedical sciences in the College of Veterinary Medicine at Cornell University and Director of the Center for Vertebrate Genomics, had access to a network that provided nearly 65 human pancreatic islet samples from cadavers for the study.
At least 14 pancreatic islet miRNAs that are associated with Type 2 diabetes in humans were found by the researchers using extensive next-generation sequencing and a robust sample size.
We have defined in the largest cohort of human islets to date the miRNAs that might be most relevant for Type 2 diabetes. We have defined in the largest cohort of human islets to date the miRNAs that might be most relevant for Type 2 diabetes.”
Praveen Sethupathy, Professor, Physiological Genomics, Department of Biomedical Sciences, Cornell University
In animal cells, miRNAs were first discovered in 2001. The first study to show their significance to physiology was published shortly after, in 2004, and it focused on a miRNA that controls the function of pancreatic islets.
Numerous research on miRNAs that could be relevant to pancreatic islets have been published since then, but few of them have used human tissue samples, and none have been as extensive as this one.
Sethupathy added, “There has 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.”
The comparatively high sample size reveals the degree of diversity in miRNA expression level or islet quantity throughout the human population. Though eventually, this type of study would require many hundreds of samples for a broader picture, the researchers were able to identify a few chromosomal loci explaining heterogeneity in miRNA expression with the help of the genetic data they had on all the patients.
One of these loci was discovered in the same region of the genome that is linked to features connected to Type 2 diabetes, which could indicate a unique mechanism for how Type 2 diabetes develops.
There were some striking similarities between the most altered miRNAs in the islets of individuals with Type 2 diabetes and those discovered in earlier rodent studies, but there were also some glaring discrepancies.
“These represent interesting candidates to investigate further in human models of pancreatic islets,” Sethupathy further stated.
According to Sethupathy, future research will need to concentrate on developing and analyzing human models of Type 2 diabetes, such as organoids or genetically altered islets.
Taylor, H. J., et al. (2023). Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2206797120