Deploying insulin granule-granule fusion to rescue deficient insulin secretion in diabetes.

According to our current understanding of insulin exocytosis, insulin granules dock on the plasma membrane, undergo priming and then wait for calcium-triggered fusion. In this issue of Diabetologia, Hoppa et al (doi 10.1007/s00125-011-2400-5 ) report that cholinergic stimulation induces granule-granule, or multivesicular, fusion to effect more efficient insulin release. Other exocytotic modes of insulin secretion, particularly those induced by incretin stimulation, include orderly granule fusion with granules already fused with the plasma membrane, called sequential exocytosis, and recruitment of newcomer granules to fuse with plasma membrane with minimal time for docking and priming. The molecular machineries that mediate these distinct exocytotic modes of granule-granule fusion and newcomer granules remain undefined, but they could be therapeutically targeted to couple to cholinergic and incretin stimulation to rescue the deficient glucose-stimulated insulin secretion in diabetes.