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Enzymes in patients with diabetes may help detect signs of CKD
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Researchers looking at patients with diabetes for more than 50 years and who never developed kidney disease found higher levels of a certain group of enzymes involved in glucose metabolism compared to those with diabetes who did develop kidney disease.
The study built on the findings from a 2017 Joslin Medalist Study of protective factors and diabetic kidney disease (DKD). Medalists are patients who have lived with diabetes for more than 50 years. The research team was led by Hetal Shah, MD, MPH, research associate at Joslin Diabetes Center and HMS Instructor in Medicine, along with Daniel Gordin, MD, PhD, adjunct faculty at Joslin and associate professor at the University of Helsinki in Finland, and George King, MD, Joslin senior vice president and chief scientific officer and HMS professor in medicine.
That Joslin Medalists have low rates of complications has intrigued researchers worldwide, Gordin said.
“That built up the rationale that there must be something protecting these people from diabetic kidney disease. This would explain how these individuals have been able to live with insulin dependent diabetes for so many years,” he said in a release from the Joslin Diabetes Center.
Search for protective factors
In the study, which recruited 1,008 U.S. patients with more than 50 years of well-documented type 1 diabetes, researchers set out to investigate the following three questions related to the 2017 discovery:
- Was PKM2 protective in non-Medalists, or patients with diabetes less than 50 years?
- Was PKM2 circulating in the Medalists’ plasma, or was it only found in the kidney? and
- Do the Medalists have any other protective factors to be explored?
“The hypothesis of this study was that the up-regulation of PKM2 and enzymes of glucose metabolism and TCA cycle protecting from diabetic kidney disease as found in individuals with extreme duration of type 1 diabetes (Medalists) could be replicated and extended in two tissues, glomeruli and plasma, of people with type 1 diabetes of shorter duration and type 2 diabetes,” the authors wrote in the article. “Hence, we aimed to extend our previous findings on the elevations of glomerular PKM2 and four other glycolytic enzymes in both type 1 and type 2 diabetes.
“Additionally, we sought to replicate the glomerular metabolomic and proteomic findings from CKD-protected Medalists by conducting similar analyses of plasma in a larger sample of Medalists and discover new markers of renal protection through these unbiased omic screens,” they wrote.
To answer the first question, researchers studied post-mortem kidneys donated by patients in all the cohorts they wanted to investigate. For the second question, they used proteomic and metabolomic techniques to study the circulating plasma of Medalists. Finally, they looked at the plasma and identified a number of metabolites and proteins that were also elevated. They mapped the associated genetic pathways to understand the cause and effect of the elevations.
“We were able to replicate the findings of the elevated PKM2 in those with good kidney function in both type 1 and type 2 diabetes,” Shah said in the release. “Also, through the plasma proteomic and metabolomic studies in the Medalists, we found that there's this amyloid precursor protein, or APP, that shows up as a potential protective factor against diabetic kidney disease.”
More studies needed
High levels of HPP were also associated with an increased risk for Alzheimer’s disease, according to the release.
“[But it also seems to be] potentially protective in multiple vulnerable tissues in people with diabetes. With that said, we would need further studies to confirm this,” Shah said.
Understanding the DKD protective factors could have clinical implications. If a biomarker circulates in the bloodstream, it could allow doctors to perform a simple blood test to determine a patient’s risk for developing DKD. They could then create personalized intervention courses.
Once the protective mechanisms are explicitly mapped, they could even be used as therapeutic targets, Joslin officials noted.
“Diabetic kidney disease is a devastating disease,” Gordin said. “It is a powerful driver of cardiovascular disease, and also, eventually, mortality. We have urgent need to find something to help these people. All [these studies] take time, but this is very promising.”
Reference:
www.joslin.org/joslin-news.html
Disclosure s : Funding for the 50-Year Medalist Study was provided by the National Institute of Diabetes, Digestive, and Kidney Diseases, the Juvenile Diabetes Research Foundation, the Tom Beatson Jr 284 Foundation and many individual Medalists. This study was also supported by a basic research grant from Sanofi-Aventis Deutschland GmbH. Gordin was supported by the Mary K. Iacocca Fellowship provided by the Iacocca Foundation and grants from the Wilhelm and Else Stockmann Foundation, the Medical Society of Finland (Finska Läkaresällskapet), the Finnish Medical Foundation and the Biomedicum Helsinki Foundation supported the study.
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