Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

doi:10.1073/pnas.0936260100

Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

^*Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; ^†Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; and ^‡Department of Regenerative Medicine, Faculty of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan

Edited by Roger H. Unger, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 5, 2003 (received for review October 15, 2002)

Abstract

Glucagon-like peptide (GLP) 1 is produced through posttranslational processing of proglucagon and acts as a regulator of various homeostatic events. Among its analogs, however, the function of GLP-1-(1–37), synthesized in small amounts in the pancreas, has been unclear. Here, we find that GLP-1-(1–37) induces insulin production in developing and, to a lesser extent, adult intestinal epithelial cells in vitro and in vivo, a process mediated by up-regulation of the Notch-related gene ngn3 and its downstream targets, which are involved in pancreatic endocrine differentiation. These cells became responsive to glucose challenge in vitro and reverse insulin-dependent diabetes after implantation into diabetic mice. Our findings suggest that efficient induction of insulin production in intestinal epithelial cells by GLP-1-(1–37) could represent a new therapeutic approach to diabetes mellitus.

Footnotes

↵ § To whom correspondence should be addressed at: Department of Regenerative Medicine, Faculty of Medicine, Yokohama City University, 3–9 Fuku-ura, Kanazawa-ku, Yokohama City, Kanagawa 236-0004, Japan. E-mail: rtanigu{at}med.yokohama-cu.ac.jp.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

En,

embryonic day n;

ngn,

neurogenin;

GLP,

glucagon-like peptide;

VEGF,

vascular endothelial growth factor;

rt,

room temperature;

STZ,

streptozotocin;

TP,

transplant;

GLP-1R,

GLP 1 receptor;

HNF,

hepatocyte nuclear factor