A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.
OBJECTIVE
Glucagon, which raises blood glucose levels by stimulating hepatic glucose production, is produced in alpha-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 alpha-cells might convert the alpha-cell from a hyperglycemia-promoting cell to one that would improve glucose homeostasis.


METHODS
We compared the effect of transplanting encapsulated PC2-expressing alpha TC-1 cells with PC1/3-expressing alpha TCDeltaPC2 cells in normal mice and low-dose streptozotocin (STZ)-treated mice.


RESULTS
Transplantation of PC2-expressing alpha-cells increased plasma glucagon levels and caused mild fasting hyperglycemia, impaired glucose tolerance, and alpha-cell hypoplasia. In contrast, PC1/3-expressing alpha-cells increased plasma GLP-1/GLP-2 levels, improved glucose tolerance, and promoted beta-cell proliferation. In GLP-1R(-/-) mice, the ability of PC1/3-expressing alpha-cells to improve glucose tolerance was attenuated. Transplantation of PC1/3-expressing alpha-cells prevented STZ-induced hyperglycemia by preserving beta-cell area and islet morphology, possibly via stimulating beta-cell replication. However, PC2-expressing alpha-cells neither prevented STZ-induced hyperglycemia nor increased beta-cell proliferation. Transplantation of alpha TCDeltaPC2, but not alpha TC-1 cells, also increased intestinal epithelial proliferation.


CONCLUSIONS
Expression of PC1/3 rather than PC2 in alpha-cells induces GLP-1 and GLP-2 production and converts the alpha-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 alpha-cell may be therapeutically useful in the context of diabetes.
Wideman
Rhonda D
RD
Department of Cellular and Physiological Sciences, Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Covey
Scott D
SD
Webb
Gene C
GC
Drucker
Daniel J
DJ
Kieffer
Timothy J
TJ
D000818:Animals; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D000067757:Glucagon-Like Peptide-1 Receptor; D050416:Glucagon-Secreting Cells / Q000201:enzymology* / Q000378:metabolism / Q000637:transplantation*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052336:Proglucagon / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000235:genetics*; D045706:Proprotein Convertase 2 / Q000172:deficiency / Q000235:genetics*; D018027:Receptors, Glucagon / Q000172:deficiency
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D052336:Proglucagon; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D005947:Glucose