A Potent and Highly Selective VPAC2 Agonist Enhances Glucose-Induced Insulin Release and Glucose Disposal
A Potential Therapy for Type 2 Diabetes
- Manami Tsutsumi1,
- Thomas H. Claus1,
- Yin Liang1,
- Yaxin Li1,
- Ling Yang1,
- Jian Zhu1,
- Fernando Dela Cruz1,
- Xianbu Peng1,
- Hongxing Chen1,
- Stephanie L. Yung2,
- Sarah Hamren2,
- James N. Livingston1 and
- Clark Q. Pan2
- 1Department of Metabolic Disorders Research, Pharmaceutical Division, Bayer Corporation, West Haven, Connecticut
- 2Department of Molecular Technologies, Biotechnology, Bayer Corporation, Berkeley, California
Abstract
Pituitary adenylate cyclase—activating peptide (PACAP) and vasoactive intestinal peptide (VIP) activate two shared receptors, VPAC1 and VPAC2. Activation of VPAC1 has been implicated in elevating glucose output, whereas activation of VPAC2 may be involved in insulin secretion. A hypothesis that a VPAC2-selective agonist would enhance glucose disposal by stimulating insulin secretion without causing increased hepatic glucose production was tested using a novel selective agonist of VPAC2. This agonist, BAY 55-9837, was generated through site-directed mutagenesis based on sequence alignments of PACAP, VIP, and related analogs. The peptide bound to VPAC2 with a dissociation constant (Kd) of 0.65 nmol/l and displayed >100-fold selectivity over VPAC1. BAY 55-9837 stimulated glucose-dependent insulin secretion in isolated rat and human pancreatic islets, increased insulin synthesis in purified rat islets, and caused a dose-dependent increase in plasma insulin levels in fasted rats, with a half-maximal stimulatory concentration of 3 pmol/kg. Continuous intravenous or subcutaneous infusion of the peptide reduced the glucose area under the curve following an intraperitoneal glucose tolerance test. The peptide had effects on intestinal water retention and mean arterial blood pressure in rats, but only at much higher doses. BAY 55-9837 may be a useful therapy for the treatment of type 2 diabetes.
Footnotes
-
Address correspondence and reprint requests to Clark Q. Pan, 800 Dwight Way, PO Box 1986, Berkeley, CA 94701-1986. E-mail: clark.pan.b{at}bayer.com.
The authors (except for Y. Liang) are employed by Bayer Corporation.
Received for publication 30 July 2001 and accepted in revised form 5 February 2002.
aa, amino acid; AUC, area under the curve; Bmax, maximum binding capacity; EC50, half-maximal stimulatory concentration; GLP, glucagon-like peptide; IC50, half-maximal inhibitory concentration; IPGTT, intraperitoneal glucose tolerance test; Kd, dissociation constant; MAP, mean arterial pressure; PACAP, pituitary adenylate cyclase–activating polypeptide; SPA, scintillation proximity assay; VIP, vasoactive intestinal peptide.
- DIABETES
