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Visit the diabetes ForumHealth scientists from the University of Utah have identified a rare genetic mutation which might explain the predominance of type 2 diabetes in some families.
The discovery, which was found within multiple generations of one family, could pave the way for improved treatments for people living with diabetes and kidney failure, regardless of whether they possess the mutated genes.
Marcus Pezzolesi, the study’s corresponding author and U of U Health associate professor of internal Medicine in the Division of Nephrology, said: “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.
“What’s exciting is that there are therapies being developed that could improve this condition not just within this family but more broadly among fast spectrum of patients with diabetes who are at risk of kidney disease.”
Prior diabetes research has already found that people classed as overweight or obese produce inadequate amounts of the hormone adiponectin.
Within the body, adiponectin is crucial in promoting insulin sensitivity, inhibiting cell death and decreasing inflammation. Therefore, individuals with less adiponectin are at an increased risk of insulin resistance, type 2diabetes, kidney disease and other life-threatening conditions.
To explore the potential genetic causes of diabetic nephropathy (diabetic kidney disease), the researchers collated and analysed the DNA samples of 14 members of the same family. Across three generations, six of the family members had diabetes and end-stage kidney disease.
Using genome sequencing, the scientists isolated a defect in the ADIPOQ gene, which is responsible for encoding the adiponectin protein. Through this, they discovered that the mutation shortens the gene, inhibiting its ability to produce the hormone which breaks down ceramides – a fatty cholesterol-like substance. People with the inherited gene mutation have higher levels of ceramides than those without it.
Studies have shown that ceramides are an impetus for developing type 2 diabetes and may also contribute to diabetic nephropathy.[1]
By analysing human embryonic kidney cells in a laboratory setting, the researchers discovered that a single copy of this mutation was powerful enough to decrease adiponectin production. They now believe this mutation occurs in about one in every 57,0000 people.
In total, those with the genetic mutation had 85% less adiponectin and30% higher amounts of ceramides in their blood compared to other family members(the control group) who did not have the defective gene.
William Holland, a co-corresponding author of the study and a U of U health associate professor of Nutrition and Integrative Physiology, said: “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.
“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,” concluded Holland.
Pezzolesi added: “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.”
This study was originally published in NPJ Genom Med.
[1] https://healthcare.utah.edu/publicaffairs/news/2022/06/6-ceramides-gastric-bypass.php
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