BAY R3401: A Blood-Glucose Lowering Prodrug's Impact on Phosphorylase a and b Activities

What is it about?

The article discusses the effects of BAY R3401, a blood-glucose lowering prodrug, on hepatic glycogenolysis. The prodrug reduces basal and glucagon-stimulated hepatic glycogenolysis and reduces phosphorylase a and a + b activities in liver extracts of rats treated with BAY R3401. However, the effect on phosphorylase a is not the primary action of BAY R3401. The active metabolite of BAY R3401, BAY W1807, is a potent inhibitor of muscle phosphorylase b and acts as a competitive inhibitor with respect to the stimulation of the enzyme by AMP. BAY R3401 reduces glycogenolysis by both inactivation and inhibition of residual phosphorylase a. The inhibitor facilitates the inactivation of phosphorylase a in intact liver, hepatocytes, and gel-filtered homogenates, and directly inhibits phosphorylase a in an appropriate assay system and perfused liver. BAY R3401 may promote glycogen deposition by suppressing futile glycogen cycling driven by phosphorylase a and activating glycogen synthase. BAY U6751, a dihydropyridine-2,3-dicarboxylic acid, is a potent inhibitor of hepatic glycogen breakdown and can be used as a potential research tool to control (postabsorptive) hyperglycemia in type 2 diabetes.

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Why is it important?

This research is important as it helps to further our understanding of hepatic glycogen handling and its role in regulating hepatic glucose output. Additionally, it identifies potential adjuvants in the treatment of type 2 diabetes. Key Takeaways: 1. BAY R3401 markedly reduces basal and glucagon-stimulated hepatic glycogenolysis 2. BAY R3401 reduces glycogenolysis by inactivation and inhibition of residual phosphorylase a 3. The dihydropyridine-2,3-dicarboxylic acid BAY U6751 is a potent inhibitor of hepatic glycogen breakdown and may be developed as an adjuvant in the control of (postabsorptive) hyperglycemia in type 2 diabetes 4. BAY R3401 suppresses hepatic glycogenolysis by allosteric inhibition and by the dephosphorylation of phosphorylase a.