Biochem Soc Trans. 2005 Apr;33(Pt 2):371-4.

Small molecule glucokinase activators as novel anti-diabetic agents.

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AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. Brendan.Leighton@astrazeneca.com

Abstract

The monomeric enzyme GK (glucokinase) has a low affinity for glucose and, quantitatively, is largely expressed in the liver and pancreatic beta-cells, playing a key 'glucose sensing' role to regulate hepatic glucose balance and insulin secretion. Mutations of GK in man can be inactivating, to cause a form of diabetes mellitus, or activating, to lower blood glucose levels. Recently, models of GK protein structure have helped to elucidate the role of inactivating and activating mutations, with the latter revealing an allosteric binding site, possibly for an unknown physiological activator. However, this discovery was pre-dated by Drug Discovery projects that have identified small organic molecules that activate pancreatic and liver GK enzyme activity. These compounds stimulate insulin secretion in islets and glucose metabolism in hepatocytes. The profile of these GK activators, both in vitro and in vivo and the potential role that GK activators play in lowering blood glucose levels in Type II diabetes mellitus will be discussed.

PMID:: 15787609; [PubMed - indexed for MEDLINE]

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Cited by 3 PubMed Central articles

Liver Glucokinase(A456V) Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase. [Int J Endocrinol. 2011]
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