The Rockefeller University

Other

The General Hospital Corporation

Svetlana Mojsov

Yang Wei

Joel F Habener

Douglas I Buckley

Joanne B Mallory

Derivatives of glucagon-like peptide I (GLP-1) and especially GLP-1 (7-37) have been found to have insulinotropic activity. The invention pertains to a composition comprising an acid addition salt of GLP-I (7-37) and to a composition comprising a carboxylate salt of GLP-I (7-37). The invention also pertains to method of treating type II diabetes mellitus by providing derivatives of GLP-I (7-37) to the patient.

Insulinotropic hormone derivatives and uses thereof

The invention relates to an energy homeostasis peptide hormone receptor, and in particular, a second common PACAP/VIP receptor (PACAP/VIP R-2 or R-2B) cDNA expressed in human adipocytes. Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two structurally related peptides with multiple physiological effects. The present receptor recognizes PACAP-38 and VIP with similar affinity and is coupled to the cAMP-mediated signal transduction pathway. Transcripts of the second common PACAP/VIP R-2 receptor are also found in human brain and in a number of peripheral tissues, such as pancreas, muscle, heart, lung, kidney, stomach and at low levels in the liver, while transcripts of PACAP/VIP R-2B are not found in pancreas, stomach or kidney. Comparison of the tissue distribution of PACAP/VIP R-2 to that of the other two types of PACAP receptors (PACAP-Type 1 and the other common PACAP/VIP R-1) by RNase protection shows that each of the three PACAP receptors is expressed in a unique set of human peripheral tissues. However, PACAP/VIP R-2 is receptor with broadest distribution in human tissues. Thus, some of the physiological effects of PACAP-38 and VIP in peripheral tissues, especially in pancreas and skeletal muscle, could be mediated through the energy homeostasis peptide hormone receptor, and particularly the second common PACAP/VIP receptor.

Receptor for peptide hormones involving in energy homeostasis

Receptor for peptide hormones involved in energy homeostasis, and method

The invention provides effective analogs of the active GLP-1 peptides, 7-34, 7-35, 7-36, and 7-37, which have improved characteristics for treatment of diabetes Type II. These analogs have amino acid substitutions at positions 7-10 and/or are truncated at the C-terminus and/or contain various other amino acid substitutions in the basic peptide. The analogs may either have an enhanced capacity to stimulate insulin production as compared to glucagon or may exhibit enhanced stability in plasma as compared to GLP-1 (7-37) or both. Either of these properties will enhance the potency of the analog as a therapeutic. Analogs having D-amino acid substitutions in the 7 and 8 positions and/or N-alkylated or N-acylated amino acids in the 7 position are particularly resistant to degradation in vivo.

GLP-1 analogs useful for diabetes treatment

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New York, NY, United States of America

Svetlana Mojsov