Authors: McCormack, J.G.; Westergaard, N.; Kristiansen, M.; Brand, C.L.; Lau, J.

Source: Current Pharmaceutical Design, Volume 7, Number 14, 1 September 2001 , pp. 1451-1474(24)

Publisher: Bentham Science Publishers

Abstract:

The inappropriate overproduction of glucose by the liver is one of the key contributors to the hyperglycaemia of the diabetic state, and thus is a logical site of intervention for novel anti-diabetic approaches. Metformin is the only currently marketed anti-hyperglycaemic drug whose action is attributed largely to its having inhibitory effects on hepatic glucose production, but its molecular site and mechanism(s) of action remain unknown, whereas the liver acting PPARalpha agonists have their effects primarily on lipid metabolism. This review therefore rather focuses on candidate molecular targets within the liver for anti-hyperglycaemic therapy, and describes potential rate-controlling receptors and enzymes within the glucose producing pathways (glycogenolysis and gluconeogenesis). Most focus is directed towards inhibitors of the enzymes glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase, and towards glucagon receptor antagonists, as these appear to be the most advanced in preclinical and clinical development, although progress with other potential targets is also described. Evidence of the anti-diabetic potential of such agents from animal studies is presented, and the relative merits of each approach are reviewed and compared. It is likely that such agents will become important additions to the therapeutic approaches to combat diabetes.

Keywords: anti-diabetic therapy; anti-hyperglycaemic therapy; metformin; hgp; glucose phosphatase g pase; t-translocase inhibitors; fructose bisphatese; glycogen phosphorylase inhibitors; gp inhibitors; glucagon receptor antagonists; hyperglycaemia

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612013397393

Publication date: 2001-09-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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