Peptide YY (PYY) improves insulin resistance through multiple mechanisms — its two circulating forms act via different receptors to suppress appetite, enhance insulin sensitivity in tissues, and protect pancreatic beta cells.
Two forms, two mechanismsPYY(3-36) suppresses appetite and enhances peripheral insulin sensitivity via Y2R, while PYY(1-36) protects beta cells via Y1R — complementary actions for metabolic disease treatment
What the researchers found
PYY deficiency is closely linked to insulin resistance development. The two circulating forms have distinct roles: PYY(3-36) acts primarily through Y2 receptors in the hypothalamus (suppressing appetite) and in peripheral tissues (adipose, skeletal muscle, liver) to enhance insulin sensitivity. PYY(1-36) acts through Y1 receptors to protect pancreatic beta cells and fine-tune insulin secretion. PYY(3-36) also promotes weight loss by delaying gastric emptying, indirectly improving insulin resistance through weight reduction. The review identifies PYY as playing an important role in glucose homeostasis.
Why it matters
While GLP-1 drugs have dominated the metabolic drug landscape, PYY represents another gut peptide with significant therapeutic potential that's less developed. Understanding PYY's dual mechanisms — central appetite suppression and peripheral insulin sensitization — could lead to new drug candidates or combination therapies. PYY-based treatments could complement GLP-1 drugs by targeting different receptor systems and metabolic pathways, potentially enhancing overall treatment effectiveness.
How the study worked
Narrative review synthesizing published research on PYY biology, receptor signaling (Y1R, Y2R), and effects on insulin sensitivity across multiple tissues. Covers both basic science research on PYY mechanisms and clinical/translational studies exploring PYY's therapeutic potential for insulin resistance and metabolic diseases.
What this study cannot tell us
This is a narrative review without systematic methodology or meta-analysis. PYY-based therapies remain largely preclinical, with limited human clinical trial data. The relative contribution of PYY's appetite-suppressing versus direct insulin-sensitizing effects is difficult to disentangle. The review doesn't address potential adverse effects of PYY-based therapies or challenges in drug development (stability, delivery, dosing).
How to read the evidence
This is a narrative review synthesizing evidence from basic science and translational studies. While it provides a comprehensive overview of PYY biology and therapeutic potential, it does not present new data or use systematic review methodology.
When this study was published
Published in 2026 in Frontiers in Endocrinology, this review captures the most current understanding of PYY's role in metabolic disease at a time when gut peptide drug development is booming.
The bigger picture
The success of GLP-1 drugs has sparked enormous interest in other gut peptide hormones as metabolic drug targets. PYY is among the most promising — it's co-released with GLP-1 from the same gut cells and has complementary mechanisms. Several pharmaceutical companies are developing PYY-based therapies or GLP-1/PYY combinations. Understanding the distinct roles of PYY's two forms and their receptor preferences is essential for rationally designing the next generation of peptide-based metabolic therapies.
Questions still open
- Could PYY analogs be combined with GLP-1 drugs to achieve greater insulin sensitization than either alone?
- Would long-acting PYY(3-36) analogs provide sustained appetite suppression and metabolic improvement for obesity treatment?
- Is PYY deficiency a measurable biomarker that could identify patients most likely to benefit from PYY-based therapies?
Common questions
What is Peptide YY and how is it different from GLP-1?
Could PYY become a treatment for diabetes or obesity?
Read the original research
The role of PYY in improving insulin resistance.
Frontiers in endocrinology, 17, 1784709
Citation
Liu, Chunyan; Ren, Na; Zhang, Haixin; Ma, Jian. (2026). The role of PYY in improving insulin resistance.. Frontiers in endocrinology, 17, 1784709. https://doi.org/10.3389/fendo.2026.1784709