3D Illustration of human kidneys to illustrate kidney transplants
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A rare genetic mutation could 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. The discovery — a defect in ADIPOQ, which encodes the adiponectin protein — was made within multiple generations of a single family. But the researchers say it could ultimately lead to better treatments for a range of patients with and without the inherited mutation.

“We can use these findings as a starting point for the development of personalized medicines that mimic the beneficial effects of adiponectin and diminishes the risk of diabetes and kidney disease,” said William Holland, PhD, a co-corresponding author of the study and a U of U Health associate professor of Nutrition and Integrative Physiology.

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

The rate of type 2 diabetes has increased significantly in recent years, and now more than 35 million people in US alone have the condition. It’s known that there is a genetic component to the disease and there is much work ongoing to uncover the most relevant variants.

This team started from the premise that people who are overweight or obese produce less adiponectin, a hormone that promotes insulin sensitivity, inhibits cell death, and decreases inflammation. As a result, these individuals are more prone to insulin resistance, type 2 diabetes, kidney disease, and other life-threatening conditions.

To determine if this might point to a genetic cause for diabetic kidney disease, Pezzolesi and colleagues analyzed DNA samples from 14 members of a single family collected at the Joslin Diabetes Center. In all, six of the family members across three generations had diabetes and end-stage kidney disease.

“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.” Said Marcus Pezzolesi, PhD, MPH, the study’s corresponding author and a U of U Health associate professor of Internal Medicine in the Division of Nephrology.

He added that, “What’s exciting is that there are therapies being developed that could improve this condition not just within this family but more broadly among a vast spectrum of patients with diabetes who are at risk of kidney disease.”

The researchers used whole genome sequencing to isolate a defect in ADIPOQ. The mutation shortens the gene, disrupting its ability to produce the hormone, which breaks down ceramides, a fatty substance similar to cholesterol. As a result, people with the mutation have higher levels of ceramides. Previous studies suggest 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 just a single copy of this mutation was capable of decreasing adiponectin production. The researchers determined that this mutation occurs in about one in every 57,000 people.

Overall, carriers of the genetic mutation had about 85% less adiponectin and 30% higher levels of ceramides circulating in their blood relative to non-carriers within this same family, who were used as a control group.

“What’s most exciting for me is that this finding allows us to confirm decades of research in animals,” said Holland. “The biological effects of adiponectin in regulating insulin sensitivity, glucose tolerance, and ceramide levels is well established in mice, and the current study shows that a loss of adiponectin impairs metabolic health in humans.”

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