Allosteric activators of glucokinase: potential role in diabetes therapy.

Grimsby J, Sarabu R, Corbett WL, Haynes NE, Bizzarro FT, Coffey JW, Guertin KR, Hilliard DW, Kester RF, Mahaney PE, Marcus L, Qi L, Spence CL, Tengi J, Magnuson MA, Chu CA, Dvorozniak MT, Matschinsky FM, Grippo JF
Science. 2003 301 (5631): 370-3

PMID: 12869762 · DOI:10.1126/science.1084073

Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.

MeSH Terms (33)

Adaptor Proteins, Signal Transducing Allosteric Regulation Animals Blood Glucose Carrier Proteins Diabetes Mellitus, Type 2 Dose-Response Relationship, Drug Drug Evaluation, Preclinical Enzyme Activation Enzyme Activators Glucokinase Glucose Glucose Tolerance Test Homeostasis Humans Hypoglycemic Agents Insulin Insulin Secretion Intracellular Signaling Peptides and Proteins Islets of Langerhans Keto Acids Liver Liver Glycogen Male Mice Mice, Inbred C57BL Mice, Obese Proteins Rats Rats, Wistar Recombinant Proteins Stereoisomerism Thiazoles

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