Overexpression of a dominant negative GIP receptor in transgenic mice results in disturbed postnatal pancreatic islet and beta-cell development.
The expression of a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn) under the control of the rat pro-insulin gene promoter induces severe diabetes mellitus in transgenic mice. This study aims to gain further insight into the effect of the expression of a dominant negative GIPR on glucose homeostasis and postnatal development of the endocrine pancreas. The diabetic phenotype of GIPRdn transgenic animals was first observed between 14 and 21 days of age (urine glucose>1000 mg/dl). After onset of diabetes, serum glucose was significantly higher and insulin values were significantly lower in GIPRdn transgenic mice vs. non-transgenic littermate controls. Morphometric studies of pancreatic islets and their endocrine cell types were carried out at 10, 30 and 90 days of age. The total islet and total beta-cell volume of transgenic mice was severely reduced as compared to control mice, irrespective of the age at sampling (p<0.05). The total volume of isolated insulin positive cells that were not contained within established islets was significantly reduced in transgenic mice, indicating disturbed islet neogenesis. These findings demonstrate in vivo evidence that intact signaling of G-protein coupled receptors is involved in postnatal islet and beta-cell development and neogenesis of the pancreatic islets.
Herbach
Nadja
N
Institute of Veterinary Pathology, Veterinaerstrasse 13, 80539 Munich, Germany. herbach@patho.vetmed.uni-muenchen.de
Goeke
Burkhard
B
Schneider
Marlon
M
Hermanns
Walter
W
Wolf
Eckhard
E
Wanke
Ruediger
R
D000818:Animals; D000831:Animals, Newborn; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011384:Proinsulin / Q000235:genetics; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000097:blood; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001786:Blood Glucose; D018076:DNA, Complementary; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D011964:Receptors, Gastrointestinal Hormone; D052216:Glucagon-Like Peptide 1; D004247:DNA; D005934:Glucagon; D011384:Proinsulin; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose