Targeting Hepatic Glucokinase in Type 2 Diabetes

Abstract

Glucokinase (hexokinase IV) has a major role in the control of blood glucose homeostasis because it is the predominant hexokinase expressed in the liver, has a very high control strength on hepatic glucose disposal (1), and is the glucose sensor for insulin secretion in pancreatic β-cells (2). Glucokinase is currently considered a strong candidate target for antihyperglycemic drugs for type 2 diabetes (2–4). This is supported by the impact of mutations in the glucokinase gene on blood glucose concentration in humans. Inactivating mutations that lower the enzyme affinity for glucose or compromise glucokinase expression cause diabetes (maturity onset diabetes of the young type 2), whereas activating mutations lower blood glucose (2). Pharmacological activators of glucokinase (GKAs) that mimic the effect of activating mutations represent a potential novel strategy for antihyperglycemic therapy (2–4). Type 2 diabetes is associated with defective regulation of hepatic glucose metabolism, involving elevated glucose production in euglycemic conditions and subnormal clearance of glucose by the liver after a meal because of delayed suppression of hepatic glucose production and impaired conversion of glucose to glycogen (5,6). This inefficient clearance of glucose by the liver is due at least in part to impaired regulation of glucose production and usage by hyperglycemia, a process sometimes described as decreased “autoregulation” or “glucose effectiveness” (7). Whether the defect in diabetes in humans involves decreased glucokinase activity is not established. Hepatic glucokinase activity was shown to be either elevated in newly diagnosed type 2 diabetic patients (8) or decreased in obese subjects with diabetes (9). Hepatic glucokinase is regulated by an inhibitory protein (glucokinase regulatory protein [GKRP]) that binds glucokinase with high affinity at basal glucose concentrations (5 mmol/l) and sequesters glucokinase in the nucleus in an inactive state (1,10). In the postprandial state, …