Combined Treatment Of Glucagon-like Peptide-1 Analogue Exendin-4 And BM-MSC Restored Islet Function In STZ-induced Diabetic Rat

Diabetes has become a growing public health threat to human, the prevalence of which is estimated to be 366 million worldwide and is predicted to rise to 522 million by 2030. Despite the fact that the primary causes for type 1 and type 2 diabetes differ, all diabetics will benefit from treatments that replenish their beta cell mass. Though the disease can be treated with antidiabetic drugs or subcutaneous insulin injection, these treatments do not provide the same degree of glycemic control as functional pancreatic beta cells and do not prevent the debilitating consequences of the disease. Treatments that replenish beta cell mass in diabetic patients could allow for the long-term restoration of normal glycemic control and thus represent a potentially curative therapy.Mesenchymal stem cells (MSCs) appear as an ideal tool for treatment of different disease and regeneration of injured tissues since they can differentiate into replacement cells in damaged tissues, modulate their local environment, activate endogenous progenitor cells, and secrete various factors. The antidiabetic effect of MSCs has been demonstrated in different animal models of diabetes. However, the relative contribution of MSC regenerative mechanisms to this therapeutic effect is still poorly understood.Considering their immunomodulatory potential and secretion of antinflammatory cytokine and antiapototic factors, MSCs might contribute to islet regeneration due to modify the organ microenvironment.Recently, convincing experiments have established that under certain conditions of near-total beta-cell ablation in mouse model alpha cells can directly transdifferentiate into beta cells. The studies show a stepwise transition of α-cells to bihormonal cells (cells co-expressing glucagon and insulin) to β-cells.Our previous study has shown that intravenously administered MSCs in STZ-induced diabetic rats can ameliorate hyperglycemia and recover pancreatic islets probably by promoting the alpha-beta cellular conversion.Nevertheless, the newly formed beta cells derived from alpha cells appear to be not fully functional, and random blood glucose cannot be completely normalized. Methods to promote this conversion from alpha to beta cells and the maturation of newly formed beta cells, demand further investigation.Many putative beta-cell growth factors have been identified, one of the most promising being glucagon-like peptide-1 (GLP-1), a peptide secreted from intestinal L-cells. GLP-1 and exendin-4, a long-acting GLP-1 receptor agonist, increase the beta-cell mass in rodents with surgically or chemically induced diabetes through stimulation of beta-cell proliferation and islet neogenesis and inhibition of beta-cell apoptosis. Moreover, GLP-1 plays an important role in the differentiation of endocrine cells in the developing pancreas and appears to do so by inducing the expression of pancreatic and duodenal homeobox gene (also known as PDX-1), which is required for pancreas development and the expression of beta-cell-specific genes. In addition, it has been reported previously that GLP-1 and exendin 4 is capable of inducing the differentiation of ductal progenitor cells and embryonic stem cells into islet endocrine cells. Thus, GLP-1 may be an important morphogen both for the embryonic development of the pancreas and for the neogenesis of beta-cells in the islets of the adult pancreas.It raises the possibility that GLP-1 can promote the maturation of immature beta cells through the known actions of GLP-1 to promote the growth and survival of beta cells.In the present study, we demonstrated that a combination therapy with MSCs and exendin-4 can promote both the transdifferantation from alpha-cells to beta-cells and the maturation of newly formed beta cells transdifferentiated from alpha cells, then finally fully restore islet function and achieve long-term restoration of normal glycemic control in STZ-induced diabetic mouse model.In summary, this study provides a potentially achievable therapeutic strategy of producing beta-cells for diabetes therapies.