A Critical Role for β-Catenin in Modulating Levels of Insulin Secretion from β-Cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization

Abstract

The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases β-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that β-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional co-activator of β-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating β-catenin from the plasma membrane pool to the nucleus. We show that β-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that β-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that β-catenin levels modulate Ca-dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion.

Feeding and glucagon‐like peptide‐1 receptor activation stabilise β‐catenin in specific hypothalamic nuclei in male rats

“…Hence, feeding‐induced stabilisation of β‐catenin in hypothalamic neurones may result in increased synaptic potential as a result of increased transynaptic connectivity via increased adhesion, and increased secretion by synaptic vesicle recruitment to the presynaptic membrane . We have observed a similar phenomenon in pancreatic β‐cells, where β‐catenin is stabilised in response to glucose stimulation in a cAMP/protein kinase A dependent manner, associated with increased serine 552 phosphorylation . β‐catenin stabilisation in β‐cells is important for the secretion of insulin, and knockdown via small interfering RNA transfection suppressed glucose‐dependent insulin secretion …”

“…We have previously reported that elevations in glucose levels rapidly stabilised β‐catenin in macrophages and pancreatic β‐cells . Hence, we hypothesised that TCF/β‐catenin signalling might represent a novel glucose‐sensing mechanism in the hypothalamus.…”

“…Factors that inhibit GSK3 activity, or stabilise β‐catenin via phosphorylation at carboxy‐terminal serine residues 552 or 675, will also increase cytoplasmic levels of β‐catenin and promote its functions. We have found that glucose directly stabilises β‐catenin in β‐cells and that this is necessary for insulin secretion . Moreover, changes in the β‐catenin transcriptional co‐factor, transcription factor 7‐like 2 (TCF7L2), in pancreatic β‐cells have an impact on insulin secretion, potentially mediating the actions of agents that enhance insulin secretion such as glucagon‐like peptide (GLP)‐1 .…”

“…We have found that glucose directly stabilises β-catenin in β-cells and that this is necessary for insulin secretion. [7][8][9] Moreover, changes in the β-catenin transcriptional co-factor, transcription factor 7-like 2 (TCF7L2), in pancreatic β-cells have an impact on insulin secretion, [10][11][12] potentially mediating the actions of agents that enhance insulin secretion such as glucagon-like peptide (GLP)-1. 13 Taken together, these data suggest that nutrient and hormonal modulation of the Wnt/β-catenin pathway might represent an important mechanism regulating glucose homeostasis.…”

Possible role of TCF7L2 in the pathogenesis of type 2 diabetes mellitus

“…A study indicated that b-catenin plays a critical role in modulating insulin secretion and that the overexpression of the transcriptional co-activator of b-catenin, TCF7L2, attenuates insulin secretion [28]. The mechanism of how the overexpression of b-catenin influences insulin secretion remains unclear.…”