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- Title
Improved glucose tolerance and acinar dysmorphogenesis by targeted expression of transcription factor PDX-1 to the exocrine pancreas.
- Authors
Heller, R. Scott; Heller, R S; Stoffers, D A; Bock, T; Svenstrup, K; Jensen, J; Horn, T; Miller, C P; Habener, J F; Madsen, O D; Serup, P
- Abstract
The homeodomain protein PDX-1 is critical for pancreas development and is a key regulator of insulin gene expression. PDX-1 nullizygosity and haploinsufficiency in mice and humans results in pancreatic agenesis and diabetes, respectively. At embryonic day (e) 10.5, PDX-1 is expressed in all pluripotential gut-derived epithelial cells destined to differentiate into the exocrine and endocrine pancreas. At e15, PDX-1 expression is downregulated in exocrine cells, but remains high in endocrine cells. The aim of this study was to determine whether targeted overexpression of PDX-1 to the exocrine compartment of the developing pancreas at e15 would allow for respecification of the exocrine cells. Transgenic (TG) mice were generated in which PDX-1 was expressed in the exocrine pancreas using the exocrine-specific elastase-1 promoter. These mice exhibited a marked dysmorphogenesis of the exocrine pancreas, manifested by increased rates of replication and apoptosis in acinar cells and a progressive fatty infiltration of the exocrine pancreas with age. Interestingly, the TG mice exhibited improved glucose tolerance, but absolute beta-cell mass was not increased. These findings indicate that downregulation of PDX-1 is required for the proper maintenance of the exocrine cell phenotype and that upregulation of PDX-1 in acinar cells affects beta-cell function. The mechanisms underlying these observations remain to be elucidated.
- Subjects
PANCREATIC physiology; PANCREATIC acinar cells; ADIPOSE tissues; ANIMAL experimentation; APOPTOSIS; BIOCHEMISTRY; BLOOD sugar; COMPARATIVE studies; ELECTRON microscopy; GENES; GLUCOSE tolerance tests; IMMUNOHISTOCHEMISTRY; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MICE; PANCREAS; POLYMERASE chain reaction; PROTEINS; PROTEOLYTIC enzymes; RATS; RESEARCH; EVALUATION research; REVERSE transcriptase polymerase chain reaction
- Publication
Diabetes, 2001, Vol 50, Issue 7, p1553
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.50.7.1553