Renal cell metabolism in diabetic men predisposes to renal disease

Men with diabetes have a higher risk than women of suffering from diabetes-associated or diabetic nephropathy, a serious complication of this pathology that causes damage to the kidneys and an increased cardiovascular risk. Now, an international study published in Science Translational Medicine has shown that part of these differences are related to energy metabolism, the process by which cells generate energy. The study, led by the Scientific from Manresa Dr. Sergi Clotet Freixas and Dra. Ana Konvalinka both from the University Health Network de Toronto (Canada) and in which the Hospital del Mar Research Institute participated, has determined substantial differences in this process between the two sexes. A researcher from the Vall d'Hebron Research Institute (VHIR) has also participated.

To reach these conclusions, it has been possible to determine different characteristics between the renal tubular cells of men and women without any pathology. In this way "we have been able to see that there is a differential energy metabolism between men and women at the renal level, producing more damage in men, which translates into markers of worse renal evolution and greater mortality from any cause", explains Dr. Clara Barrios, an author of the study, assistant physician in the Nephrology Department and researcher at the Hospital del Mar Research Institute.

In this sense, it has been certified that the use of glucose to generate energy in people with diabetes can generate more renal damage in the case of men. "Male tubular cells have more activated mitochondrial respiration, which leads to increased oxidative stress and programmed cell death (apoptosis). When we simulate diabetes, the renal tubular cells of men increase the number of damage markers compared to those of women," says Dr. Marta Riera, a researcher at the Hospital del Mar Research Institute and an author of the study. In fact, men's cells use more glucose and also more glutamine in energy metabolic pathways.

In women's kidneys, on the other hand, the army of molecules that feeds the kidney cells has a soldier that does the opposite: it is a metabolite called pyruvate, which is much more present in women's kidneys than in men's. The authors of the study found that the higher the pyruvate levels, the higher the resistance to developing diabetic kidney disease. According to Dr Clotet, lead author of the study, this element acts as an antioxidant: "It binds to and blocks stress-generating molecules". Women who decrease the presence of pyruvate are also more at risk of developing the disease, and this opens the door to looking for strategies that promote pyruvate accumulation in both men and women, while avoiding over-activity of the TCA cycle. These extremes still need to be investigated in a sex-specific manner, as well as intensifying the study of mechanisms to prevent diabetic kidney disease.

All this has a direct relationship with the presence of male hormones, as could be seen in the five-year follow-up of the patients studied, three groups at different stages of diabetic disease. Moreover, these differences can be easily checked in a blood test, looking for metabolites resulting from the process of energy metabolism in the cells. "In the near future we will move towards personalized treatment in people with diabetes and chronic kidney disease, where gender is clearly a factor to be taken into account", also confirms Dr. María José Soler, an author of the study, clinical head of Nephrology and Dialysis of the Nephrology Department and Head of the research group of Nephrology and kidney transplantation at VHIR.

Determining this fact may make it possible to personalize the treatment of patients, adapting it to the reality of the quality of the process used by their cells to generate energy. The work has revealed metabolic pathways of interest to be studied as potential therapeutic targets. It may also provide a series of markers that can serve as prognostic factors for mortality and negative evolution of patients and for assessing their response to treatment. As Dr. Barrios comments, "many doors are open for diagnostic and research use to see if we can modulate these affected pathways and thus stimulate the energy consumption of renal tubular cells to be less harmful to the kidney".

Diabetic nephropathy is a chronic complication of diabetes. It is responsible for about 30% of patients on dialysis and is the first cause of renal transplantation.