PDX-1 expression is associated with islet proliferation in vitro and in vivo.
BACKGROUND
Transcription factor pancreatic duodenal homeobox-1 (PDX-1) is critical for beta-cell differentiation and insulin gene expression. In this study, we investigated the role of PDX-1 in ductal-to-islet cell transdifferentiation, islet cell apoptosis, and proliferation in addition to other regulators associated with these processes in two developing beta-cell models.


METHODS
CAPAN-1 cells were cultured with the GLP-1 analogue Exendin-4 (Ex-4) to induce transdifferentiation to an insulin-producing phenotype. Expression patterns of PDX-1, somatostatin receptors (SSTR) 1, 2, and 5, p27, and p38 were analyzed. To model pancreatic regeneration in vivo, subtotal pancreatectomies were performed in rats and remnant pancreata were compared to sham laparotomy controls to determine islet size, morphology, apoptosis, and PDX-1 expression.


RESULTS
In Ex-4-treated cells, PDX-1 expression increased 67% above basal levels within 24 h and was followed by a 10-fold decline in expression by the end of the study. Expression of cell-cycle inhibitor p27 was down-regulated by 81% at 24 h, while levels of the pro-apoptotic modulator p38 significantly increased 4-fold. When compared to controls, SSTR1 expression declined, while SSTR2 and SSTR5 expression were significantly up-regulated in treated cells. Immunofluorescence of pancreatic remnants following subtotal pancreatectomy revealed increased PDX-1 staining at 24 h followed by a significant decline at 72 h post-pancreatectomy.


CONCLUSIONS
GLP-1 analogue Ex-4 resulted in up-regulation of PDX-1 in CAPAN-1 cells and PDX-1 was up-regulated in proliferating islets following subtotal pancreatectomy in rats. The increase was seen in the first 24 h. These findings suggest a possible relationship between PDX-1 and the state of islet proliferation, islet-to-ductal transdifferentiation, apoptosis, and the expression of SSTRs.
Feanny
Mark A
MA
The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Fagan
Shawn P
SP
Ballian
Nikiforos
N
Liu
Shi-He
SH
Li
Zhijun
Z
Wang
Xiaoping
X
Fisher
William
W
Brunicardi
F Charles
FC
Belaguli
Narasimhaswamy S
NS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D000077270:Exenatide; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D010180:Pancreatectomy; D010455:Peptides / Q000494:pharmacology; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology
C493962:Cdkn1b protein, rat; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011498:Protein Precursors; D017481:Receptors, Somatostatin; C115977:Sstr2 protein, rat; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; C101130:somatostatin receptor type 1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C013737:preproinsulin; C094573:somatostatin receptor 5; D011384:Proinsulin; D000077270:Exenatide; C093733:somatostatin receptor 2