The composition and interaction of alpha, beta, and delta cells in human islets directly influence insulin secretion and diabetes risk.
Study Overview
The Integrated Islet Distribution Program (IIDP) consortium published an integrative analysis of human islets from 299 organ donors without diabetes in Nature Communications. The study combined morphological, functional, and genetic data to create a comprehensive profile of islet health and function.
Key Findings
Islet cell composition drives function. Endocrine cell composition—specifically the proportion of alpha, beta, and delta cells—directly affects secretory capacity.
Sex and ancestry matter. Females and males differ significantly in endocrine cell composition, and these variations also appear across ethnicities or predicted genetic ancestries.
Genetic risk for Type 2 diabetes linked to delta cells. Donors with higher genetic risk of Type 2 diabetes (T2D) had a higher percentage of delta cells, measured by delta cell area.
More delta cells, worse insulin secretion. A higher delta cell percentage was associated with poorer insulin secretion, because delta cells secrete somatostatin, which suppresses insulin release.
Key genes and transcription factors identified. Expression of over 300 genes implicated in T2D genetic risk scores was examined, with notable enrichment in delta cells for the transcription factor HHEX and other targets like GLP1R.
Methodology
The study employed standardized assessment of islet morphology, purity, and viability. The analysis established direct links between islet cell composition, dynamic physiology, human genetics, and predicted genetic ancestry. The team carefully controlled for demographic and islet-processing confounding factors.
Implications
Understanding the composition and interactions among alpha, beta, and delta cells informs diabetes pathogenesis and the development of:
- Stem cell-derived islets
- CRISPR-edited primary human islets for beta-cell replacement therapy
Consortium and Data Access
The IIDP is directed by City of Hope. The investigative team includes:
- Human Islet Phenotyping Program at Vanderbilt Health/Vanderbilt University
- Human Islet Genotyping Initiative at Stanford Medicine
- Indiana University School of Medicine
- City of Hope
Images of isolated islets are accessible via the IIDP Islet Collection on Pancreatlas. Genetic risk scores and functional data are available through the IIDP Research Data Repository.
Future Directions
Researchers plan to leverage the dataset for multiomic assessments and evaluate relationships in donor cohorts including controls, prediabetes, and diabetes.
Acknowledgments and Support
The study acknowledges organ donors and their families for making this research possible. Supported by:
- NIH grants (U24DK098085, U42RR017673, F30DK134041, T32GM007347, T32GM152284, R01DK129469, P30DK020593)
- Breakthrough T1D
- The Leona M. and Harry B. Helmsley Charitable Trust
- Resources provided by PanKbase and the Human Pancreas Analysis Program