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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.
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