A team from the University of Montreal Hospital Research Centre (CRCHUM) has discovered a novel link between chronic kidney disease and diabetes. When kidneys fail, urea that builds up in the blood can cause diabetes, concludes a study published today in the Journal of Clinical Investigation.
"We identified molecular mechanisms that may be responsible for increased blood glucose levels in patients with non-diabetic chronic kidney disease. Our observations in mice and in human samples show that the disease can cause secondary diabetes," said Dr. Vincent Poitout, researcher, CRCHUM Director, and principal investigator of the study.
Chronic kidney disease is characterized by the progressive and irreversible loss of kidney function in filtering and eliminating toxins from the blood. Eventually, those affected must undergo dialysis or kidney transplantation to eliminate toxins from their bloodstream.
It is well known that type 2 diabetes is one of the causes of chronic kidney disease. The nephrologist Laetitia Koppe, who has just completed a postdoctoral fellow in Dr. Poitout's laboratory, has proven that the opposite is also true. "About half of those affected by chronic kidney disease have abnormal blood sugar levels. I wondered why. We conducted experiments in mice and found impaired insulin secretion from pancreatic beta cells, as observed in diabetes. We observed the same abnormalities in samples of pancreatic cells from patients with chronic kidney disease," explained Dr. Koppe.
The researchers highlighted the surprisingly toxic role of urea, a nitrogenous waste product normally filtered by the kidneys and excreted in urine. "In patients with chronic renal failure, the kidneys are no longer able to eliminate toxins. Urea is part of this cocktail of waste that accumulates in the blood. In nephrology textbooks, urea is presented as a harmless product. This study demonstrates the opposite, that urea is directly responsible for impaired insulin secretion in chronic kidney disease," argued Koppe.
At the heart of pancreatic beta cells, Drs. Koppe and Poitout identified a particular protein, called phosphofruktokinase 1. "The function of this protein is altered by an increase in blood urea, which occurs in chronic kidney disease. Increased urea causes impaired insulin secretion from the pancreatic beta cells. This creates oxidative stress and excessive glycosylation of phosphofructokinase 1, which causes an imbalance of blood glucose and may progress to diabetes," said Dr. Poitout, who is also professor at the University of Montreal and the Canada Research Chair in Diabetes and Pancreatic Beta-Cell Function.
The study is important because it reveals a link and rather novel mechanism between chronic kidney disease and diabetes. "Further studies are required to validate these findings in humans. But if our observations are confirmed, it will mean that patients with non-diabetic chronic kidney disease are at risk of developing diabetes. One might then suggest therapeutic approaches, such as taking antioxidants, which may protect pancreatic beta cells and reduce the risk of developing diabetes," said Dr. Poitout.
About the study
The study "Urea impairs beta cell glycolysis and insulin secretion in chronic kidney disease," will be published online in the Journal of Clinical Investigation on August 15, 2016. Drs. Vincent Poitout and Laetitia Koppe are principal investigator and lead author of the study, respectively. The study is funded primarily by the U.S. National Institutes of Health (NIH) (R01DK58096), the Canadian Institutes of Health Research (CIHR) (MOP 77686), and the Réseau de recherche en santé cardiométabolique, diabète et obésité of the Fonds de recherche du Québec - Santé (FRQS). For more information, see the study:
About the CRCHUM
The University of Montreal Hospital Research Centre (CRCHUM) is one of the largest hospital-based research centres in North America. Our mission is to improve the health of adults through a continuum of research from basic science, to population health, to clinical research. More than 1,950 people work at the CRCHUM, including 439 researchers and 700 students and research trainees: http://crchum.
About the University of Montreal
Deeply rooted in Montreal and dedicated to its international mission, the University of Montreal is one of the top universities in the French-speaking world. Founded in 1878, the University of Montreal today has 16 faculties and schools, and together with its two affiliated schools, HEC Montreal and Polytechnique Montreal, constitutes the largest centre of higher education and research in Quebec and one of the major centres in North America. It brings together 2,500 professors and researchers and welcomes more than 60,000 students.
Source: University of Montreal Hospital Research Centre (CRCHUM)
Communications Advisor, CHUM