Mahmoud Cenin and his colleagues at Harvard Medical School and at the MGH Diabetes Center in Boston have found that mice without diabetes develop a metabolic disorder that mimics the disease. Although such mice aren’t typically used as models for human metabolic conditions, they are useful for studying the biology, genetics, and drug therapies of diabetes.

Scientists first discovered the disorder in a small group of wild mice, but since then additional diabetes mice have appeared in labs around the globe. The finding has prompted a worldwide hunt for the cause of these diseases.

Researchers found mutations in gene transcription and protein processing pathways that are responsible for turning off the body’s pancreases. The pancreases have to work in concert to create one cell in the body. However, in a person whose pancreas is under attack, the cells can be shut down because of insulin resistance.

Cenin and his colleagues studied the pancreases of healthy and diabetes mice, but since the animals’ health was determined simply by calculating the average daily glucose concentration in their blood, the researchers couldn’t directly link gene changes with diabetes symptoms and progression.

Cenin and his colleagues, however, determined that the mice with the genetic changes have three stages to the disease. In the first stage, they developed impaired glucose utilization, a deficiency in converting glucose into usable energy. In the second stage, they developed the characteristic hyperglycemia, a disease characterized by high blood glucose levels, and the final stage, they reached the pathological state known as β-cell failure.

Cenin’s team found that mutations in at least four of the genes that process protein in the pancreas could promote glucose intolerance and subsequent hyperglycemia and β-cell failure. The researchers also found other mutations that produced β-cell failure with an increased risk of developing the disease.

“We have demonstrated that gene mutations from the same family, or from mutations that were present in multiple generations, could be responsible for the pathogenesis of different forms of diabetes,” said Cenin. “We now have to figure out the relationship with the body’s response to the disease, its gene expression, and its mechanisms.”

The findings may eventually be used to develop therapies for the inherited disease.

Next steps for the scientists include studying the genetic mutations associated with the disease and identifying the most aggressive targets of gene therapy. In the future, they hope to focus their research on a