Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes

Apoptosis is the major cause of death of insulin-producing beta-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic beta-cells. Interestingly, halplodeficiency of Klotho (KL+/-) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic beta-cells. Conversely, in vivo beta-cell-specific expression of mouse Klotho gene (mKL) attenuated beta-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 beta-cells. mKL abolished STZ- and TNF alpha-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and beta-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin beta 1. Therefore, these cell-based studies indicated that Klotho protected beta-cells by inhibiting beta-cell apoptosis through activation of the integrin beta 1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo beta-cell-specific expression of mKL improved glucose tolerance, attenuated beta-cell apoptosis, enhanced insulin storage in beta-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected beta-cells in T1DM via attenuating apoptosis.