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A Switch from PC2 to PC1/3 Expression in Transplanted -cells is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice

¹ Laboratory of Molecular and Cellular Medicine, Departments of Cellular & Physiological Sciences and
⁴Surgery, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3
² Department of Medicine, University of Chicago, 5841 S. Maryland Ave, Chicago, Illinois 60637, AMB N216
³ Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada, 600 University Avenue, Toronto, Ontario, M5G 1X5

Correspondence: tim.kieffer{at}ubc.ca

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-1 (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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