The ghrelin receptor (GHSR) is predominantly co-expressed with pancreatic polypeptide (PP) in pancreatic islets of both mice and humans, and is upregulated in beta cells by type 2 diabetes, revealing PP cells as key ghrelin/LEAP2 targets.
85% PP cell coexpressionThe majority of ghrelin receptor-expressing cells in mouse pancreas coexpress pancreatic polypeptide, making PP cells — not beta cells — the primary ghrelin targets
What the researchers found
In mice, 85% of GHSR-expressing islet cells coexpress PP and 50% coexpress SST. In humans, 59% coexpress PPY and 95% coexpress SST. GHSR expression is upregulated in beta cells by T2DM. LEAP2 and GHSR antagonists elevated plasma PP.
Why it matters
Understanding where ghrelin acts in the pancreas is critical for developing ghrelin-based diabetes therapies. Finding PP cells as primary targets redefines how ghrelin and LEAP2 regulate pancreatic function.
The numbers in context
85% GHSR cells coexpress PP (mouse); 59% in human; 95% coexpress SST (mouse); GHSR upregulated in T2D beta cells; LEAP2 elevates plasma PP
How the study worked
Histochemical analysis using Ghsr-IRES-Cre reporter mice. Single-cell transcriptomics of mouse and human pancreas. Plasma PP correlations with fat mass and LEAP2. PP response to GHSR antagonist and LEAP2 administration.
Who was studied
Ghsr reporter mice, human pancreas single-cell datasets, male C57BL mice
What this study cannot tell us
Reporter mouse approach may not capture all GHSR-expressing cells. Single-cell transcriptomics detects mRNA, which may not perfectly reflect protein expression. Human data from multiple datasets with variable methodology. Functional significance of GHSR on PP cells needs testing.
How to read the evidence
Moderate evidence: comprehensive approach combining reporter mice, single-cell transcriptomics, and pharmacological studies in both species.
When this study was published
Published 2021. The ghrelin-LEAP2 regulatory system continues to be actively studied for metabolic applications.
The bigger picture
The ghrelin-LEAP2 system is emerging as a key metabolic regulatory axis. Identifying PP cells as primary pancreatic targets adds complexity to our understanding and could influence the design of ghrelin-based therapies for diabetes and obesity.
Questions still open
- What is the functional consequence of ghrelin acting on PP cells versus beta cells?
- Does the diabetes-induced GHSR upregulation in beta cells contribute to disease progression?
- Could targeting the ghrelin receptor on PP cells provide metabolic benefits?
Common questions
What is ghrelin and why does it matter for diabetes?
What is LEAP2?
Read the original research
High Coexpression of the Ghrelin and LEAP2 Receptor GHSR With Pancreatic Polypeptide in Mouse and Human Islets.
Endocrinology, 162(10)
Citation
Gupta, Deepali; Dowsett, Georgina K C; Mani, Bharath K; Shankar, Kripa; Osborne-Lawrence, Sherri; Metzger, Nathan P; Lam, Brian Y H; Yeo, Giles S H; Zigman, Jeffrey M. (2021). High Coexpression of the Ghrelin and LEAP2 Receptor GHSR With Pancreatic Polypeptide in Mouse and Human Islets.. Endocrinology, 162(10). https://doi.org/10.1210/endocr/bqab148