Study identifies role for peroxisomes in protecting insulin and maintaining beta cell health

Researchers at LSU's Pennington Biomedical Research Center have identified a previously underappreciated role for tiny structures inside cells called peroxisomes in protecting insulin and maintaining the health and maturity of insulin-producing pancreatic beta cells.

Peroxisomes are small structures inside cells that help remove harmful substances but also break down fats. In animal studies, researchers disrupted these structures and found it damaged the cells that produce insulin (called beta or β cells) in three ways: promoted oxidative stress (a kind of cellular wear and tear), altered the chemical structure of the hormone insulin, and reduced signs that the cells were fully mature and functioning normally. Strangely, the animals released more insulin in response to sugar, yet their bodies were less able to keep blood sugar under control.

The study, published in JCI Insight, helps explain how problems inside cells may drive the loss of healthy insulin production seen in diabetes. "Reduced peroxisomal function increases insulin secretion, promotes insulin oxidation, and impairs β cell maturity" was led by Dr. Jason Collier and Dr. Susan Burke of Pennington Biomedical, along with collaborators from The University of Tennessee, Vanderbilt University Medical Center and The University of Alabama at Birmingham.

A closer look at the cellular machinery behind insulin

Peroxisomes are tiny structures inside cells that help process fats and manage cellular damage produced during normal metabolism. They play important roles in energy balance and in maintaining the balance between reactive oxygen species, which can damage cells, and the body's antioxidant defenses.

Beta cells are particularly vulnerable to oxidative stress, and they rely on carefully coordinated metabolic processes to produce and release insulin. While previous research has established that peroxisomes are important to cellular metabolism, their specific role in pancreatic beta cell function and maturity has been less well understood.

Beta cell dysfunction is a hallmark of type 2 diabetes, but the cellular processes that cause beta cells to lose their ability to function normally are not fully understood. The new findings suggest that disruptions in the way beta cells process fats and manage oxidative stress may contribute to this dysfunction.

To investigate the role of peroxisomes, the researchers used genetically modified animal models in which the gene Pex5, which is required for normal peroxisomal function, was deleted specifically in pancreatic cells or insulin-producing beta cells. The researchers then evaluated glucose tolerance, insulin secretion, oxidative stress, metabolism and markers of beta cell maturity.

Beta cells are highly sensitive to changes in their metabolic environment. Our findings indicate an important role for peroxisomes to help beta cells manage a heathy environment, protect insulin from damage and maintain a mature identity. This gives us another piece of the puzzle for understanding how beta cells become dysfunctional and points to new questions about whether these pathways could be relevant to metabolic disease in humans."

Dr. Jason Collier, Director of the Islet Biology and Inflammation Laboratory

More insulin did not mean better blood sugar control

Animals with impaired peroxisomal function developed problems controlling their blood sugar early in life, a condition known as glucose intolerance. Despite this impaired glucose regulation, the animals showed increased insulin secretion from beta cells.

The researchers found that some of the insulin being secreted had undergone oxidation, meaning the insulin proteins had experienced chemical changes associated with oxidative stress. Using advanced mass spectrometry, the researchers identified oxidized insulin proteins as well as a truncated insulin-derived peptide in animal models with peroxisomal deficiency.

The findings suggest that producing more insulin is not necessarily sufficient for maintaining normal glucose regulation. The integrity of the insulin protein and the health of the beta cells that produce it also appear to be important. Research findings support the premise that loss of functional peroxisomes places beta cells under significant metabolic and oxidative stress.

Peroxisomes also appear to help maintain beta cell identity

Healthy beta cells have specialized characteristics that allow them to efficiently produce and release insulin. Researchers found that impaired peroxisomal function reduced markers associated with this mature beta cell identity.

This suggests that peroxisomes may play a role not only in protecting insulin from oxidative modification and degradation, but also in helping beta cells maintain the specialized characteristics necessary for normal function.

The effects also differed between male and female animal models. Male animals developed a more pronounced metabolic phenotype, including glucose intolerance and increased insulin secretion, while females showed a milder metabolic response. Both males and females, however, demonstrated evidence of reduced beta cell maturity.

"These findings provide new insight into the relationship between cellular metabolism, oxidative stress, insulin integrity and beta cell health," said Dr. Burke, Director of the Immunogenetics Laboratory. "Additional research will be needed to determine whether impaired peroxisomal function contributes to beta cell dysfunction in people with obesity, prediabetes, diabetes or other metabolic diseases."

Other Pennington Biomedical researchers involved in the study included Caroline Cothern, Maggie Ducote, Thomas Martin, Melissa Linden, Robert Noland, David Burk, Krisztian Stadler and Sujoy Ghosh, along with collaborators from The University of Tennessee, Vanderbilt University Medical Center and The University of Alabama at Birmingham. The study was supported by the National Institutes of Health through a P20 award to Dr. Burke.