Researchers at IIT Mandi have identified a drug molecule that can be used to treat diabetes. The molecule, called PK2, is able to trigger the release of insulin from the pancreas and can potentially be used 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.
ONGOING TREATMENT : Diabetes is associated with insufficient release of insulin from pancreatic beta cells in response to blood sugar levels. The release of insulin involves many complex biochemical processes. One of these processes involves protein structures called GLP1R present in cells. In one of these processes, a hormone molecule, called GLP1, released after the ingestion of a meal, binds to proteins, called GLP1R. This triggers the release of insulin.
Current drugs used for the treatment of 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 seek to find simpler, stable, inexpensive and effective drugs for type 1 and type 2 diabetes,” the statement said, quoting study author Dr. Prosenjit Mondal, associate professor at the Faculty of Basic Sciences.
THE ALTERNATIVE: To find alternatives to these commonly used drugs, the research team first used computer simulation methods to screen for various small molecules that can bind to GLP1R. They identified the molecules PK2, PK3 and PK4 as having good binding capacities with GLP1R. In the end, 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 on GLP1R proteins in human cells and found that it is able to bind well to GLP1R proteins. This showed that PK2 can potentially trigger insulin release from beta cells,” said co-author Dr Khyati Girdhar from IIT Mandi.
ORAL OPTION: The researchers found that PK2 was rapidly absorbed from the gastrointestinal tract, meaning it can be used as an oral medication rather than an injection. After two hours of administration, PK2 was found distributed in the liver, kidneys and pancreas of the mice, but there was no trace of it in the heart, lungs and spleen. There was a small amount present in the brain, showing that the molecule may be able to cross the blood-brain barrier. It was removed from circulation in about 10 hours, according to the statement.
“Beyond increasing insulin release, PK2 was also able to prevent and even reverse the loss of beta cells, a cell essential for insulin production, making it effective for type 1 and type 2 diabetes,” Dr. Mondal said.
To test the biological effects of PK2, the researchers gave 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 mice treated with PK2 compared to the control group.
The article was authored by Dr Mondal and co-authored by Professor Subrata Ghosh, School of Basic Sciences; IIT Mandi, 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 from IIT Mandi; and Dr Durgesh Kumar Dwivedi (Regional Ayurvedic Research Institute, Gwalior).
PAPER: “Design, Synthesis, and Biological Evaluation of an Oral Small-Molecule Glucagon-Like-Peptide-1 Receptor Agonist,” Khyati Girdhar et al, Journal of Molecular Biology.
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