The role of the GTPase ARFRP1 on insulin secretion from pancreatic β-cells

Background:

Insulin secretion from pancreatic β-cells is essential for an intact glucose metabolism. Upon synthesis and maturation, insulin is stored in granules until secreted. At least two different populations of insulin storing vesicles exist, mediating first and second waves of insulin secretion. The formation of intracellular vesicles is mainly mediated by GTPases. ARFRP1 is a trans-Golgi residing small GTPase involved in intracellular sorting events. The aim of this study was to clarify the role of ARFRP1 on intracellular trafficking of insulin and its secretion from β-cells.

Methods:

Arfrp1 ^β-cell-/- mice were generated by intercrossing Arfrp1 ^flox/flox with Ins1 ^Cre mice. Knockout and control animals of both genders were kept on standard diet during phenotypic analysis. All final experiments were performed with 12 to 15-week-old animals.

Results:

Phenotypic monitoring of Arfrp1 ^β-cell-/- mice showed no changes of body parameters compared to control animals throughout the study. However, elevated blood glucose levels were observed already in 5-week-old mice, whereas plasma insulin levels were unchanged until week 12. Arfrp1 ^β-cell-/- mice showed an impaired glucose clearance during an oral glucose tolerance test. Ex vivo analysis of isolated islets from Arfrp1 ^β-cell-/- mice as well as perifusion experiments showed dramatic reduction in first and second phase of insulin secretion. Morphometric analysis of pancreatic sections from Arfrp1 ^β-cell-/- and control animals revealed a tendency towards bigger islets in the knockout animals suggesting a compensatory effect.

Conclusion:

ARFRP1 is required for both first and second phase of insulin secretion from β-cells. However, the molecular steps mediated by ARFRP1 need to be identified.