Researchers at IIT Mandi have identified a drug molecule that can be used to treat diabetes. The molecule, called PK2, can trigger the release of insulin by the pancreas and has potential as an orally administered drug for diabetes, IIT Mandi said in a press release.
The research results were published in the Journal of Biological Chemistry.
CURRENT TREATMENT: Diabetes is associated with insufficient insulin release by the beta cells of the pancreas in response to blood glucose levels. The release of insulin involves many complicated biochemical processes. One such process involves protein structures called GLP1R that are present in cells. In one such process, a hormone molecule called GLP1, which is released after ingesting a meal, binds to proteins called GLP1R. This triggers the release of insulin.
Drugs currently used to treat diabetes, such as exenatide and liraglutide, mimic GLP1 and bind to GLP1R to trigger insulin release. However, these drugs are administered as injections, and they are expensive and unstable after administration. “We’re trying to find simpler drugs that are stable, cheap, and effective for both type 1 and type 2 diabetes,” the publication quoted study author Dr. Prosenjit Mondal, Associate Professor at the School of Basic Sciences.
THE ALTERNATIVE: To find alternatives to these commonly used drugs, the research team first used computer simulation methods to screen different small molecules that can bind to GLP1R. They identified the molecules PK2, PK3 and PK4 with good binding abilities to GLP1R. Finally, they chose PK2 because of its better solubility. The researchers then synthesized PK2 in the lab for further testing.
“We first tested the binding of PK2 to GLP1R proteins in human cells and found that it could bind well to GLP1R proteins. This indicated that PK2 could potentially trigger insulin release from the beta cells,” said co-author Dr. Khyati Girdhar quoted from the IIT Mandi.
ORAL OPTION: The researchers found that PK2 is rapidly absorbed from the gastrointestinal tract, meaning it can be used as an oral drug rather than an injection. After administration for 2 hours, PK2 was found distributed in the liver, kidney and pancreas of the mice, but there was no trace of it in the heart, lung and spleen. A small amount was present in the brain, indicating that the molecule may be able to cross the blood-brain barrier. It was phased out in about 10 hours, the press release said.
“Besides increasing insulin release, PK2 was also able to prevent and even reverse the loss of beta cells, a cell essential for insulin production, making them prevalent in both type 1 and type 2 diabetes.” is effective,” said Dr. Mondal.
To test the biological effects of PK2, the researchers administered it orally to experimental mice developing diabetes and measured glucose levels and insulin secretion. There was a six-fold increase in serum insulin levels in PK2-treated mice over the control group.
The paper was written by Dr. Mondal and co-authored by Prof. Subrata Ghosh, School of Basic Sciences; IIT Mandi, together with Dr. Sunil Kumar, ICAR-IASRI, PUSA, New Delhi; dr Budheswar Dehury, ICMR RMRC, Bhubaneswar; dr Girdhar, Shilpa Thakur, Dr. Abhinav Choubey, Dr. Pankaj Gaur, Surbhi Dogra, Bidisha Biswas by IIT Mandi; and dr Durgesh Kumar Dwivedi (Regional Ayurveda Research Institute, Gwalior).
PAPER: “Design, synthesis, and biological evaluation of a small molecule oral glucagon-like peptide-1 receptor agonist,” Khyati Girdhar et al., Journal of Molecular Biology.
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