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Finan, B. ; Ma, T.* ; Ottaway, N.* ; Müller, T.D. ; Habegger, K.M.* ; Heppner, K.M.* ; Kirchner, H.* ; Holland, J.* ; Hembree, J.* ; Raver, C.* ; Lockie, S.H.* ; Smiley, D.L.* ; Gelfanov, V.* ; Yang, B.* ; Hofmann, S. ; Bruemmer, D.* ; Drucker, D.J.* ; Pfluger, P.T. ; Perez-Tilve, D.* ; Gidda, J.* ; Vignati, L.* ; Zhang, L.* ; Hauptman, J.B.* ; Lau, M.* ; Brecheisen, M.* ; Uhles, S.* ; Riboulet, W.* ; Hainaut, E.* ; Sebokova, E.* ; Conde-Knape, K.* ; Konkar, A.* ; DiMarchi, R.D.* ; Tschöp, M.H.

Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.

Sci. Transl. Med. 5:209ra151 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dependent Insulinotropic Polypeptide ; Gastric-inhibitory Polypeptide ; High-fat Diet ; Pancreatic Beta-cells ; Glucose-intolerance ; Enteroinsular Axis ; Lipoprotein-lipase ; Glycemic Control ; Peptide Yy3-36 ; Body-weight
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 5, Issue: 209, Pages: , Article Number: 209ra151 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Regeneration Research (IDR)