U of Utah Health: Discovery of rare genetic mutation could lead to better diabetes treatment – State of Reform

A rare genetic mutation may help explain why some families are more susceptible to diabetes and kidney failure, according to a new study led by University of Utah health scientists. They say the discovery, made within several generations of one family, could eventually lead to better treatment of these conditions among a range of patients, regardless of whether they inherited the mutation or not.

“In the past we’ve seen sporadic cases here and there, but this is the first family to demonstrate that this mutation can be inherited,” says Marcus Pezzolesi, Ph.D., MPH, corresponding author of the study and associate professor of internal medicine at U of U Health in the Division of Nephrology. “It is exciting that there are therapies being developed that could ameliorate this condition not only within this family, but more broadly among a wide range of diabetic patients who are at risk of kidney disease.”

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

Scientists have long known that overweight or obese people produce less adiponectin, 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.

Pezzolessi Research Laboratory

Pezzolesi’s research team studies how diabetes occurs, diabetic complications and chronic kidney disease. Photo: Kristan Jacobsen

To determine whether there might be a genetic cause for diabetic kidney disease, Pezzolesi and colleagues analyzed DNA samples from 14 members of one family collected at the Joslin Diabetes Center. A total of six family members in three generations had diabetes and end-stage renal disease.

Digging deeper, the researchers used whole-genome sequencing to isolate a defect in a gene called ADIPOQ, which encodes the protein adiponectin. The mutation truncates the gene, disrupting its ability to produce the hormone that breaks down ceramides, a fatty substance similar to cholesterol. As a result, people with the mutation have higher levels of ceramides. Previous studies have shown that ceramides are a driving force behind the onset of type 2 diabetes and may contribute to diabetic kidney disease.

In laboratory studies of human embryonic kidney cells, the researchers found that only one copy of this mutation was able to reduce adiponectin production. The researchers found that this mutation occurs in about one in 57,000 people.

“It is exciting that there are therapies being developed that could ameliorate this condition not only within this family, but more broadly among a wide range of diabetic patients who are at risk of kidney disease.” – Marcus Pezzolesi, Ph.D

Overall, carriers of the genetic mutation had about 85 percent less adiponectin and 30 percent higher levels of ceramides circulating in their blood than noncarriers in the same family, who were used as a control group.

“What’s most exciting to me is that this finding allows us to confirm decades of animal research,” said William Holland, Ph.D., study co-author and U of U Health Associate Professor of Nutrition and Integrative Physiology . “The biological effects of adiponectin in regulating insulin sensitivity, glucose tolerance, and ceramide levels are well established in mice, and the present study shows that loss of adiponectin impairs metabolic health in humans.”

Although the study was conducted in one family, Holland says, its findings could have broad implications for the diagnosis and treatment of these conditions in many people.

“We can use these findings as a starting point to develop personalized drugs that mimic the beneficial effects of adiponectin and reduce the risk of diabetes and kidney disease,” he says.

This press release was provided by University of Utah Health.

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