Abstract
One week of treatment with EGF and gastrin (EGF/G) was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in beta cell mass, which was partially driven by neogenesis and beta cell proliferation as assessed by beta cell lineage tracing and BrdU-labeling experiments, respectively. Acinar cell lineage tracing failed to show an important contribution of acinar cells to the newly formed beta cells. No appearance of transitional cells co-expressing insulin and glucagon, a hallmark for alpha-to-beta cell conversion, was found, suggesting that alpha cells did not significantly contribute to the regeneration. An important fraction of the beta cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced beta cell neogenesis and proliferation, even though beta cell mass remained significantly depleted, suggesting ongoing beta cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced beta cell regeneration in alloxan-diabetic mice is driven by beta cell neogenesis, proliferation and recovery of insulin. The glucose-lowering effect of the treatment might play an important role in the regeneration process.
Highlights
Type 1 and type 2 diabetes result from inadequate beta cell mass, which leads to persistent hyperglycemia
From one day after alloxan injection, mice were treated with the combination of epidermal growth factor (EGF) and gastrin (EGF/G) for one week
EGF/G treatment one day after alloxan administration, reversed hyperglycemia to normal within one day, and this persisted until the end of experiment
Summary
Type 1 and type 2 diabetes result from inadequate beta cell mass, which leads to persistent hyperglycemia. Beta Cell Regeneration after EGF and Gastrin attractive possibility is the restoration of a functional beta cell mass by stimulating endogenous regeneration of beta cells within the pancreas with pharmacological agents To this end, drugs should be developed that stimulate beta cell neogenesis, replication and/or survival. Drugs should be developed that stimulate beta cell neogenesis, replication and/or survival This could offer a much more accessible therapy for both type 1 and type 2 patients, provided that in the former, a way can be found to prevent autoimmune destruction of the regenerated beta cells. The combination of gastrin hormone and epidermal growth factor (EGF) was among the first combination of compounds that was proposed to stimulate beta cell mass increase or regeneration in beta cell-depleted or autoimmune diabetic mice and has been incorporated in clinical trials [8]. We used the beta cell genetic lineage tracing method, first described by Dor et al, which is generally accepted as the only method allowing direct and unequivocal proof of beta cell neogenesis [14, 15]
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