The microtubule network in β-cells 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 that hormones secreted by α-cells regulate microtubule dynamics in β-cells through receptors for glucagon (GcgR) and glucagon-like peptide 1 (GLP-1R). Activation of GcgR or GLP-1R destabilizes microtubules in β-cells, 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, β-cells in islets with a higher α-cell–to–β-cell 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, β-cells located near α-cells show faster microtubule remodeling upon glucose stimulation than those more distant from α-cells. Consequently, islets with a higher α-cell–to–β-cell 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 lower α-cell–to–β-cell ratios. These combined results suggest that α-cells use glucagon-mediated and/or GLP-1–mediated paracrine signaling to fine-tune β-cell secretion via microtubule remodeling.
- Glucagon/glucagon-like peptide 1 sensitizes glucose-induced microtubule remodeling in β-cells.
- Microtubule density in islets inversely correlates with the α-cell–to–β-cell ratio.
- Glucose-stimulated insulin secretion levels in single islets positively correlate with their α-cell–to–β-cell ratio.
- Glucagon and microtubule destabilization mobilize the same granule pool.
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