Prospects for Pharmacologic Inhibition of Hepatic Glucose Production

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.

Glucose derived inhibitors of glycogen phosphorylase

“…Thus, the enzyme has become a validated target in combatting non-insulindependent or type 2 diabetes mellitus (NIDDM or T2DM), and its inhibitors are considered as potential antidiabetic agents. The biochemical and pharmacological background of this research has been amply summarized in several reviews of the past decade, therefore, the reader is kindly referred to those papers [3][4][5][6][7][8].…”

N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods

“…2,6,7 Glycogen phosphorylase (GP) is the enzyme responsible for glycogen breakdown to produce glucose and related metabolites for energy supply. 4,8,9 Due to its key role in modulation of glycogen metabolism, pharmacological inhibition of GP has been regarded as an effective therapeutic approach to treating type 2 diabetes. 10,11 Besides the liver tissue GP isoenzymes are also located in muscle and brain tissue with increased overall homology and high levels of identity at the catalytic site.…”

Novel design principle validated: Glucopyranosylidene-spiro-oxathiazole as new nanomolar inhibitor of glycogen phosphorylase, potential antidiabetic agent

“…Evidence are accumulating that in the non-insulin dependent (type 2) form of diabetes mellitus, 2 comprising more than 90% of all diagnosed cases, 3,4 elevated hepatic glucose output is the most important cause of hyperglycemia. [5][6][7][8] Thus, GP is a validated target for the treatment of type 2 diabetes and its inhibition appears of great interest in both academia and industry. [9][10][11] GP has six known binding sites for which several inhibitors have been identified.…”