Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired
| Autor: | Mamdouh H. Kedees, Gladys Teitelman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
Selective Estrogen Receptor Modulators endocrine system endocrine system diseases medicine.medical_treatment Transgene Dipeptidyl Peptidase 4 Green Fluorescent Proteins Estrogen receptor Biology Biochemistry Glucagon-Like Peptide-1 Receptor Mice Genes Reporter Insulin-Secreting Cells Glucose Intolerance medicine Receptors Glucagon Animals Hypoglycemic Agents Insulin Protease Inhibitors Promoter Regions Genetic Molecular Biology Cell Proliferation Glucose tolerance test medicine.diagnostic_test Integrases Cell growth Venoms Molecular Bases of Disease Cell Biology Molecular biology Recombinant Proteins Tamoxifen Phenotype Receptors Estrogen Apoptosis Exenatide Beta cell Peptides |
| Popis: | We used cre-lox technology to test whether the inducible expression of Cre minimize the deleterious effect of the enzyme on beta cell function. We studied mice in which Cre is linked to a modified estrogen receptor (ER), and its expression is controlled by the rat insulin promoter (RIP). Following the injection of tamoxifen (TM), CreER- migrates to the nucleus and promotes the appearance of a reporter protein, enhanced yellow fluorescent protein (EYFP), in cells. Immunocytochemical analysis indicated that 46.6 ± 2.1% insulin cells of adult RIPCreER- EYFP expressed EYFP. RIPCreER-EYFP (+TM) mice were normoglycemic throughout the study, and their glucose tolerance test results were similar to control CD-1 mice. However, an extended exposure to reagents that stimulate insulin synthesis was detrimental to the survival of IN+EYFP+cells. The administration of an inhibitor of the enzyme dipeptidyl-peptidase (DPP4i), which prevents the cleavage of glucagon-like peptide (GLP-1), to adult RIPCreER-EYFP mice lead to a decrease in the percentage of IN+EYFP+ to 17.5 ± 1.73 and a significant increase in apoptotic cells in islets. Similarly, a 2-week administration of the GLP-1 analog exendin 4 (ex-4) induced an almost complete ablation of IN+ expressing a different reporter protein and a significant decrease in the beta cell mass and rate of beta cell proliferation. Since normal beta cells do not die when induced to increase insulin synthesis, our observations indicate that insulin cells expressing an inducible RIPCre transgene are functionally deficient. Studies employing these mice should carefully consider the pitfalls of the Cre-Lox technique. |
| Databáze: | OpenAIRE |
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