New Markers Protect in Diabetic Kidney Disease; Hope for Therapy

Researchers have identified several enzymes that may protect against diabetic kidney disease (DKD) and could potentially be used to develop new therapeutics for the condition.

The study was published online earlier this month in Diabetes Care.

In particular, the work finds that people without DKD, despite having a long duration of type 1 diabetes, had elevated levels of pyruvate kinase M2 (PKM2) in their renal glomeruli, the part of the kidney that filters waste products from the blood.

This suggests that PKM2 may play a strong protective role against kidney disease, say the authors, led by Daniel Gordin, MD, DMSc, of the Joslin Diabetes Center, Boston, Massachusetts, and University of Helsinki, Finland.

The study also identified another molecule, amyloid precursor protein (APP), that could also be protective against DKD.

The results could be used to develop biomarkers to help determine risk for developing DKD, as well as for personalized interventions for the condition, in addition to the potential for new therapeutics, say the authors.

"DKD is a devastating disease. It is a powerful driver of cardiovascular disease, and also, eventually, mortality. We have an urgent need to find something to help these people. All [these studies] take time, but this is very promising," commented Gordin in a press release from Joslin.

Something Protects Some Patients From DKD

The study grew out of previous observations from the Joslin Medalist Study, which included over 1000 people who had had type 1 diabetes for 50 years or more but had not developed diabetic complications. Past work by this group found that people without kidney disease had higher levels of a group of enzymes related to glucose metabolism in their renal glomeruli.

Specifically, levels of pyruvate kinase M2 (PKM2) were 2.7 times higher in the glomeruli of Medalist participants without kidney disease (Nat Med. 2017;23:753-762). PKM2 plays a role in both the breakdown of glucose and the Krebs cycle, which is vital for the release of energy from carbohydrates, fats, and proteins.

"That built up the rationale that there must be something protecting these people from DKD. This would explain how these individuals have been able to live with insulin-dependent diabetes for so many years," Gordin explained.

The researchers set out to investigate three questions related to the findings of the Medalist study. First, was PKM2 protective in non-Medalists? Second, was PKM2 circulating in the Medalists' plasma or was it only found in the kidney? And third, do the Medalists have any other protective factors to be explored?

So they conducted further experiments, in plasma as well as renal tissue, and extended their research to a more diverse population of patients with type 2 diabetes and shorter duration type 1 diabetes.

First, they examined post-mortem kidney tissue from non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (controls, n = 5).

Results showed a trend toward lower levels of PKM2 in individuals with type 2 diabetes compared to those without diabetes (P = .08), as well as in those with severe DKD compared to those with preserved renal function (P = .07).

There was also upregulation of four enzymes involved in glycolysis, one of which was PKM2, in individuals with type 2 diabetes but without DKD.

For the second question, they used cutting-edge proteomic and metabolomic techniques to study the circulating plasma of Medalists.

For the third question, they looked at the plasma and identified a number of metabolites and proteins that were also elevated. And they mapped the associated genetic pathways to understand the cause and effect of the elevations.

Taken together, the plasma studies suggest PKM2 may be protective in other tissues besides the kidney, and the protein and metabolite studies suggest that protection against DKD may involve controlling free glucose within the cells and neutralizing toxic metabolites.

"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," said co-first author Hetal Shah, MD, MPH, also of the Joslin Diabetes Center.

APP Also Protective

And the researchers found that individuals without DKD had significantly elevated levels of APP compared to those with kidney disease (P = .01), suggesting APP "is a potential protective factor against DKD," Shah added.

This last result is surprising, says Shah, as APP may have antithrombotic properties but its main known association is an increased risk for Alzheimer's disease.

"[APP 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," she noted.

The authors mention several study limitations. Among them the fact that the new study only included protein analysis from individuals with a long duration type 1 and type 2 diabetes, and that it could not confirm findings from the previous study in individuals with a shorter duration of type 1 diabetes.

The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, JDRF, the Tom Beatson Jr 284 Foundation, Sanofi-Aventis Deutschland, Iacocca Foundation, Wilhelm and Else Stockmann Foundation, Medical Society of Finland, Finnish Medical Foundation, and Biomedicum Helsinki Foundation. Author Weier Qi is an employee of AstraZeneca. Authors Aimo Kannt and Takanori Shinjo are employees of Sanofi-Aventis. Author Hillary Keenan is an employee of Sanofi-Genzyme.

Diabetes Care. Published online May 10, 2019. Abstract

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