Characterization of intestinal and pancreatic dysfunction in VPAC1-Null mutant mouse

Dorit Fabricius, Bahri Karacay, Damon Shutt, Whitney Leverich, Blanca Schafer, Erika Takle, Daniel Thedens, Geetika Khanna, Sudhanshu Raikwar, Baoli Yang, Mary E. Desmond, Mary Sue O'Dorisio

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Objectives: These studies examined the effect of homozygous deletion of vasoactive intestinal peptide receptor type 1 (VPAC1) on development and function of intestines and pancreas. Methods: Genetically engineered VPAC1-null mutant mice were monitored for growth, development, and glucose homeostasis. Expression of VPAC1 was examined during embryonic development using VPAC1 promoter-driven β-galactosidase transgenic mice. Results: Homozygous deletion of VPAC1 resulted in fetal, neonatal, and postweaning death owing to failure to thrive, intestinal obstruction, and hypoglycemia. Histological findings demonstrated disorganized hyperproliferation of intestinal epithelial cells with mucus deposition and bowel wall thickening. The pancreas demonstrated small dysmorphic islets of Langerhans containing α, β, and δ cells. Expression of a VPAC1 promoter-driven transgene was observed in E12.5 and E14.5 intestinal epithelial and pancreatic endocrine cells. Vasoactive intestinal peptide receptor type 1-null mutant animals had lower baseline blood glucose levels compared to both heterozygous and wild-type littermates. Vasoactive intestinal peptide receptor type 1-deficient mice responded to oral glucose challenge with normal rise in blood glucose followed by rapid hypoglycemia and failure to restore baseline glucose levels. Insulin challenge resulted in profound hypoglycemia and inadequate glucose homeostasis in VPAC1-null mutant animals. Conclusions: These observations support a role for VPAC1 during embryonic and neonatal development of intestines and endocrine pancreas.

Original languageEnglish
Pages (from-to)861-871
Number of pages11
JournalPancreas
Volume40
Issue number6
DOIs
StatePublished - Aug 2011

Keywords

  • VPAC1-null mutant mouse
  • intestine
  • pancreas

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