RGD Reference Report - Insulin receptor-overexpressing beta-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation. - Rat Genome Database

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Insulin receptor-overexpressing beta-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.

Authors: Kim, MH  Hong, SH  Lee, MK 
Citation: Kim MH, etal., PLoS One. 2013 Jul 9;8(7):e67802. doi: 10.1371/journal.pone.0067802. Print 2013.
RGD ID: 10403045
Pubmed: PMID:23874448   (View Abstract at PubMed)
PMCID: PMC3706479   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0067802   (Journal Full-text)

To investigate the therapeutic efficacy and mechanism of beta-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved beta-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of beta-catenin/PPARgamma complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of beta-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by beta-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing beta-cells.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Diabetes Mellitus treatmentIMP 10403045 RGD 
Experimental Diabetes Mellitus treatmentISOINSR (Homo sapiens)10403045; 10403045 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Insr  (insulin receptor)

Genes (Mus musculus)
Insr  (insulin receptor)

Genes (Homo sapiens)
INSR  (insulin receptor)


Additional Information