According to the CDC, about 38 million Americans suffer from diabetes, and it is the fourth leading cause of death in the United States. More concerning is that the incidence of diabetes—especially type 2 (T2D) or adult-onset diabetes—is increasing.

Diabetes is caused by the inability of pancreatic b-cells to make or other cells to use insulin. An autoimmune process has long been suspected to be involved. Skeletal muscle and b-cells in patients with T2D have multiple morphological and functional defects.1,2

Recently, a team of researchers at the University of Michigan explored this mitochondrial dysfunction and showed how it might be linked to diabetes.3 The team, led by Scott Soleimanpour, MD and Emily M. Walker, PhD, examined mitochondrial quality control that maintains appropriate mitochondrial function under stress conditions. More specifically, they looked at three pathways that lead to impairments in mitochondrial quality control: decreased mitoDNA levels, preventing elimination of damaged mitochondria, and inhibition of mitochondrial fusion. The initial experiments were done in mice, but the findings were repeated in human pancreatic islet cells.

Interestingly, the result was the same for all three pathways. In all cases, the stress response resulted in interference with the maturation of b-cells. Blocking the stress response allowed them to mature as normal. Thus, these insights suggest that blocking the stress response might be a beneficial therapeutic strategy.

A conversation with Dr. Walker.

T2D is linked to diet. Do your results offer any insight into that link?

In two of our models of impaired mitochondrial quality control, the animals were placed on a high-fat diet to model individuals eating a western-style diet. We saw a much stronger stress response and loss of b-cell maturity when the animals were on this diet. There are a lot of negative impacts for b-cells when they are required to produce more insulin to compensate for weight gain, and also, there are many studies showing that fatty acids themselves damage b-cells. In our study, the high-fat diet sped up the mitochondrial stress responses likely because of this increased damage due to the food they were eating.

Can you speculate on the nature of the signaling molecules that illicit the response?

Our study found that it was the integrated stress response that includes changes to signaling molecules, such as eIF2α, and a transcription factor called ATF4. Activation of this signaling pathway and these factors induced changes in the nucleus that changed what genes were expressed in both b-cells and liver cells. We saw increases in the stress response target genes and decreases in genes that help the cell to have mature function and identity.

Your results provide a window on the process of normal b-cell development. Do you have any thoughts on those mechanisms?

We know that b-cells need proper mitochondrial function to maintain cell maturity. We also know that, during differentiation of stem cells into b-cells, this doesn’t happen in a complete way. Other work in our lab is focused on how to improve mitochondrial function in stem cell-derived b-cells to help them mature better, and we’re just starting to figure out pathways that can help this happen.

The use of ISRIB to block the stress response is an intriguing result. Is that a viable possibility for a therapy? 

Clinical trials for next generation drugs related to ISRIB are being performed to treat different diseases, including ALS. Additionally, another group has investigated the benefits of ISRIB on reducing the immune cells involved in type 1 diabetes. We are interested in following up on potential positive effects of ISRIB, or newer versions of the drug, on islets from T2D donors.

What do you see as the next steps in this research?

Our next steps include what I mentioned above in relation to inhibiting the integrated stress response (with ISRIB or other drugs) and seeing if they positively affect T2D donor islets. We would also like to determine if our findings in liver are applicable to human disease, such as metabolic dysfunction-associated steatotic liver disease.

What interested you in mitochondria in the first place?

We grow up learning about how mitochondria are the “powerhouse of the cell,” but what is really fascinating is that mitochondria do a whole lot of other things in the cell besides just making energy. In this work, we’ve shown that they can actually signal to the nucleus and change the way the DNA is packaged to make certain genes turn off and on! Because metabolism is so important to a cell, it’s really interesting to figure out how exactly the mitochondria direct changes in ways far beyond energy production.

 

References

1Flannick J, Mercader JM, Fuchsberger C, et al. (2019) Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570: 71–76.

2Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307: 384–387.

3Walker EM, Pearson GL, Lawlor N, et al. (2025) Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. Science. DOI: 10.1126/science.adf2034