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bioRxiv · 10.1101/2024.10.21.619544

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

Ho, K.-H.·Barmaver, S.·Ho, R.·Yagan, M.·Ahmed, H. K.·Kaverina, I.·Gu, G.
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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

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Ho, K.-H., Barmaver, S., Ho, R., Yagan, M., Ahmed, H. K., Kaverina, I., Gu, G.. 2024-10-23. 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. https://doi.org/10.1101/2024.10.21.619544

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