Researchers identify microtubule mechanism and role in insulin secretion.


Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells maintains glucose homeostasis and prevents diabetes. Despite decades of studies, knowledge about what controls the precise amount of insulin release on a given stimulus is incomplete.  Now, a study from researchers at Vanderbilt University has shown that microtubules act as a cellular potentiometer to precisely control insulin secretion and suggest that disturbance of this control may contribute to beta cell dysfunction and type 2 diabetes.  The team state that strategies to destabilize microtubules, perhaps using targeted drug delivery to the pancreas, could increase insulin secretion as a way to treat diabetes.  The opensource study is published in the journal Developmental Cell.

Earlier studies from the team began using pancreatic beta cells as a model to study microtubule function, to explore how microtubules traffic cargo such as insulin granules from the cell interior to the periphery. Using compounds to destroy the microtubules, the lab stimulated the pancreatic islets with glucose and measured how much insulin was secreted. With the delivery highways missing, they expected to see a reduction in insulin secretion; instead, they observed a strong increase in secretion.   The current study shows that is in fact microtubules that negatively regulate insulin secretion in beta cells.

The current study took out microtubules in mice and showed that both glucose-stimulated insulin secretion and glucose clearance from the blood increased compared to mice with intact microtubules.  The researchers also found that the microtubule meshwork was more dense in beta cells from mice with diabetes, compared to control mice.  The lab state that the findings suggest that in response to the increased demand for insulin in diabetes, microtubules become more dense and less dynamic as a feedback mechanism, ultimately shutting down beta cell function.

To validate this the team applied super-resolution microscopy techniques to show that in beta cells, microtubules do not form highway-like tracks; instead, they form a complex mesh.  Results show that the insulin granules ‘walk’ randomly on the microtubule mesh, and the microtubules regulate the number of granules at the cell periphery to prevent over-secretion.  Data findings show that glucose destabilizes microtubules just inside the cell surface to release the microtubule hold on insulin granules and allow secretion.

The team surmise that there is an association between anti-cancer therapies that target microtubules and increased risk of diabetes in treated patients. They go on to add that their study suggests that cancer treatments that stabilize microtubules may reduce insulin secretion and promote diabetes.  For the future, the researchers state they are investigating how glucose regulates microtubule dynamics, they are also interested in studying human islets from patients with diabetes. They go on to conclude that such islets have usually lost the ability to secrete insulin, and, therefore, it may be possible to restore insulin secretion by manipulating microtubule dynamics.

Source: Vanderbilt laboratories

 

A Model of the Rheostat Function of MTs in b Cells Dense MTs trap insulin granules in the cell center and promote their random walk. Non-directional granule movement leads to rapid granule withdrawal from the cell periphery, balanced with granule arrival. Glucose stimuli trigger both MT nucleation and destabilization. MT destabilization in the cell center reduces trapping. MT destabilization at the cell periphery decreases frequency of withdrawal and leads to free diffusion of detached granules, allowing for their docking. Enhanced MT nucleation at the Golgi balances MT destabili- zation, leading to fine rheostat regulation of granule availability for release. Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells. Kaverina et al 2015.

A Model of the Rheostat Function of MTs in b Cells. Dense MTs trap insulin granules in the cell center and promote their random walk. Non-directional granule movement leads to rapid granule withdrawal from the cell periphery, balanced with granule arrival. Glucose stimuli trigger both MT nucleation and destabilization. MT destabilization in the cell center reduces trapping. MT destabilization at the cell periphery decreases frequency of withdrawal and leads to free diffusion of detached granules, allowing for their docking. Enhanced MT nucleation at the Golgi balances MT destabilization, leading to fine rheostat regulation of granule availability for release. Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells. Kaverina et al 2015.

 

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