Publication Date:
2003-07-19
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grimsby, Joseph -- Sarabu, Ramakanth -- Corbett, Wendy L -- Haynes, Nancy-Ellen -- Bizzarro, Fred T -- Coffey, John W -- Guertin, Kevin R -- Hilliard, Darryl W -- Kester, Robert F -- Mahaney, Paige E -- Marcus, Linda -- Qi, Lida -- Spence, Cheryl L -- Tengi, John -- Magnuson, Mark A -- Chu, Chang An -- Dvorozniak, Mark T -- Matschinsky, Franz M -- Grippo, Joseph F -- New York, N.Y. -- Science. 2003 Jul 18;301(5631):370-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12869762" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing
;
Allosteric Regulation
;
Animals
;
Blood Glucose/metabolism
;
*Carrier Proteins
;
Diabetes Mellitus, Type 2/*drug therapy/metabolism
;
Dose-Response Relationship, Drug
;
Drug Evaluation, Preclinical
;
Enzyme Activation
;
Enzyme Activators/chemistry/pharmacology
;
Glucokinase/*metabolism
;
Glucose/*metabolism
;
Glucose Tolerance Test
;
Homeostasis
;
Humans
;
Hypoglycemic Agents/chemistry/pharmacology
;
Insulin/blood/*secretion
;
Islets of Langerhans/*drug effects/secretion
;
Keto Acids/metabolism
;
Liver/*drug effects/metabolism
;
Liver Glycogen/biosynthesis
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Mice, Obese
;
Proteins/metabolism/pharmacology
;
Rats
;
Rats, Wistar
;
Recombinant Proteins/metabolism
;
Stereoisomerism
;
Thiazoles/chemistry/*pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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