US Pharm. 2024;49(11):3.
Two recently reported clinical studies add to the overall store of knowledge of diabetes on a molecular level, portending possible prevention and treatment advances against the ubiquitous endocrine disease.
Researchers at the Jackson Laboratory (JAX) in Bar Harbor, Maine, discovered that DNA sequence changes that are known to increase a person’s risk for diabetes are linked to how well pancreatic cells handle molecular stress. In people with these changes, the insulin-producing cells in the pancreas may be more likely to fail or die when exposed to stress and inflammation.
“Ultimately we want to develop new ways to prevent and treat type 2 diabetes by targeting the genes and pathways that are perturbed in people who are most susceptible to the disease,” said Michael L. Stitzel, associate professor at JAX and co–senior author of the study published online in Cell Metabolism. “These findings give us new insight into some of those genes and pathways.”
The work points toward dozens of genes that connect cell stress and diabetes risk. When living cells face challenges, including damage, inflammation, or nutrient changes, they activate protective responses to try to cope with and reverse the stress. Over time, however, sustained stress can overwhelm the cells.
In the pancreas islet beta cells, two types of cell stress have been implicated in the development of type 2 diabetes: endoplasmic reticulum (ER) stress and cytokine stress. Dr. Stitzel and his colleagues homed in on one gene that was altered by both ER stress and cytokine stress. Called MAP3K5, the gene was shown to alter islet beta-cell death in mice containing a diabetes-causing mutation in the insulin-encoding gene. Eliminating or blocking MAP3K5, on the other hand, made the islet cells more resilient to ER stress and less likely to die.
Early studies of selonsertib, a drug targeting MAP3K5, showed that it could reduce the risk of severe diabetes complications. The new results point toward another possible role of the drug—in preventing diabetes in people most at risk for the disease.
In other recent diabetes research, a study from Karolinska Institute in Sweden published in Science Translational Medicine showed that people with type 2 diabetes have lower levels of the protein that breaks down and converts creatine in the muscles. This leads to impaired function of the cell mitochondria.
“This reduced protein level leads to impaired creatine metabolism in the muscle. This may explain why people with type 2 diabetes accumulate creatine in their blood,” said Principal Investigator Anna Krook, professor in the Department of Physiology and Pharmacology at Karolinska Institute. “The findings indicate that impaired creatine metabolism is a consequence of type 2 diabetes, rather than a cause of the disease,” she concluded.
To comment on this article, contact rdavidson@uspharmacist.com.
