A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal - A potential therapy for type 2 diabetes

被引:111
作者
Tsutsumi, M
Claus, TH
Liang, Y
Li, YX
Yang, L
Zhu, J
Dela Cruz, F
Peng, XB
Chen, HX
Yung, SL
Hamren, S
Livingston, JN
Pan, CQ
机构
[1] Bayer Corp, Div Pharmaceut, Dept Metab Disorders Res, West Haven, CT USA
[2] Bayer Corp, Biotechnol, Dept Mol Technol, Berkeley, CA USA
关键词
D O I
10.2337/diabetes.51.5.1453
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (K-d) 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.
引用
收藏
页码:1453 / 1460
页数:8
相关论文
共 49 条
[1]   Comparative effects of PACAP and VIP on pancreatic endocrine secretions and vascular resistance in rat [J].
Bertrand, G ;
Puech, R ;
Maisonnasse, Y ;
Bockaert, J ;
LoubatieresMariani, MM .
BRITISH JOURNAL OF PHARMACOLOGY, 1996, 117 (04) :764-770
[2]   Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic β-cells and effects of PACAP-38 on components of the insulin secretory system [J].
Borboni, P ;
Porzio, O ;
Pierucci, D ;
Cicconi, S ;
Magnaterra, R ;
Federici, M ;
Sesti, G ;
Lauro, D ;
D'Agata, V ;
Cavallaro, S ;
Marlier, LNJL .
ENDOCRINOLOGY, 1999, 140 (12) :5530-5537
[3]   Glucagon-like peptide 1 improves the ability of the β-cell to sense and respond to glucose in subjects with impaired glucose tolerance [J].
Byrne, MM ;
Gliem, K ;
Wank, U ;
Arnold, R ;
Katschinski, M ;
Polonsky, KS ;
Göke, B .
DIABETES, 1998, 47 (08) :1259-1265
[4]  
Champion HC, 1996, ANN NY ACAD SCI, V805, P429
[5]   Minireview: The glucagon-like peptides [J].
Drucker, DJ .
ENDOCRINOLOGY, 2001, 142 (02) :521-527
[6]   GLUCAGONLIKE PEPTIDE-I STIMULATES INSULIN GENE-EXPRESSION AND INCREASES CYCLIC-AMP LEVELS IN A RAT ISLET CELL-LINE [J].
DRUCKER, DJ ;
PHILIPPE, J ;
MOJSOV, S ;
CHICK, WL ;
HABENER, JF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (10) :3434-3438
[7]   INSULINOTROPIC HORMONE GLUCAGON-LIKE PEPTIDE-I(7-37) STIMULATION OF PROINSULIN GENE-EXPRESSION AND PROINSULIN BIOSYNTHESIS IN INSULINOMA BETA-TC-1 CELLS [J].
FEHMANN, HC ;
HABENER, JF .
ENDOCRINOLOGY, 1992, 130 (01) :159-166
[8]   PACAP and PACAP receptors in insulin producing tissues: localization and effects [J].
Filipsson, K ;
Sundler, F ;
Hannibal, J ;
Ahren, B .
REGULATORY PEPTIDES, 1998, 74 (2-3) :167-175
[9]   PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice [J].
Filipsson, K ;
Pacini, G ;
Scheurink, AJW ;
Ahrén, B .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1998, 274 (05) :E834-E842
[10]   Pituitary adenylate cyclase-activating polypeptide stimulates insulin and glucagon secretion in humans [J].
Filipsson, K ;
Tornoe, K ;
Holst, J ;
Ahren, B .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1997, 82 (09) :3093-3098