Role of Glucokinase Enzyme in the Treatment of Type 2 Diabetes

Abstract

Type 2 diabetes is distinguished by increased amount of glucose in blood. It may be caused by inappropriate pancreatic β-cell secretion associated with insulin resistance, which is most evident in the liver and skeletal muscle [1]. Because diabetes has a polygenic base and several genes (over 20 according to the most recent count) are implicated in its aetiology, western lifestyles characterised by little exercise and a high caloric intake are key contributing factors to the global diabetes epidemic(T2D) [2]. Current therapies, like as dietary adjustments and pharmacological therapy such as insulin, appear to be ineffective in reversing the trend. As a result, novel techniques, such as the development of new chemical entities with unique modes of action, are required. The glucose phosphorylating enzyme glucokinase (GK) has been recognised as an excellent drug target for designing and developing antidiabetic drugs due to its glucose sensor function in pancreatic cells and as a rate-controlling enzyme for clearance of liver carbohydrate and synthesis of glycogen, all of which are inhibited in diabetic patients (T2D) [3]. GK is a critical regulator of glucose-dependent insulin release in pancreatic beta cells, as well as a significant player in blood glucose regulation. It increases glycogen synthesis in hepatic cells and is a crucial actor in blood glucose regulation [4-5]. Variants in the GK gene, such as nonsense, missense, and other mutations, can cause a variety of diabetes. GK mutation-related diabetes is included in the maturity onset diabetes (MODY) category with the label MODY2. In comparison to the general population, patients with MODY2 exhibited reduced hepatic glycogen generation after three meals, and their hyperglycaemia had a weak inhibitory influence on liver glucose performance [6-8]. In the early twenty-first century, La Roche's creation of allosteric GK activators was a watershed moment. It provided pharmaceutical advice for the GK glucose sensor model, as well as a possible experimental approach and hope for a novel diabetes cure. Since then, both academia and industry have conducted substantial research into GK activators [9-11].

GK acts as a "glucose sensor" in pancreatic cells, triggering insulin secretion in response to glucose, and as a "glucose gate-keeper" in hepatic cells, enabling glucose absorption as well as glycogen synthesis and storage. GK's intended substrate glucose is phosphorylated to glucose-6-phosphate (with magnesium adenosine triphosphate) as it is active (G6P). G6P is a glycogen synthase activator as well as a substrate for glycogen synthesis [12-15].When glucose levels are beyond the physiological range, GK activity is restricted by its poor affinity for glucose (Km_0.5 of 7-8 mmol/L), so both biochemical properties and kinetics play a dual function. GK is not blocked by G6P and it has a non-Michaelis-Menten kinetics and an inflection point of 4-5 mmol/L, which is comparable to the insulin secretion threshold. This guarantees a graded response to changes in glucose levels, and GK activity enters a plateau period when glucose levels are near to the physiological limit for insulin secretion caused by glucose (5 mM) [16-17].Below 10 mM concentration of glucose, this enzyme present in the liver is retained as an idle complex in association with endogenous inhibitor, the glucokinase regulatory protein (GKRP), which confers much lower affinity for its substrate [18-19]. GKRP acts as a competitive glucose regulator in the hepatic cell, sequestering GK when blood glucose levels are low and detaching from enzyme GK when blood glucose levels are high [20]. As a result of the foregoing GK-mediated mechanisms, blood glucose levels are reduced in both direct and indirect ways. As a result, it seems reasonable to suggest that controlling GK activity could be a novel way to interfere with glucose homeostasis, given that GK activation lowers glucose levels and GK activity is low in T2DM patients [21].

The chemical composition of these small compounds (GKAs) can be used to categorize them (carbon-, urea-, 1,2,4-substitutedaryl-, 1,3,5-substituted aryl- centred or other) [22-24]. Enantioselective GKAs that accomplish their activity in hepatic cells with or without causing disruption in the inhibitory complex, i.e., GK-GKRP interaction, are another alternative for categorization [25-26]. GKAs also improve glucose elimination and decrease hepatic glucose synthesis. Every GKA can cause a different conformation of the active form of the allosteric site of GK, and the resulting complexes can have different enzymatic kinetic profiles [27].Insulin release is controlled by glucose and its metabolism, with glucose phosphorylation being the rate-limiting step. Glucose induces ATP or raises the ratio of ATP/ADP in pancreatic cells via glycolysis or tricarboxylic acid cycle, which leads to the closure of ATP-dependent K⁺ channels and depolarization of pancreatic cell membranes. This process promotes the activation of voltage-gated Ca²⁺ channels and extracellular Ca²⁺ influx, which enhances insulin production. In previous investigations, several small molecule GKAs were discovered to promote insulin production from pancreatic cells via a Ca²⁺-dependent route [28-29].In hepatic cells, GKRP regulates GK function. GK is concentrated in the nucleus at low glucose concentrations and forms an inactive GK-GKRP complex with GKRP. When blood glucose levels rise, it separates from the complex and goes to the cytoplasm, where it is metabolised. GKAs can directly activate GK and help dissociate the GK/GKRP complex, which activates GK and increases glycolysis and glycogen production [30]. Over the past years, several GKAs have been discovered. Small molecules like PF 04937319, TMG-123, R1511 or GK3HMS5552, TTP3999, Dorzagliatin, and PF-04937319 have all been demonstrated to effectively manage blood glucose levels in the clinical trials. Other drugs in clinical investigation include R1440 GKA2, GKA 50, YH GKA, PSN 010, MK-0941, ZYGK1, Ro-28-1675. AZD6370, Piragliatin, DS-7309, and ARRY-403 were also withdrawn from the clinical investigations due to their toxicity and loss of efficacy after continuous use [30-34].

The most notable problems with GKAs include hypoglycaemias, the onset of fatty liver, hepatic cell lipidosis, and reduced efficacy over time. In actuality, hypoglycaemia and dyslipidaemia as a result of the overstimulating effects of pancreatic and hepatic GK, respectively, were regarded as potential concerns during the early phases of GKA expansion [35-36]. Piragliatin and MK-0941 were found to be more likely to produce hypoglycaemia episodes. To mitigate this risk, partial activators with a higher glucose requirement were developed to lower the probability of activation at low glucose levels [37]. According to the research, this is the first stage of non-alcoholic fatty liver disease, which can range from basic steatosis to its more complex version, steatohepatitis [38]. While a spike in fatty acid levels of less than 20% is not as substantial as that generated by a high-glycaemic low-fat diet, it is nonetheless undesirable in the T2D patients with dyslipidaemia, NAFLD, and high blood pressure [39-40].

In T2D patients, small compounds that activate GK give an alternate option for restoring/improving glycaemic homeostasis. GKAs increase insulin secretion and glycogen synthesis, which reduces hepatic glucose generation. Despite a series of failures in its development, GKAs has reawakened interest, particularly since introduction of dorzagliatin, a novel dual-acting GKA, and TTP399, a hepato-selective GKA.