Scientists, including one of Indian-origin, have identified the key inflammatory mechanisms linked to type 1 diabetes and obesity-related kidney dysfunction, an advance that may lead to new biomarkers and therapeutics. “We found that insulin deficiency and insulin resistance, two hallmarks of diabetes, seem to be associated with increased sphingomyelin in the kidney, which trigger damaging inflammatory mechanisms,” said Kumar Sharma, professor at the University of California, San Diego.
Researchers analysed the kidneys of experimental mice with type 1 diabetes and mice fed a high-fat diet. They found increased amounts of sphingomyelin, a type of fatty acid commonly found in cell membranes and nervous tissue, in both experimental groups.
Specifically, the sphingomyelin are believed to drive an increase in the ratio of adenosine triphosphate (ATP) and adenosine monophosphate-activated protein (AMP) in glomerular cells of the kidney in mice with diabetes, obesity or both, Sharma said.
ATP and AMP are molecules involved in intracellular energy transfer and glomerular cells are key in the filtering of blood, one of the primary functions of the kidney. “ATP is involved in every cellular function. It is the energy currency of the cell,” said Sharma. “But too much ATP causes inflammation. We believe that sphingomyelin fuels increases in ATP and decreases in AMP that result in inflammation which leads to cell dysfunction, fibrosis and endothelial damage underlying diabetic kidney disease,” he said.
Normally, ratios of ATP and AMP are tightly regulated, depending on energy needs of the cell. “The mechanisms triggered by diabetes and obesity, such as increased ATP, seem to disrupt that balance,” Sharma said.
Previously, it was not known exactly how ATP was affected in this process. “Due to difficulties in the stability of ATP, it was uncertain whether there was increased ATP or decreased ATP production with diabetes,” Sharma said. Researchers used mass spectrometry imaging to answer this question by identifying these difficult to measure molecules in frozen tissues.
Diabetic kidney disease is the leading cause of end-stage kidney disease, and a major risk factor for cardiovascular disease. The study’s insights could have major impact on developing new biomarkers and novel therapeutics for diabetic and obesity-related complications, such as kidney disease, said Sharma. “It may be possible to create new treatments by blocking ATP and the inflammatory pathways consequent to that or by developing ways to reduce the amount or activity of sphingomyelin in the kidney.” The study was published in the journal EBioMedicine.