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Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia

Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and... Insulin gene expression is restricted to islet β cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors 1,2 . The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function 3 . PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes 4,5,6,7 . Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by ‘loss-of-function’ studies 8,9,10,11 . We used a ‘gain-of-function’ approach to test whether PDX-1 could endow a non-islet tissue with pancreatic β-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a β-cell phenotype, may provide a valuable approach for generating ‘self’ surrogate β cells, suitable for replacing impaired islet-cell function in diabetics. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Medicine Springer Journals

Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia

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References (31)

Publisher
Springer Journals
Copyright
Copyright © 2000 by Nature America Inc.
Subject
Biomedicine; Biomedicine, general; Cancer Research; Metabolic Diseases; Infectious Diseases; Molecular Medicine; Neurosciences
ISSN
1078-8956
eISSN
1546-170X
DOI
10.1038/75050
Publisher site
See Article on Publisher Site

Abstract

Insulin gene expression is restricted to islet β cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors 1,2 . The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function 3 . PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes 4,5,6,7 . Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by ‘loss-of-function’ studies 8,9,10,11 . We used a ‘gain-of-function’ approach to test whether PDX-1 could endow a non-islet tissue with pancreatic β-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a β-cell phenotype, may provide a valuable approach for generating ‘self’ surrogate β cells, suitable for replacing impaired islet-cell function in diabetics.

Journal

Nature MedicineSpringer Journals

Published: May 1, 2000

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