The findings reveal that microtubules act as a cellular "rheostat" to precisely control insulin secretion and suggest that disturbance of this control may contribute to beta cell dysfunction and type 2 diabetes. Targeting the microtubule regulation of insulin secretion may offer new ways to treat diabetes.
The researchers used compounds to destroy the microtubules, then 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 team destroyed microtubules in mice and showed that both glucose-stimulated insulin secretion and glucose clearance from the blood increased compared to mice with intact microtubules.
Applying super-resolution microscopy techniques, the investigators discovered that in beta cells, microtubules do not form highway-like tracks. Instead, they form a complex mesh.
"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," author said.
Glucose, she explained, destabilizes microtubules just inside the cell surface to release the microtubule hold on insulin granules and allow secretion.
Strategies that destabilize microtubules -- perhaps using targeted drug delivery to the pancreas -- could increase insulin secretion as a way to treat diabetes, the researchers suggested.
The researchers also found that the microtubule meshwork was more dense in beta cells from mice with diabetes, compared to control mice.
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.