Pancreatic islet α cells regulate microtubule stability in neighboring β cells to tune insulin secretion and induce functional heterogeneity in individual mouse and human islets.

Unlabelled: We have reported that the microtubule (MT) network in β cells attenuates this function by withdrawing insulin secretory granules (ISGs) away from the plasma membrane. Thus, high glucose-induced MT remodeling is required for robust glucose-stimulated insulin secretion (GSIS). We now show that α-cell secreted hormones, Gcg and/or Glp1, regulate the MT stability in β cells. Activating the receptors of Gcg or Glp1 (GcgR or Glp1R) with chemical agonists induces MT destabilization in β ells in the absence of high glucose. In contrast, inhibiting these receptors with antagonists attenuates high glucose-induced MT destabilization. Supporting the significance of this regulation, the MT networks in β cells of islets with higher α/β cell ratio are less stable than those with lower α/β cell ratio. Within each individual islet, β cells that are located close to α cells show faster MTs remodeling upon glucose stimulation than those away. Consequently, islets with higher α/β cell ratio secrete more insulin in response to high glucose and plasma membrane depolarization, which is recapitulated by direct Gcg stimulation. These combined results reveal a new MT-dependent pathway by which α cells, using Gcg and or Glp1-mediated paracrine signaling, tune β-cell secretion. In addition, the different α-β cell ratios in individual islets lead to their heterogeneous secretory responses, which may be important for handling secretory function needs under different physiological conditions.

Highlights: Gcg sensitizes glucose-induced MT remodeling in mouse and human β cellsMT density in single islets anti-correlates with α/β cell ratioGSIS levels in single islets positively correlate with α/β cell ratioDifferent α/β cell ratio contributes to heterogeneity of single islet GSIS.