The metabolic relevance of the UDP-glucose receptor P2Y14

Introduction: The G protein-coupled receptor P2Y₁₄ is activated by UDP, UDP-glucose and other UDP-sugars. Northern blot and qPCR analyses showed that P2Y₁₄ is widely expressed in human and mouse tissues. Most studies focus on P2Y₁₄ presence in immune cells, suggesting a physiological relevance in immune and inflammatory responses. Although the highest expression is found in the gastrointestinal (GI) tract and adipose tissue little is known about the metabolic relevance of P2Y₁₄.

Aim: To clarify the physiological role of P2Y₁₄ with specific focus on energy homeostasis we use a P2Y₁₄-deficient mouse model.

Methods: P2Y₁₄-knockout (KO) mouse strain expresses the bacterial LacZ reporter gene to monitor the physiological expression pattern of P2Y₁₄. KO and wild-type (WT) mice were compared in numerous functional tests including glucose- and insulin tolerance tests under standard and western-type diets.

Results: We found that P2Y₁₄ is mainly expressed in a subpopulation of smooth muscle cells of the GI tract, pancreas, salivary glands, blood vessels, lung and uterus. Among other phenotypical differences KO mice showed a significantly impaired glucose tolerance following oral and intraperitoneal glucose application. By performing insulin tolerance and insulin secretion tests we could pinpoint this phenotype to a reduced insulin release from pancreatic islets lacking P2Y₁₄.

Conclusion: Our study revealed P2Y₁₄ as a new modulator of proper insulin secretion. Further, transcriptome analysis of pancreatic islets will contribute to understand the intracellular signal transduction pathways of the P2Y₁₄-receptor.