BOSTON – (July 23, 2018) – Researchers have long sought drugs that could help to prevent diabetic kidney disease (DKD), which afflicts about 40% of people with type 2 diabetes. Among the current contenders are a class of diabetes management drugs known as DPP-4 inhibitors.

Scientists at Joslin Diabetes Center now have shown that in mouse models of the disease, the DPP-4 inhibitor linagliptin produces two signs of prevention against kidney damage, says Robert C. Stanton, MD, chief of Joslin’s Kidney and Hypertension Section and Associate Professor of medicine at Harvard Medical School.

Mice given linagliptin saw reduced growth in kidney size and lower urinary excretion of the protein albumin, says Stanton, who is senior author on a paper describing the work in the PLOS One journal. Both conditions are associated with DKD.

Stanton emphasizes that although the animal experiments provide important clues about linagliptin and DKD, actual evidence on any preventive effects in humans will come from a large clinical trial of the drug that is wrapping up this year.

Importantly, the Joslin research also demonstrated for the first time that biological mechanisms that defend tissues against damage from oxidants (reactive oxygen molecules) are critical to achieving linagliptin’s preventive effect in the mouse models of DKD.

“Oxidants are important molecules in our health, but they have to be kept in balance,” Stanton says. “Diabetes is associated with a double whammy situation, where you have a stimulation of molecules that make too many oxidants and you also have a downregulation of antioxidant proteins that would normally take care of excess production of oxidants.”

The Joslin team discovered that linagliptin appeared to repair two of the main antioxidant biological pathways, helping these pathways to resume their normal defensive roles.

The investigators went on to study antioxidant protection in mouse models of DKD that were genetically modified to produce less of a protein called G6PD, which is a key link that provides an essential molecule called NADPH upon which the entire antioxidant system relies.

“Linagliptin didn’t protect these mice, suggesting that an intact antioxidant system is needed to make the system work,” Stanton says.

Animal studies in other labs also have found that DPP-4 inhibition can be beneficial in protecting kidneys. However, solid evidence for its role in humans is waiting on reports from the CARMELINA (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus) trial, a large international study launched in 2013.

If linagliptin does protect kidneys in human with type 2 diabetes, that will heighten interest in developing drugs that increase production of G6PD and/or other proteins in the antioxidant pathways, which is a major goal of Stanton’s work.

“Over the years, there have been tremendous research efforts by many groups suggesting that these antioxidant pathways are critical for a number of diseases, including diabetes, cancer and heart disease,” he says.

Drug candidates to strengthen antioxidant pathways, however, have not been very effective so far as they are not specific enough. Stanton predicts that such treatments will need to be tightly tailored to specific molecular targets in the pathways—a strategy that has paid off well in cancer and other medical fields of medical research.

Joslin’s Netanya Spencer and Zhihong Yang were co-first authors on the paper. Jensyn Cone Sullivan from Beth Israel Deaconess Medical Center and Thomas Klein of Boehringer-Ingelheim also contributed.

The work was supported by an unrestricted grant from Boehringer-Ingelheim.

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