Diabetes is the most common and serious chronic disease worldwide, characterized by insufficient insulin to maintain proper blood glucose levels. It affects more than 12% of Americans and is the eighth leading cause of death in the U.S., with an estimated economic cost of more than $400 billion annually.
Mouse models of diabetes have advanced the understanding of disease pathophysiology; however, critical differences in the function and architecture of mouse and human pancreatic islets necessitate a comprehensive study of human islets to translate basic science research findings. Pancreatic islets are multicellular miniorgans containing endocrine cells that play a crucial role in regulating blood glucose.
In the largest study of its kind, published in Nature Communications, the multisite Integrated Islet Distribution Program (IIDP) consortium reports an integrative analysis of human islets from 299 organ donors without diabetes, generated by the phenotyping and genotyping initiatives within the IIDP. The IIDP is the largest source of human islets for research in the U.S.
The study applied a standardized approach to comprehensively evaluate pancreatic islet morphology, purity and viability. The investigative team directly linked islet endocrine cell composition to islet beta and alpha cell dynamic physiologic profiles and to human genetics, including genetic risk scores (GRS) for Type 1 diabetes (T1D) and Type 2 diabetes (T2D), and predicted genetic ancestry across a diverse group of organ donors. The investigators controlled for potentially confounding demographic and islet-processing features that have been shown to affect in vitro hormone secretory responses.
Their findings show that the composition of the three primary islet endocrine cell types — glucagon-producing alpha cells, insulin-producing beta cells, and somatostatin-producing delta cells — impacts islet secretory capacity; that females and males have different endocrine cell compositions; and that individuals of different ethnicities or genetically predicted ancestries also display these variations. Investigators also found something striking about genetics and T2D. Donors with a higher genetic risk of T2D were more likely to have a higher percentage of delta cells in the islets, as measured by delta cell area.
This matters because islet delta cells, although relatively few, secrete the hormone somatostatin, which suppresses insulin secretion. Consistent with this, a higher percentage of delta cells was associated with poorer insulin secretion. Moreover, the team examined expression of more than 300 genes implicated in the T2D GRS and found an enrichment in delta cells with at least one transcription factor, HHEX, supported by a body of evidence for a role in delta cell identity and proliferation, and others (e.g., GLP1R) of high translational relevance.
Overall, this investigation demonstrates the power of integrating multimodal data to better understand disease mechanisms, establish causality and generate new directions for therapeutic development and diabetes prevention. The composition and interactions among alpha, beta and delta cells have implications not only for understanding diabetes pathogenesis but also for creating stem cell-derived islets and immune-system-evading CRISPR-edited primary human islets for beta-cell replacement therapy.
The IIDP is housed at and directed by City of Hope's Arthur Riggs Diabetes and Metabolism Research Institute. Investigators with the Human Islet Phenotyping Program (HIPP) at Vanderbilt Health/Vanderbilt University, the Human Islet Genotyping Initiative (HIGI) at Stanford Medicine , Indiana University School of Medicine, and City of Hope make up the investigative team. The HIPP and the HIGI are both part of the IIDP.
Images of isolated human islets, including visualization of alpha, beta and delta cells, used in these analyses are accessible through the IIDP Islet Collection on the Pancreatlas platform, built on FAIR principles by authors of this study (Diane Saunders, PhD, Jean-Philippe Cartailler, PhD, and Marcela Brissova, PhD) with support from The Leona M. and Harry B. Helmsley Charitable Trust. Genetic risk scores and functional data are available through the IIDP Research Data Repository.
Knowledge of human islet biology, function and cell composition, as well as their association with human genetics, has accelerated over the past decade, largely through the work of the IIDP, the HIPP and the HIGI, and through the thousands of investigators worldwide these groups support by providing high-quality pancreatic islets and standardized methodologies for islet genotyping and phenotyping. This ensures islets are studied consistently, facilitates integration of data generated across the diabetes research community, and fosters collaboration.
Future studies are expected to leverage this rich dataset to link islet functional characteristics and composition to multiomic assessments and evaluate these relationships in donor cohorts, including controls and those with prediabetes and diabetes, particularly to understand cell-specific contributions to diabetes risk and disease pathophysiology.
The IIDP consortium acknowledges the support of organ donors and their families, without whom their study of human pancreatic islets would not be possible.
"Working with human islets is a great privilege and responsibility, as each human islet preparation brought to the investigator's laboratory is accompanied by family consent for organ donation," the team stated. "We hope this work can raise awareness of organ donation for research, which has helped us understand the fundamentals of human islet biology, and will pave the way for new therapies and diabetes prevention."
The team also hopes its work will help remove barriers to beta cell replacement therapy using human islet transplantation in the United States, especially as new calcineurin-free immunosuppressive therapies become available.
Co-first authors of this study are Carmella Evans-Molina, MD, PhD, at Indiana University School of Medicine; Yasminye Pettway, PhD, at Vanderbilt University; Diane Saunders, PhD, at Vanderbilt Health; and Seth Sharp, PhD, at the Stanford School of Medicine. Co-corresponding authors of the study are Marcela Brissova , PhD, at Vanderbilt Health; Evans-Molina; Anna Gloyn, DPhil, at the Stanford School of Medicine; and Joyce Niland, PhD, at City of Hope.
The work was supported by the National Institutes of Health (grants U24DK098085, U42RR017673, F30DK134041, T32GM007347, T32GM152284, R01DK129469 and P30DK020593), Breakthrough T1D, and The Leona M. and Harry B. Helmsley Charitable Trust.
Resources were provided by PanKbase ( https://www.pankbase.org ), which is supported by NIH grants U24DK138515 and U24DK138512, as well as supplemental funds from the NIH Office of Data Science Strategy (U01DK128847). The consortium used data from the database ( https://hpap.pmacs.upenn.edu/ ) of the Human Pancreas Analysis Program, which is part of the Human Islet Research Network.
