A Tale of Two Epidemics: A Transcriptomic Study of Fentanyl Effects on Type II Diabetes

Background: Synthetic opioids, such as fentanyl, are the leading cause of overdose. It is understood that opioids have hyperglycemic effects. For example, it has been demonstrated that insulin secretion is decreased in rat islets upon treatment with fentanyl. However, how synthetic opioid abuse alters insulin secretion and endocrine transcriptomic profiles has yet to be fully described. Spatial molecular imaging (SMI) offers a novel opportunity to determine at the cellular and molecular level these potential metabolic alterations in the islets of Langerhans of the pancreas. We hypothesize that transcriptional profiles associated with endocrine cellular dysfunction in the islets of Langerhans will be increased in fentanyl-positive patients. Methods: Pancreatic tissues from 300 patients were analyzed utilizing a Nanostring CosMx SMI [6000-plex]. Data was analyzed using R 4.0, Seurat v5 and sf packages. Electronic health records (EHR) were used to stratify patients based on fentanyl screening and A1c levels. The spatial transcriptomic profiles of fentanyl positive patients were compared to non-fentanyl users and diabetic groups. Identifying genes for endocrine cells were also compared across these groups. Results: Transcriptomic profiles of fentanyl positive patients correlated best with fentanyl negative, prediabetic patients. Decreases in insulin mRNA was demonstrated in endocrine cells in fentanyl patients compared to their sex and age matched, fentanyl-negative counterparts. We observed a “transitionary” cell type that demonstrated transcriptomic features of both alpha and beta cells. There was a higher proportion of this “transitionary” cell population in fentanyl positive patients. In addition, genes associated with insulin production and oxidative stress production, such as CALD1 and OXR1 respectively, were decreased in the beta cells of fentanyl-positive patients Furthermore, INSR was downregulated in neighboring endocrine cells to beta cells. Conclusions: Our data suggest fentanyl abuse correlated to a metabolically unhealthy transcriptomic profile. Decreases in insulin mRNA was demonstrated in endocrine cells in fentanyl patients compared to their sex and age matched counterparts. This parallels previous literature of rat islets treated with fentanyl showing decreases in insulin secretion. Furthermore, the increase in the “transitionary” cell type in fentanyl-positive patients suggested an increase in endocrine dysfunction associated with synthetic opioid usage. In addition, decreases in genes vital for proper beta cell function ( CALD1 and OXR1 ) indicated beta cell dysfunction. The demonstration of INSR downregulation in other endocrine cells suggested alteration in cellular communication in the islets of Langerhans. This communication is vital for maintaining glucose homeostasis. Future studies utilizing this data set will continue to examine potential differences in cellular neighborhoods between fentanyl positive and fentanyl negative patients and potentially identify the metabolic and transcriptomic basis for the increased incidence of diabetes in opioid users. Saint Louis University This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.