Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

doi:10.1073/pnas.0600655103

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Laboratories of *Molecular and Cellular Medicine and
^§Molecular Signaling in Diabetes and Departments of
^†Cellular and Physiological Sciences and
^¶Surgery, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3;
^‡Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Room 3084, 950 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4; and
^‖enGene, Inc., 100-2386 East Mall, Vancouver, BC, Canada V6T 1Z3

Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved June 7, 2006 (received for review January 25, 2006)

Abstract

Glucagon-like peptide 1 (GLP-1) is a hormone that has received significant attention as a therapy for diabetes because of its ability to stimulate insulin biosynthesis and release and to promote growth and survival of insulin-producing β cells. While GLP-1 is produced from the proglucagon precursor by means of prohormone convertase (PC) 1/3 activity in enteroendocrine L cells, the same precursor is differentially processed by PC2 in pancreatic islet α cells to release glucagon, leaving GLP-1 trapped within a larger fragment with no known function. We hypothesized that we could induce GLP-1 production directly within pancreatic islets by means of delivery of PC1/3 and, further, that this intervention would improve the viability and function of islets. Here, we show that adenovirus-mediated expression of PC1/3 in α cells increases islet GLP-1 secretion, resulting in improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. PC1/3 expression in α cells also improved performance after islet transplantation in a mouse model of type 1 diabetes, possibly by enhancing nuclear Pdx1 and insulin content of islet β cells. These results demonstrate a unique strategy for liberating GLP-1 from directly within the target organ and highlight the potential for up-regulating islet GLP-1 production as a means of treating diabetes.

Footnotes

**To whom correspondence should be addressed. E-mail: tim.kieffer{at}ubc.ca
Author contributions: R.D.W., C.B.V., J.D.J., A.T.C., and T.J.K. designed research; R.D.W., I.L.Y.Y., and T.D.W. performed research; R.D.W. analyzed data; and R.D.W. and T.J.K. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

GLP-1,

glucagon-like peptide 1;

PC,

prohormone convertase;

T1D,

type 1 diabetes;

moi,

multiplicity of infection;

STZ,

streptozotocin;

Ad,

adenovirus