ABSTRACT
Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucose/biosynthesis , Hypoglycemic Agents/pharmacology , Liver/drug effects , Liver/metabolism , Animals , Carrier Proteins/metabolism , Diabetes Mellitus, Type 2/metabolism , Enterohepatic Circulation/drug effects , Humans , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Transcription Factors/agonists , Transcription Factors/antagonists & inhibitorsABSTRACT
A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.
Subject(s)
Glucose/biosynthesis , Liver/drug effects , Liver/metabolism , Animals , Depression, Chemical , HumansABSTRACT
The interaction of methylene violet (MV) and 4-bromomethylene violet (BrMV) with calf thymus and supercoiled phi X174 phage RF I DNA is reported. Measurements employing UV-visible absorption spectroscopy and equilibrium dialysis give evidence for the formation of complexes by each dye with DNA in the dark. They covalently bind to DNA, and MV nicks DNA, when the nucleic acid/dye mixtures are irradiated with visible light in a deoxygenated environment. Quantum efficiencies for singlet oxygen formation are 0.27 and 0.25 for MV and BrMV, respectively. A higher value (0.49) is observed for 4-iodomethylene violet (IMV).
