A rare genetic mutation may help explain why some families are more prone to diabetes and kidney failure, according to a new study led by University of Utah health scientists. The discovery, found across generations in a family, could ultimately lead to better treatments for these diseases for a range of patients, whether or not they inherited the mutation, they said.

"In the past, we have seen sporadic cases everywhere, but this is the first family to demonstrate that this mutation can be inherited.” Dr. Marcus Pezzolesi said, who is the corresponding author of the study and associate professor of nephrology at the American College of Health. "Excitingly, treatments are being developed not only to improve the situation in this family, but also to improve in a wider range of diabetic patients at risk for kidney disease.”

The study was conducted in collaboration with the Joslin Diabetes Center and Harvard Medical School in Boston and published in NPJ Genomic Medicine.

Scientists have long known that people who are overweight or obese produce less adiponectin. Adiponectin is a hormone that promotes insulin sensitivity, inhibits cell death, and reduces inflammation. As a result, these people are more prone to insulin resistance, type 2 diabetes, kidney disease, and other life-threatening conditions.

To determine whether there may be a genetic cause of diabetic nephropathy, Pezzolesi and colleagues analyzed DNA samples from 14 members of a family collected from the Joslin Diabetes Center. In three generations, a total of six family members had diabetes and end-stage renal disease.

To investigate more deeply, the researchers used whole genome sequencing to isolate a protein called ADIPOQ, which encodes adiponectin protein. The mutation shortens the gene and disrupts its ability to produce hormones that break down ceramide, a cholesterol-like fat substance. Thus, humans with this mutation have higher ceramide levels. Previous studies have suggested that ceramide is the driving force behind the onset of type 2 diabetes and may lead to diabetic nephropathy.

In laboratory studies of human embryonic kidney cells, the researchers found that one copy of the mutation reduced adiponectin production. The researchers determined that the mutation emerged in approximately one in 57,000 people.

Overall, carriers of this gene mutation had approximately 85% lower adiponectin levels and 30% higher ceramide levels in blood compared to noncarriers of the same family as controls.

"I am most excited that this finding confirms decades of research in animals," Dr. William Holland said, one of the corresponding authors of the study and associate professor of nutrition and comprehensive physiology at the University Health Department. "The biological effects of adiponectin in regulating insulin sensitivity, glucose tolerance, and ceramide levels are well documented in mice, and the current study suggests that loss of adiponectin impairs metabolic health in humans."

Holland says although the study was conducted in a single family, its findings could have broad implications for the diagnosis and treatment of these diseases in many people. "We can use these findings as a starting point for the development of personalized medicines that mimic the beneficial effects of adiponectin and reduce the risk of diabetes and kidney disease," he said.