Researchers at the Indian Institute of Technology (IIT) Mandi, Himachal Pradesh, India have identified a drug molecule that can be used as a viable treatment for Type 1 and Type 2 diabetes. The molecule known as Prokineticin-2 or PK2, can trigger insulin release by the pancreatic beta (β) cells. It shows great potential as an oral medication for managing diabetes.
India is deemed the world’s diabetic capital with an ever-increasing count of diabetics by the day. Diabetes mellitus is a chronic, long-term health condition in which the conversion of food (particularly carbohydrates and starch) into energy is dysregulated.
The food consumed by an individual is broken down into sugar (or glucose) molecules and subsequently released into the bloodstream. When the blood glucose levels are elevated, the pancreatic cells secrete insulin. Conversely, at low blood glucose levels, the production of insulin is reduced. Therefore, insulin or the blood glucose-regulating hormone acts as a key to allow the blood glucose to enter the cells of the body for peripheral utilization in the form of energy.
Diabetes is characterized by inadequate insulin release by the β islet cells of the pancreas in response to the glucose levels in the bloodstream. Type 1 diabetes (commonly referred to as insulin-dependent/juvenile/childhood-onset diabetes) occurs due to a lack of insulin production. These patients require daily insulin administration for regulating blood glucose.
Type 2 diabetes (commonly referred to as non-insulin-dependent, or adult-onset diabetes) is characterized by insufficient utilization of insulin. The common symptoms of diabetes are increased urination (polyuria), increased thirst (polydipsia), increased hunger (polyphagia), changes in vision, fatigue, and loss of body weight. Over time, diabetes, if uncontrolled, can lead to adverse health complications, such as kidney disease (nephropathy), eye disorders (retinopathy), nerve disorders (neuropathy), and cardiovascular illness.
Insulin release involves several biochemical processes of the body. One such process involves the use of protein structures known as glucagon-like peptide-1 receptors (GLP1R) which are present intracellularly. A hormonal protein molecule, called GLP1, is released after meals. This molecule binds to the GLP1R proteins, and subsequently, the GLP1-GLP1R binding triggers the release of insulin.
According to Dr. Prosenjit Mondal, Associate Professor at the School of Basic Sciences, IIT Mandi, the currently used anti-hyperglycemic agents such as liraglutide and exenatide are administered as injections. These drugs are expensive and are unstable post-administration. This warrants the need for simpler therapies that are stable, economically viable, and efficiently regulate blood glucose levels in both Type 1 and Type 2 diabetics.
About the study
The researchers at IIT Mandi used computer simulation methods to find alternatives to the commonly used oral hypoglycemic drugs. They screened various molecules that demonstrated binding with the GLP1R protein. In the screening, PK2, PK3, and PK4 showed adequate binding with GLP1R. However, the scientists selected PK2 due to its enhanced solubility. The researchers then synthesized PK2 in the laboratory for further analysis.
Dr. Khyati Girdhar, IIT Mandi, mentioned in the news release that the PK2 molecule can trigger insulin release by the pancreatic beta cells.
Based on the experiments, the researchers found that the PK2 molecule demonstrated rapid absorption by the gastrointestinal tract, indicating that the drug molecule could be administered orally instead of via injections. Two hours post administration, the scientists found PK2 in the kidney, liver, and pancreas of mice without any traces of the molecule in the lungs, spleen, and heart.
However, PK2 was detected in small amounts in the brain, which indicated that the drug molecule could cross the blood-brain barrier. PK2 was eliminated from circulation in approximately 10 hours. PK2 not only enhanced insulin release but prevented and reversed the loss of β cells. Therefore, PK2 could be an effective therapeutic approach to manage Type 1 and Type 2 diabetes.
For evaluating the biological effects of the PK2 molecule, the research team orally administered the drug to mice developing diabetes and monitored the blood glucose and insulin levels. The analysis results showed six-times higher insulin levels in the mice post administration of PK2 compared to the control mice.
The research findings have been published in the Journal of Biological Chemistry.
Dr. Pooja Toshniwal Paharia is a Consultant Oral and Maxillofacial Physician and Radiologist, M.DS (Oral Medicine and Radiology) from Mumbai. She strongly believes in evidence-based radiodiagnosis and therapeutic regimens for benign, potentially malignant, or malignant lesions and conditions either arising from the oral and maxillofacial structures or manifesting in the associated regions.