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A Switch From Prohormone Convertase (PC)-2 to PC1/3 Expression in Transplanted -Cells Is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice

¹ Department of Cellular and Physiological Sciences, Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
² Department of Medicine, University of Chicago, Chicago, Illinois
³ Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
⁴ Department of Surgery, Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada

Address correspondence and reprint requests to Dr. Timothy J. Kieffer, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3. E-mail: tim.kieffer{at}ubc.ca

Abbreviations: AUC, area under the curve; GLP, glucagon-like peptide; IPGTT, intraperitoneal glucose tolerance test; PC, prohormone convertase; PCNA, proliferating cell nuclear antigen; PGDP, proglucagon-derived peptide; STZ, streptozotocin

OBJECTIVE—Glucagon, which raises blood glucose levels by stimulating hepatic glucose production, is produced in -cells via cleavage of proglucagon by prohormone convertase (PC)-2. In the enteroendocrine L-cell, proglucagon is differentially processed by the alternate enzyme PC1/3 to yield glucagon-like peptide (GLP)-1, GLP-2, and oxyntomodulin, which have blood glucose–lowering effects. We hypothesized that alteration of PC expression in -cells might convert the -cell from a hyperglycemia-promoting cell to one that would improve glucose homeostasis.

RESEARCH DESIGN AND METHODS—We compared the effect of transplanting encapsulated PC2-expressing TC-1 cells with PC1/3-expressing TCPC2 cells in normal mice and low-dose streptozotocin (STZ)-treated mice.

RESULTS—Transplantation of PC2-expressing -cells increased plasma glucagon levels and caused mild fasting hyperglycemia, impaired glucose tolerance, and -cell hypoplasia. In contrast, PC1/3-expressing -cells increased plasma GLP-1/GLP-2 levels, improved glucose tolerance, and promoted ß-cell proliferation. In GLP-1R^–/– mice, the ability of PC1/3-expressing -cells to improve glucose tolerance was attenuated. Transplantation of PC1/3-expressing -cells prevented STZ-induced hyperglycemia by preserving ß-cell area and islet morphology, possibly via stimulating ß-cell replication. However, PC2-expressing -cells neither prevented STZ-induced hyperglycemia nor increased ß-cell proliferation. Transplantation of TCPC2, but not TC-1 cells, also increased intestinal epithelial proliferation.

CONCLUSIONS—Expression of PC1/3 rather than PC2 in -cells induces GLP-1 and GLP-2 production and converts the -cell from a hyperglycemia-promoting cell to one that lowers blood glucose levels and promotes islet survival. This suggests that alteration of proglucagon processing in the -cell may be therapeutically useful in the context of diabetes.

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