α-catenin isoforms are regulated by glucose and involved in regulating insulin secretion in rat clonal β-cell models.

Abstract

The recent finding that β-catenin levels play an important rate-limiting role in processes regulating insulin secretion lead us to investigate whether its binding partner α-catenin also plays a role in this process. We find that levels of both α-E-catenin and α-N-catenin are rapidly up-regulated as levels of glucose are increased in rat clonal β-cell models INS-1E and INS-832/3. Lowering in levels of either α-catenin isoform using siRNA resulted in significant increases in glucose stimulated insulin secretion (GSIS) and this effect was attenuated when β-catenin levels were lowered indicating these proteins have opposing effects on insulin release. This effect of α-catenin knockdown on GSIS was not due to increases in insulin expression but was associated with increases in calcium influx into cells. Moreover, simultaneous depletion of α-E catenin and α-N catenin decreased the actin polymerisation to a similar degree as latrunculin treatment and inhibition of ARP 2/3 mediated actin branching with CK666 attenuated the α-catenin depletion effect on GSIS. This suggests α-catenin mediated actin remodelling may be involved in the regulation of insulin secretion. Together this indicates that α-catenin and β-catenin can play opposing roles in regulating insulin secretion, with some degree of functional redundancy in roles of α-E-catenin and α-N-catenin. The finding that, at least in β-cell models, the levels of each can be regulated in the longer term by glucose also provides a potential mechanism by which sustained changes in glucose levels might impact on the magnitude of GSIS.