Role of Glucokinase in the treatment of Type-2 Diabetes: A Short Review
AUTHORS : Chayanika Bordoloi, Damiki Laloo DOI No. : NA DOI Link. : NA Type-2 Diabetes mellitus is one of the most serious problems in the 21st century. This problem is associated with the defective metabolism of glucose. Type-2 Diabetes mellitus is responsible for elevation of fasting glucose levels in the blood, resistance to insulin, impairment of glucose regulation and glucose-induced insulin secretion. Glucokinase (GK) is an enzyme that mediates the phosphorylation reaction of glucose to glucose-6-phosphate in the presence of ATP. This reaction generally takes place in pancreatic β-cells, liver hepatocytes and hypothalamic neurons, also in intestine enterocytes. Glucokinase plays an important key role as a regulatory enzyme that maintains glucose homeostasis throughout the body. The genetic mutation study of this enzyme in humans has shown that it can cause hyperglycemia or hypoglycemia in the body which demonstrates the critical role of glucokinase in glucose metabolism.
In the early years of the 2000s, Researchers working on Type-2 Diabetes were mainly focused on the development of Glucokinase activators (GKA) which are small molecules and useful for the treatment of Type-2 Diabetes. The development of glucokinase activators proves themselves as a potential new drug treatment for Type-2 Diabetes mellitus. Several GKA has shown a good effect on animal models and patients. But someundesirable effects have shown in clinical studies of several GKA. Some of such undesirable effects were hypoglycemia, elevated circulatory triglyceride levels, and increased blood pressure. Glucokinase regulatory protein (GKRP) is found as an important protein with 68 kDa sizes and made up of a total of 626 amino acid residues. This protein is synthesized in hepatocytes and responsible for the inhibition of the glucokinase enzyme. The mechanism behind the inhibition reaction is that Glucokinase binds to the GKRP prevents it from interacting with glucose. In the case of high glucose level, the GK and GKRP complex bond breaks and the enzyme moves towards the cytoplasm. But in low glucose level condition, the GK and GKRP complex moves towards the nucleus which means complex is isolating from the hepatocyte carbohydrate metabolism. Allosteric inhibitors of the GK–GKRP interaction are can be considered as an alternative agent which will increase the GK activity and that can substitute the GKA. Therefore we can consider GK as a key target element for the potential development of Antidiabetic drugs to maintain glucose homeostasis.