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Biotech / Medical : AMLN (DIABETES DRUGS) -- Ignore unavailable to you. Want to Upgrade?

To: Jason Chesshir who wrote (1518)	10/26/1998 10:20:00 AM
From: Rudy Saucillo	Read Replies (2) \| Respond to of 2173

<<What are the medical merits of EXENDIN-4?>> Tough question which I don't have the background to answer. A quick Medline shows there is significant interest in Exendin-4 as a potential therapeutic for diabetes. I've listed below 2 abstracts which caught my attention. The first paper is a survey-type paper which cites potential advantages of Exendin-4 and GLP-1 analogs which have a longer half life than GLP-1. Could be a good start to answering your question. The second paper provides some specifics of biological action and concludes with "Our findings provide further support to the proposed use of GLP-1, or exendin-4, as a tool in the treatment of diabetes mellitus." Rudy Diabetes 1998 Feb;47(2):159-69 Glucagon-like peptides. Drucker DJ Department of Medicine, the Toronto Hospital, Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada. d.drucker@utoronto.ca Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides. ---- Arch Biochem Biophys 1997 May 1;341(1):1-7 Exendin-4 agonist and exendin(9-39)amide antagonist of the GLP-1(7-36)amide effects in liver and muscle. Alcantara AI, Morales M, Delgado E, Lopez-Delgado MI, Clemente F, Luque MA, Malaisse WJ, Valverde I, Villanueva-Penacarrillo ML Departamento de Metabolismo, Nutricion y Hormonas, Fundacion Jimenez Diaz, Madrid, Spain. The GLP-1 structurally related peptides exendin-4 and exendin(9-39)amide were found to act, in rat liver and skeletal muscle, as agonist and antagonist, respectively, of the GLP-1(7-36)amide effects on glucose metabolism. Thus, like GLP-1(7-36)amide, exendin-4 increased glycogen synthase a activity and glucose incorporation into glycogen in both tissues and also stimulated exogenous D-glucose utilization and oxidation in muscle. These effects of GLP-1(7-36)amide and exendin-4 were inhibited by exendin(9-39)amide. Our findings provide further support to the proposed use of GLP-1, or exendin-4, as a tool in the treatment of diabetes mellitus. Thus, in addition to the well-known insulinotropic action of the peptides, they act both in liver and in muscle in a manner most suitable for restoration of glucose homeostasis, with emphasis on their positive effects upon glycogen synthesis in the two tissues and on the stimulation of exogenous glucose catabolism in muscle.