Paracrine hormonal signals from islet α cells regulate microtubule dynamics in β cells to promote insulin secretion in mouse and human islets

The microtubule network inbcells attenuates insulin secretion by pulling insulin secretory granules away from the plasma membrane. Thus, high glucose-induced microtubule remodeling is required for robust glucose-stimulated insulin secretion. We now demonstrate thathormones secreted by α cells regulate microtubule dynamics in β cells through receptors for glucagon (GcgR) and Glp-1 (Glp-1R). Activation of GcgR or Glp-1R destabilizes microtubules inbcells, accompanied by increased insulin secretion. In contrast, inhibiting these receptors attenuates high-glucose-induced microtubule destabilization and decreases secretion. Supporting the physiological significance of this regulation,bcells in islets with a higher a-to-bcell ratio exhibit more dynamic microtubules than those with a lower ratio and a high-fat-diet challenge in mice, which can compromise β-cell secretion, attenuates this effect in their islets. Within individual islets,bcells located nearacells show faster microtubule remodeling upon glucose stimulation than those more distant fromacells. Consequently, islets with a highera-to-bcell ratio secrete more insulin in response to glucose stimulation and plasma membrane depolarization, results recapitulated by exogenous glucagon stimulation or chemically induced microtubule destabilization in islets with lowera-to-bcell ratios. These combined results suggest thatacells use glucagon- and/or Glp-1-mediated paracrine signaling to fine-tuneb-cell secretion via microtubule remodeling.