Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects

Abstract

Glucokinase Glucokinase (GK GK ; EC 2.7.1.1.) phosphorylates and regulates glucose metabolism in insulin-producing pancreatic beta-cells, hepatocytes, and certain cells of the endocrine and nervous systems allowing it to play a central role in glucose homeostasis glucose homeostasis . Most importantly, it serves as glucose sensor glucose sensor in pancreatic beta-cells mediating glucose-stimulated insulin biosynthesis and release and it governs the capacity of the liver to convert glucose to glycogen. Activating and inactivating mutations of the glucokinase gene cause autosomal dominant hyperinsulinemic hypoglycemia and hypoinsulinemic hyperglycemia in humans, respectively, illustrating the preeminent role of glucokinase in the regulation of blood glucose and also identifying the enzyme as a potential target for developing antidiabetic drugs antidiabetic drugs . Small molecules called glucokinase activators (GKAs) glucokinase activators (GKAs) which bind to an allosteric activator allosteric activator site of the enzyme have indeed been discovered and hold great promise as new antidiabetic agents. GKAs increase the enzyme's affinity for glucose and also its maximal catalytic rate. Consequently, they stimulate insulin biosynthesis and secretion, enhance hepatic glucose uptake, and augment glucose metabolism and related processes in other glucokinase-expressing cells. Manifestations of these effects, most prominently a lowering of blood glucose, are observed in normal laboratory animals and man but also in animal models of diabetes and patients with type 2 diabetes mellitus (T2DM T2DM ) type 2 diabetes mellitus (T2DM) . These compelling concepts and results sustain a strong R&D effort by many pharmaceutical companies to generate GKAs with characteristics allowing for a novel drug treatment of T2DM.

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

“…Allosteric activators of GK (i.e., GKAs) have been of great significance as antidiabetes drugs, and a number of diverse GKAs have been reported (5,(7)(8)(9). However, GKAs may cause serious side effects, as they change a sigmoidal activity curve of GK into a hyperbolic one (8,9), and consequently alter the sensing of blood glucose level by GK in pancreatic β-cells, resulting in hyperinsulinemic hypoglycemia.…”

“…However, GKAs may cause serious side effects, as they change a sigmoidal activity curve of GK into a hyperbolic one (8,9), and consequently alter the sensing of blood glucose level by GK in pancreatic β-cells, resulting in hyperinsulinemic hypoglycemia. As an approach to avoid the side effect, moderate or hepatocyte-specific GKAs are under development (36)(37)(38).…”

“…Defect and mutations in GK are directly associated with type 2 diabetes and maturity-onset diabetes of the young type 2 (5, 6). Thus, GK has been an important molecular target for studying blood glucose homeostasis and developing antidiabetes drugs (5,7,8). The crystal structure of human GK (hGK) revealed that GK undergoes a slow and energetically unfavorable structural rearrangement of the small domain in response to glucose during the transition from a super-open conformation into an open conformation (9).…”

Novel and emerging diabetes mellitus drug therapies for the type 2 diabetes patient

“…GK is a key enzyme in the hexokinase family that facilitates glucose homeostasis via glucose phosphorylation and metabolism mainly in the pancreatic β cells and hepatocytes [43][44][45] . GK functions as a glucose sensor in pancreatic β cells, thereby stimulating glucose-stimulated insulin secretion and regulating glucose metabolism within the liver, including gluconeogenesis, glycolysis, glycogen synthesis, glucose oxidation, lipogenesis, urea, and uric acid production [43,[45][46][47][48] .…”

“…GK functions as a glucose sensor in pancreatic β cells, thereby stimulating glucose-stimulated insulin secretion and regulating glucose metabolism within the liver, including gluconeogenesis, glycolysis, glycogen synthesis, glucose oxidation, lipogenesis, urea, and uric acid production [43,[45][46][47][48] .…”