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How Cellular Structures Regulate Insulin Secretion "Hotspots"

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Tiny, rod-like structures called microtubules in the insulin-producing cells of the pancreas help control when and where insulin is released, shows a study published in eLife.

The findings may have important implications for understanding how the body normally processes sugar and what goes wrong in diseases such as diabetes where sugar metabolism is disturbed.

Insulin secretion from cells in the pancreas called beta cells is carefully regulated by the body, with individual cells responding differently to sugar levels. But exactly how the behaviour of individual cells is regulated remains unclear. One unique feature of beta cells is that microtubules, which serve as roads for intracellular trafficking, form a mesh-like grid pattern rather than a wheel spoke-like pattern seen in many other cells. Previous studies have hinted that this may play a role in the release of insulin.

“We wanted to further explore the role of the beta cell’s microtubules in regulating insulin release in response to sugar,” says first author Kathryn Trogden, a former Postdoctoral Fellow at the Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, US.

To do this, Trogden and her colleagues analysed the timing and location of insulin secretion in individual mouse beta cells grown in the laboratory under different conditions. They found that the stability of microtubule structures varies from cell to cell and affects how much insulin is released in response to sugar. Less insulin is released in cells with static stable microtubules, and more insulin is released from cells where microtubules are dynamically turned over.

“Sugar exposure causes the microtubule structures to disassemble and release insulin,” Trogden explains. “Normally, this release occurs at specialised sites within each of the selected beta cells. These sites are known as  ‘hotspots’ of insulin secretion.” But the team found that when microtubules are missing from beta cells, secretion hotspots fire in multiple random cells rather than in selected sub-populations of cells only. The timing of insulin secretion also changes, causing prolonged and excessive release of insulin.

These microtubule-driven changes in secretion were independent of the release of calcium in the cells, which also plays a role in regulating insulin release. This suggests that there are multiple, layered systems for fine-tuning insulin release in these cells.

“Our findings uncover a new role for microtubules in tuning insulin secretion hotspots in selected cells, which leads to the precisely measured and carefully timed release of insulin in response to sugar,” concludes senior author Irina Kaverina, Professor of Cell and Developmental Biology at Vanderbilt University. “This is an important step towards understanding what underlies the functional diversity of beta cells, one of the parameters that dramatically changes in diabetes. We envision that our study will, in the long run, be impactful for future diabetes prevention and therapy.”

Kaverina adds that the next steps for her team include determining how microtubules regulate secretion sites at the molecular level and exploring how this process changes in disease conditions.

Reference: Trogden KP, Lee JS, Bracey KM, et al. Microtubules regulate pancreatic β cell heterogeneity via spatiotemporal control of insulin secretion hot spots. eLife. 2021;10:e59912. doi: 10.7554/eLife.59912

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