Biology subjects

Ho, K.-H.

Publications and source records attributed to Ho, K.-H..

4 recordsLinked to original sources

bioRxiv2024

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

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

cell biology↗

bioRxiv2022

The microtubule minus end-binding protein CAMSAP2 does not regulate microtubule dynamics in primary pancreatic β-cells but facilitates insulin secretion

Glucose stimulation induces the remodeling of microtubules in Islet {beta}-cells to potentiate glucose-stimulated insulin secretion. CAMSAP2 is a microtubule minus-end binding protein and is reported to stabilize and position microtubules in several non-{beta}-cells, such as human retinal pigment epithelium cells. In immortalized insulinoma MIN6 cells, CAMSAP2 binds to and forms short stretches at microtubule minus ends in the cytoplasm, which is consistent with the reported subcellular localization and functions of CAMSAP2 in non-{beta}-cells. Surprisingly, we found that CAMSAP2 expressed in primary islet {beta}-cells does not form short stretches in the cytoplasm, but instead is localized to the Golgi apparatus. This novel localization is specific to {beta}-but not -cells in islets and it is independent of MT-binding. Knockdown of CAMSAP2 by shRNA impairs Golgi-ER trafficking, reduces total insulin content, and attenuates GSIS without affecting the MT dynamics or releasability of insulin granules in islet {beta}-cells. Corresponding to these results, we found that primary islets and MIN6 cells express different CAMSAP2 isoforms. We propose that primary islet {beta} cells use a novel CAMSAP2 isoform for a MT-independent non-canonical function, which is to promote Golgi-ER trafficking that supports efficient production of insulin secretory granules.

cell biology↗

bioRxiv2020

Microtubules and Gαo-signaling independently regulate the preferential secretion of newly synthesized insulin granules in pancreatic islet β cells

For sustainable function, each pancreatic islet {beta} cell maintains thousands of insulin granules (IGs) at all times. Glucose stimulation induces the secretion of a small portion of these IGs and simultaneously triggers IG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, newly synthesized IGs are more likely secreted during glucose-stimulated insulin secretion. The older IGs tend to lose releasability and be degraded, which represents a futile metabolic load that can sensitize {beta} cells to workload-induced dysfunction and even death. Here, we examine the factor(s) that allows the preferential secretion of younger IGs. We show that {beta} cells without either microtubules (MTs) or Go signaling secrete a bigger portion of older IGs, which is associated with increased IG docking on plasma membrane. Yet Go inactivation does not alter the {beta}-cell MT network. These findings suggest that Go and MT regulate the preferential release of newer IGs via parallel pathways and provide two potential models to further explore the underlying mechanisms and physiological significance of this regulation in functional {beta} cells.

cell biology↗

bioRxiv2019

Microtubules Regulate Spatial Localization and Availability of Insulin Granules in Pancreatic Beta Cells.

Two key prerequisites for glucose stimulated insulin secretion (GSIS) in Beta cells are the proximity of insulin granules to the plasma membrane and their anchoring or docking to the plasma membrane (PM). While recent evidence has indicated that both of these factors are altered in the context of diabetes, it is unclear what regulates localization of insulin and its interactions with the PM within single cells. Here we demonstrate that microtubule (MT) motor mediated transport dynamics have a critical role in regulating both factors. Super-resolution imaging shows that while the MT cytoskeleton resembles a random meshwork in the cells interior, MTs near the cells surface are preferentially aligned with the PM. Computational modeling demonstrates two consequences of this alignment. First, this structured MT network preferentially withdraws granules from the PM. Second, the binding and transport of insulin granules by MT motors prevents their stable anchoring to the PM. The MT cytoskeleton thus negatively regulates GSIS by both limiting the amount of insulin proximal to the PM and preventing/breaking interactions between the PM and the remaining nearby insulin. These results predict that altering MT structure in beta cells can be used to tune GSIS. Thus, our study points to a potential of an alternative therapeutic strategy for diabetes by targeting specific MT regulators.

cell biology↗