A Switch From Prohormone Convertase (PC)-2 to PC1/3 Expression in Transplanted α-Cells Is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice
| Autor: | Timothy J. Kieffer, Scott D. Covey, Rhonda D. Wideman, Gene C. Webb, Daniel J. Drucker |
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| Rok vydání: | 2007 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Cell Survival Endocrinology Diabetes and Metabolism Prohormone convertase Proprotein convertase 2 Proprotein convertase 1 Biology Proglucagon Glucagon Glucagon-Like Peptide-1 Receptor Diabetes Mellitus Experimental Impaired glucose tolerance Islets of Langerhans Mice Internal medicine Receptors Glucagon Internal Medicine medicine Animals Glucose homeostasis Mice Knockout Glucose tolerance test medicine.diagnostic_test Glucose Tolerance Test medicine.disease Glucose Proprotein Convertase 2 Endocrinology Proprotein Convertase 1 Glucagon-Secreting Cells |
| Zdroj: | Diabetes. 56:2744-2752 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE—Glucagon, which raises blood glucose levels by stimulating hepatic glucose production, is produced in α-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 α-cells might convert the α-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 αTC-1 cells with PC1/3-expressing αTCΔPC2 cells in normal mice and low-dose streptozotocin (STZ)-treated mice. RESULTS—Transplantation of PC2-expressing α-cells increased plasma glucagon levels and caused mild fasting hyperglycemia, impaired glucose tolerance, and α-cell hypoplasia. In contrast, PC1/3-expressing α-cells increased plasma GLP-1/GLP-2 levels, improved glucose tolerance, and promoted β-cell proliferation. In GLP-1R−/− mice, the ability of PC1/3-expressing α-cells to improve glucose tolerance was attenuated. Transplantation of PC1/3-expressing α-cells prevented STZ-induced hyperglycemia by preserving β-cell area and islet morphology, possibly via stimulating β-cell replication. However, PC2-expressing α-cells neither prevented STZ-induced hyperglycemia nor increased β-cell proliferation. Transplantation of αTCΔPC2, but not αTC-1 cells, also increased intestinal epithelial proliferation. CONCLUSIONS—Expression of PC1/3 rather than PC2 in α-cells induces GLP-1 and GLP-2 production and converts the α-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 α-cell may be therapeutically useful in the context of diabetes. |
| Databáze: | OpenAIRE |
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