Abstract
To investigate the therapeutic efficacy and mechanism of β-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 β-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 β-catenin/PPARγ 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 β-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 β-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 β-cells.
Highlights
A cure for type 1 diabetes and some cases of type 2 diabetes would require the means to replace the functions of deficient insulin-secreting b-cells to regulate abnormal levels of blood glucose
INS-IR cells displayed a higher expression of b-cell marker genes including insulin, GK, and glucose transporter 2 (GLUT2) and the insulin signaling pathway intermediators such as insulin receptor substrate (IRS)-1, IRS-2 and AKT1, than the INS-1 cells (P,0.05, Figure 1A)
Our study demonstrated that IR-overexpressing b-cells have higher therapeutic potential and function than pure b-cells without gene manipulation for diabetes mellitus (DM) and activated Wnt signaling pathway, e.g., the increase in cyclin D1 and GK or the stimulation of b-catenin nuclear translocation
Summary
A cure for type 1 diabetes and some cases of type 2 diabetes would require the means to replace the functions of deficient insulin-secreting b-cells to regulate abnormal levels of blood glucose. Most studies have focused on islet or b-cell transplantation for the treatment of diabetes. Variants of transcription factor 7-like 2 (TCF7L2), a component of Wnt/b-catenin signaling, have been shown to be involved in b-cell dysfunction and the pathogenesis of type 2 diabetes [3]. A link between glucose sensing, cell proliferation and Wnt/b-catenin signaling has been reported in macrophages, b-cells, and colonic cells [4,5,6]. A dominant–negative form of TCF7L2 causes cells to arrest in the G1-phase of the cell cycle. These results strongly suggest that Wnt signaling could regulate b-cell functionality and proliferation
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