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 91麻豆天美直播 scientists. They say the discovery, made within multiple generations of a single family, could ultimately lead to better treatments for these conditions among a range of patients, no matter if they inherited the mutation or not.
"In the past, we鈥檝e seen sporadic cases here and there, but this is the first family to demonstrate that this mutation can be inherited." says the study鈥檚 corresponding author and a U of U Health associate professor of Internal Medicine in the Division of Nephrology. "What鈥檚 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 study, conducted in collaboration with Joslin Diabetes Center and the Harvard Medical School in Boston, appears in
Scientists have long known 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 there might be 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.
Digging deeper, the researchers used whole genome sequencing to isolate a defect in a gene called ADIPOQ, which encodes the adiponectin protein. 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. 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.
" What鈥檚 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."
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鈥檚 most exciting for me is that this finding allows us to confirm decades of research in animals," says a co-corresponding author of the study and a 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 is well established in mice, and the current study shows that a loss of adiponectin impairs metabolic health in humans."
Although the study was conducted in a single family, Holland says, its findings could have broad implications for diagnoses and treatment of these conditions 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 diminishes the risk of diabetes and kidney disease," he says.
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In addition to Drs. Pezzolesi and Holland, U of U Health scientists C.A. Simeone, J.L Wilkerson, A.M. Poss, J,A. Banks, J.V. Varre, J.L., Gurvara, E.J. Hernandez, B. Gorsi, D.L, Atkinson, T. Turapov, S.G. Frodsham, J.C.F. Morales, B. Moore, M. Yandell, and S.A. Summers contributed to this study. Researchers from Joslin Diabetes Center and Harvard Medical School also collaborated on this effort.
The study, was published on July 22, 2022 in NPJ Genomic Medicine.
This research was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Disease鈥檚 Diabetes Research Center Program, Ruth L. Kirschstein National Service Awards, the Juvenile Diabetes Foundation, the American Diabetes Association, the National Kidney Foundation of Utah & Idaho, Driving Out Diabetes, and the Margolis Foundation.
Competing interests: S.A. Summers is a consultant, cofounder, and shareholder of Centaurus Therapeutics.