Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin

Hideto Kojima, Takaaki Nakamura, Yukihiro Fujita, Akio Kishi, Mineko Fujimiya, Syu Yamada, Motoi Kudo, Yoshihiko Nishio, Hiroshi Maegawa, Masakazu Haneda, Hitoshi Yasuda, Itaru Kojima, Masaharu Seno, Norman C.W. Wong, Ryuichi Kikkawa, Atsunori Kashiwagi

Research output: Contribution to journalArticlepeer-review

134 Citations (Scopus)

Abstract

Immature rat intestinal stem cells (IEC-6) given the ability to express the transcription factor, pancreatic duodenal homeobox 1 (Pdx-1), yielded YK cells. Although these cells produced multiple enteroendocrine hormones, they did not produce insulin. Exposure of YK cells to 2 nmol/1 beta-cellulin yielded BYK cells that showed the presence of insulin expression in cytoplasm and that secreted insulin into culture media. By examining the mechanism of differentiation in BYK cells, we found that another transcription factor, islet factor 1 (Isl-1) was newly expressed with the disappearance of Pax-6 expression in those cells after exposure to betacellulin. These results indicated that combined expression of Pdx-1 and Isl-1 in IEC-6 cells was required for the production of insulin. In fact, overexpression of both Pdx-1 and Isl-1 in IEC-6 cells (Isl-YK-12, -14, and -15 cells) gave them the ability to express insulin without exposure to betacellulin. Furthermore, implantation of the Isl-YK-14 cells into diabetic rats reduced the animals' plasma glucose levels; glucose levels dropped from 19.4 to 16.9 mmol/1 1 day after the injection of cells. As expected, the plasma insulin concentrations were 2.7 times higher in the diabetic rats injected with Isl-YK-14 cells compared to in controls. In summary, our results indicated that immature intestinal stem cells can differentiate into insulin-producing cells given the ability to express the transcription factors Pdx-1 and Isl-1.

Original languageEnglish
Pages (from-to)1398-1408
Number of pages11
JournalDiabetes
Volume51
Issue number5
DOIs
Publication statusPublished - Jan 1 2002

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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