It has great potential to fill gaps in treatment, including that most current drugs work only against type 2 diabetes

In mice, an investigational drug reduced the complications of type 1 and type 2 diabetes by counteracting the effects of the disease: cell death, inflammation, and organ damage.

The study, which was published online on November 24 in Science Translational Medicine, found that a novel class of drugs inhibited the capacity of a protein called RAGE to transmit inflammatory signals that harm the heart and kidneys in diabetes and impair wound healing.

The findings center on the body’s immune system, which detects and eliminates invading germs and viruses. The activation of this system induces inflammation, which includes swelling and discomfort as a result of immune cells homing in on infection or injury areas. Misplaced inflammation harms tissues in many disorders, including diabetes.

RAGE229, the study’s main compound, was found to drastically minimize both short- and long-term consequences of diabetes in human cells and mice models.

“Our results establish the molecular backbone of RAGE229 as the foundation for a new approach that targets intracellular RAGE actions to counter diabetic tissue damage,” said lead study author Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology at NYU Grossman School of Medicine.

“With further refinements, RAGE229 and its descendants have great potential to fill gaps in treatment, including that most current drugs work only against type 2 diabetes.”

Diet and age (Type 2), as well as genetic differences (Type 1), are said to diminish the activity or synthesis of the hormone insulin, which maintains blood sugar levels in check after meals provide the body with energy. While elevated blood sugar induces inflammation, previous research has shown that innovative medication options could target pathways that occur later in the disease and are similar to both forms of diabetes.

High blood sugar, in particular, causes an increase in charged particles, which rip away cell components like DNA. This destroys cells, causing them to disintegrate and release their contents, including DAMPS (damage-associated molecular patterns). According to the authors, such “danger molecules” alert the body when tissue is under stress, in some situations by activating RAGE. When a DAMP binds to RAGE on a cell’s outer surface, it modifies the shape of the receptor, allowing messages to pass into the cytoplasm, the cell’s inner compartment. Schmidt and colleagues recently demonstrated that the RAGE cytoplasmic “tail” (ctRAGE) interacts with a protein called DIAPH1 to transmit instructions that activate inflammatory genes.

The present research team evaluated a library of 59,000 compounds to identify RAGE229 as the most effective inhibitor of the DIAPH1:ctRAGE interaction. The study demonstrated that mice treated with RAGE229 had a considerably reduced inflammation score of 2.5 (on a 1-5 scale) compared to animals given an inert solvent, also called a vehicle, for comparison.

Other tests demonstrated an increased risk of heart attack in diabetic patients, a danger exacerbated in part by elevated inflammation levels. The researchers discovered that when male mice with type-1 diabetes had a transient blockage of a coronary artery, simulating a heart attack, the amount of heart muscle that perished (infarct volume) downstream of the blockage was 28% in RAGE229-treated animals, compared to 38% in vehicle-treated mice.

The team then included the RAGE229 molecule in mouse chow to assess its capacity to treat long-term problems such as diabetic sores. High blood sugar levels and associated inflammation have been found to impair the cells responsible for wound closure. The researchers discovered that after 21 days, the percentage of wound closure in male type 2 diabetic mice treated with RAGE229 was 90%, compared to 65% in those treated with vehicle. At the microscopic level, both male and female mice treated with RAGE229 had considerably improved healing compared to vehicle-treated mice (histological evidence).

Additionally, the researchers discovered that male and female type 1 or type 2 diabetic mice fed RAGE229 chow had significantly less kidney damage than mice fed control chow on several measures, including decreased inflammation-induced mesangial sclerosis – protein buildup in the organs that impairs their ability to filter wastes from the bloodstream properly.

“The RAGE229 used in the our study will not the be version recommended should it move forward into human clinical trials,” said Schmidt.

“We continue to aggressively synthesize and test new compounds and chemically modifications RAGE229. These new molecules promise to yield a final drug candidate with optimal potency in the foreseeable future.”

Source: 10.1126

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