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

Abstract

We have reported that the microtubule (MT) network in {beta} 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 -cell secreted hormones, Gcg and/or Glp1, regulate the MT stability in {beta} cells. Activating the receptors of Gcg or Glp1 (GcgR or Glp1R) with chemical agonists induces MT destabilization in {beta} 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 {beta} cells of islets with higher /{beta} cell ratio are less stable than those with lower /{beta} cell ratio. Within each individual islet, {beta} cells that are located close to cells show faster MTs remodeling upon glucose stimulation than those away. Consequently, islets with higher /{beta} 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 cells, using Gcg and or Glp1-mediated paracrine signaling, tune {beta}-cell secretion. In addition, the different -{beta} cell ratios in individual islets lead to their heterogeneous secretory responses, which may be important for handling secretory function needs under different physiological conditions. HighlightsO_LIGcg sensitizes glucose-induced MT remodeling in mouse and human {beta} cells C_LIO_LIMT density in single islets anti-correlates with /{beta} cell ratio C_LIO_LIGSIS levels in single islets positively correlate with /{beta} cell ratio C_LIO_LIDifferent /{beta} cell ratio contributes to heterogeneity of single islet GSIS C_LI