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Tid: Onsdag d. 2. juni 2004 Kl.: 20.00 Sted: Auditorium 1 August Krogh Instituttet Universitetsparken 13 2100 København Ø 1896-2004 Incretin Action as the Basis for the Treatment of Type 2 Diabetes Jens Juul Holst Department of Medical Physiology, University of Copenhagen The incretin hormones are released from gut endocrine cells and potentiate glucose-induced insulin secretion and include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The current interest in the incretin hormones is due to the fact that the incretin effects is severely reduced or absent in patients with type 2 diabetes. In such patients, the secretion of GIP is normal, but its effect on insulin secretion is almost completely lost. GLP-1 secretion, on the other hand may be impaired but its insulinotropic actions are preserved effects and it may restore insulin secretion to near normal levels. Glucagon-like peptide-1 is a product of the glucagon gene and its actions include: 1) potentiation of glucose-induced insulin secretion; 2) stimulation of the expression of ß-cell genes essential for insulin secretion, including the insulin gene; 3) stimulation of ß-cell proliferation and neogenesis (by enhancing endocrine differentiation of duct cells) and inhibition of ß-cell apoptosis; 4) inhibition of glucagon secretion; 5) inhibition of gastrointestinal secretion and motility, notably gastric emptying; and 6) inhibition of appetite and food intake. These actions make GLP-1 particularly attractive as a therapeutic agent for the treatment of type 2 diabetes. Thus, continuous subcutaneous administration of GLP-1 for 6 weeks resulted in a 5 mmol/l reduction in mean plasma glucose and a reduction in HgbA1c of 1.3 %; a weight loss of 2 Kg; improved insulin sensitivity; improved ß-cell function; and the treatment was associated with no significant side effects. Unfortunately, GLP-1 is rapidly destroyed in the body by the ubiquitous enzyme, dipeptidyl-peptidase IV (DPP-IV). Clinical strategies therefore include: 1) the development of metabolically stable analogues of GLP-1 viz. activators of the GLP-1 receptor ; and 2) inhibition of DPP-IV. Orally active DPP-IV inhibitors have proven successful in experimental diabetes and several companies are now trying to develop clinically suitable inhibitors. So far the clinical experience is limited, but recent clinical studies have provided proof of concept. Metabolically stable analogues/activators include the structurally related lizard peptide, exendin-4 or analogues thereof, as well as GLP-1 derived molecules that bind to albumin and thereby assume the pharmacokinetics of albumin. These molecules are effective in animal experimental models of type 2 diabetes, and have been employed in clinical studies of up to 52 weeks’ duration. On the basis of these studies it can be concluded that a therapy of type 2 diabetes mellitus based on stimulation of GLP-1 receptors is likely to be effective and to become a clinical reality within the not too distant future. Holst JJ and Deacon CF (1998) Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47(11), 1663-1670. Hansen L, Deacon CF, Orskov C and Holst JJ. (1999) Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140(11):5356-5363. Vilsboll T, Krarup T, Madsbad S and Holst JJ. (2002) Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 45(8):1111-1119. Zander M, Madsbad S Madsen JL, and Holst JJ. (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359(9309), 824-830. Vilsboll T and Holst JJ (2004) Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 47, 654-662. Kom og hør mere i Biologisk Selskab Husk! Efter foredraget samles vi til en øl/vandfor at snakke mere med foredragsholderen eller gode venner Mødeleder: Dan Klærke, Tel.: 3528 2511, E-mail: [email protected]