Mitochondria: A Potential Target for Diabetes Treatment

Losing your β-cells leads directly to type 2 diabetes, as they are crucial for insulin production and regulation.

Mitochondria generate energy essential for cell function, but defects are linked to diseases like type 2 diabetes. Diabetic patients struggle to produce or use insulin effectively. Studies show their pancreatic β-cells have abnormal mitochondria, impairing energy production, but the cause remained unclear. A Science study by University of Michigan researchers found that dysfunctional mitochondria disrupt β-cell maturation and function in mice ().

“We wanted to determine which pathways are important for maintaining proper mitochondrial function,” said Emily M. Walker, Ph.D, a research assistant professor of internal medicine and first author of the study.

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To do so, the team damaged three components that are essential for mitochondrial function: their DNA, a pathway used to get rid of damaged mitochondria, and one that maintains a healthy pool of mitochondria in the cell.

“In all three cases, the exact same stress response was turned on, which caused β-cells to become immature, stop making enough insulin, and essentially stop being β-cells,” Walker said.

“Our results demonstrate that the mitochondria can send signals to the nucleus and change the fate of the cell.”

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The researchers also confirmed their findings in human pancreatic islet cells.

Their results prompted the team to expand their search into other cells that are affected during diabetes.

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Losing your β-cells is the most direct path to getting type 2 diabetes. Through our study we now have an explanation for what might be happening and how we can intervene and fix the root cause."

“Diabetes is a multi-system disease—you gain weight, your liver produces too much sugar and your muscles are affected. That’s why we wanted to look at other tissues as well,” said Scott A. Soleimanpour, M.D., director of the Michigan Diabetes Research Center and senior author of the study.

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The team repeated their mouse experiments in liver cells and fat-storing cells and saw that the same stress response was turned on. Both cell types were unable to mature and function properly.

“Although we haven’t tested all possible cell types, we believe that our results could be applicable to all the different tissues that are affected by diabetes,” Soleimanpour said.

Regardless of the cell type, the researchers found that damage to the mitochondria did not cause cell death.

This observation brought up the possibility that if they could reverse the damage, the cells would function normally.

To do so, they used a drug called ISRIB that blocked the stress response. They found that after four weeks, the β-cells regained their ability to control glucose levels in mice.

“Through our study we now have an explanation for what might be happening and how we can intervene and fix the root cause,” Soleimanpour said.

The team is working on further dissecting the cellular pathways that are disrupted and hope that they will be able to replicate their results in cell samples from diabetic patients.

Reference:

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues - (https://www.science.org/doi/10.1126/science.adf2034)

Source-Eurekalert